The durability of concrete structure members is dependent on several factors that should be analyzed at each stage of the construction process. Omitting any of these factors might lead to the augmentation of harmful interactions and, as an effect, to safety hazards and the degradation of a structure or its parts. The article, based on several years of studies on exploited concrete structures, presents the effects of an incorrect analysis of selected factors resulting in the occurrence of faults significantly influencing the possibility of safe use of the objects. The described cases include, but are not limited to, the consequences of an improper assessment of building conditions after a biogas explosion in a fermentation chamber, the effect of a wood dust explosion, fire temperature and firefighting action on the prestressed girders, the stages of degradation of bearing structures supporting gas tanks exploited in an aggressive environment, and the consequences of omitting the temperature load in relation to the upper surface of a plate covering the fire pond. In each case, methods of restoration of the damaged elements were proposed, and their application to engineering practice was described. The practical aspects of the conducted research and implemented interventions were indicated. At a time when effective analytical theories were not known, guidelines for determining safe sections of building elements were obtained from experimental studies ,2. ConstThe application of the principles recommended by organizations that develop international standards, such as the American Society for Testing and Materials or the European Standardization Organization, to structures operating in emergency stages is limited. Scientific methods should then be used, and the current strength parameters of basic construction materials should be obtained as a result of scientific research of the actual state of the structure .The correctness of conclusions should be ensured by obtaining reliable data from many independent sources, using various techniques and tools. Such sources may be inspections of the facility, archival documentation, or the monitoring of the deformation of structural elements. Information that has been documented experimentally constitutes the basis for calculations and analyses confirming or refuting the formulated assumptions and research results . ObtainiThe dominant factor generating the degradation stage of concrete materials and structures is insufficient durability of the materials and construction elements used, which are inadequate in terms of the operating conditions of the building. The impact of an aggressive atmospheric environment and the technological conditions in industrial plants, as well as the impact of various exceptional loads, applies to materials built during the investment stage, as well as during renovation, repair, reconstruction, or strengthening of facilities ,13.The exploited building and engineering structures are exposed to the influence of exceptional loads that are difficult to predict, e.g., explosion pressure or fire temperature ,15,16. TThe factors generating the threat stage in each of the analyzed cases are errors made at the stage of designing, shaping, and operating structural elements resulting from the so-called ‘human mistakes’. Regardless of the detected structural defects, exceptional loads, failure to comply with assembly tolerance in the case of prefabricated structures, or poor or inadequate quality of building materials, it is, in each of the analyzed cases, possible to diagnose the lack of proper supervision. It is practically impossible to avoid errors, but it is important to diagnose and eliminate them before the occurrence of signaled or unsignaled damage to buildings. The objects that were tested by the author were located in Poland.The durability of building structures is maintained if, in the expected time of operation, the object meets the assumed requirements in terms of serviceability, load-bearing capacity, and stability without reducing its performance. Fixed spherical gas tanks consist of a technological pressure device, which is a tank, and a support structure. The most common threats to safety are degraded reinforced-concrete supporting structures, because the deformation of the supports results in the disruption of the membrane operation of the tank.3 and 600 m3, based on reinforced-concrete supporting structures [A commonly used solution is the storage of propane-butane gas in spherical pressure tanks with a capacity of 195 m3 was shaped as six reinforced-concrete vertical columns, braced with a horizontal reinforced-concrete ring connecting the columns. The foundations under the columns were in the form of a reinforced-concrete foundation slab with a regular hexagonal shape. The supporting pillars were placed around the circumference of a circle (The supporting structure of the tanks with a capacity of 195 ma circle a,b. The 3 were placed on supports shaped as six supporting trestles inclined at an angle of approximately 6o to the vertical axis, resembling an inverted letter ‘Y’ (Spherical tanks with a capacity of 600 mtter ‘Y’ a,c. The After several dozen years of operation, the reinforced-concrete supporting structures were subject to the process of destruction. The degree of damage depended primarily on the initial quality of the elements made, the method of securing the concrete surface, and the aggressiveness of the environment. The methods and quality of the ongoing maintenance, which varied significantly among users, had a significant impact on the scale of the damage. In the tested structures, it was found that the concrete strength corresponded to the C16/20 or even the C12/15 class, which had a significant impact in terms of accelerating the degradation process and reducing durability [2, NOx, or Cl−, this process is significantly accelerated [The expected durability of reinforced-concrete structures used in specialized construction in the atmosphere of an industrial environment is reduced by corrosion processes caused by the action of soft rainwater. The process of reinforcement corrosion in properly constructed and operated reinforced-concrete structures, operating in an environment with lower aggressiveness classes, should be initiated after about 40 years, but in an environment polluted with aggressive substances such as SOelerated .During the operation of the carbonized elements, the corrosion products increased in volume and generated tensile stresses and, consequently, concrete scratches and loosening of the cover fragments. The damage, which facilitated the access of aggressive factors from the environment, intensified the corrosion processes, while the corrosion losses reduced the load-bearing capacity of reinforced-concrete elements .3 at an angle of 6° was the main reason for the weakening of the lower zones of the columns. Incorrectly implemented support zones for the tanks on the column heads did not ensure the correct transfer of the acting loads to the supporting elements.Degraded supporting structures posed a threat to the safety of the tanks. The inclination of the supporting structure of the tank with a capacity of 600 mStrengthening works, conditioning the safe and durable use of endangered objects, were performed after the endangered structures were excluded from operation. Repair work began by securing some of the structures located in the ground. The lower parts of the reinforced-concrete supports were stabilized by correct connections with the foundations. The degraded reinforced-concrete structure was protected against corrosion by adding reinforcing layers of C25/30 class concrete, reinforced with bars with diameters not exceeding 8 mm. The maximum diameter of the reinforcing bars used was determined by the thickness of the reinforcing layer limited by the elements of technological installations.The next stage of works was the repair of the damaged surfaces of columns and beams located above the ground level. The obtaining of the conditions of adhesion, strength, and tightness of fillings was ensured by designing the spraying technology, called shotcreting ,23. The As a result, the existing carbonated concrete substances and exposed reinforcement bars were secured and monolithized . After tThe results of many years of research and the effects of reconstruction work on degraded reinforced-concrete supporting structures allowed the use of similar methods and technologies for repairing damage to the reinforced-concrete fermentation chamber of a sewage treatment plant.The engineering facilities used in biological sewage treatment plants are designed as structures with a lifetime of at least several dozen years. In the technological process of sewage treatment plants using closed tanks, the so-called biogas, which is a natural result of chemical fermentation processes, is produced. It is an effective energy medium, although in inappropriate conditions of use, it can pose a threat to the life of service workers and cause the destruction of engineering structures, which results from their susceptibility to explosions .Exploitation of specialized structures exposed to the danger of explosion in an aggressive environment of municipal sewage implies the necessity to carry out inspections at intervals that are more frequent than required by the provisions of the construction law for a typical industrial facility. Performing detailed tests makes it possible to check whether the basic structural elements of the tanks meet the standard limit conditions in terms of load-bearing capacity and serviceability. A particularly important condition is to ensure the tightness of the chamber in which the liquid medium is collected. A technological problem is the fact that the tank cannot be used during the time necessary to carry out tests and possible repairs.Engineering structures operated in an aggressive technological environment are objects that are particularly exposed to the risk of significant degradation of the quality of construction materials during operation .The durability of the fermentation chambers is reduced by natural destruction processes. Damage caused by a reduction in the strength parameters of the materials used, short-term exposure to exceptional loads, or an unsignaled change in the static pattern of the structure of the building is significant. Natural wear and tear of materials operated for over 30 years in an aggressive environment, uncontrolled and unidentified at the stage of periodic tests, as well as improperly conducted verification of current material parameters, may generate errors in the assessment of the stage of structural damage, e.g., in terms of the impact of exceptional loads. The above-mentioned factors were the most common causes of the analyzed disasters. The state of the threat was usually intensified by the fact that sewage treatment plants are implemented in the form of a battery of several fermentation chambers cooperating with each other.3, caused by an uncontrolled increase in biogas pressure followed by an explosion (Problems related to the correct assessment of damaged facilities of a sewage treatment plant are illustrated by an example of a breakdown of a digester with a capacity of 3150 mxplosion . The pheAs a result of the tests, which were carried out under time pressure from the user, who was eager to restart the technological process as soon as possible, no current parameters of construction materials or internal damage to the reinforced-concrete structure were identified, resulting in, e.g., unsealing of the coatings and changes in the static scheme. After the explosion, the rigid connection of the cylindrical shell with the conical shell turned into a semi-hinge connection. However, the previous structural scheme, i.e., with a rigid connection, was incorrectly adopted for the assessment of the coating condition. As a result, the values of internal forces were underestimated.The results of numerical calculations verifying the post-disaster stage, which took into account the change in the static scheme, made it possible to determine the actual state of stresses and deformations in the concrete structure. The exceeding of both the ultimate and serviceability limit conditions justified the occurrence of cracks in the monolithic wall structure and the tank cover.According to the provisions of the law, the structure was subjected to a water test before the facility was put into operation and after repair works were carried out on the damaged conical cover. Defects in the form of leaks found at that time were the basis for a reassessment of the condition of the tank.After completing supplementary tests on defects and actual material solutions, the state of stress of the structure at the design stage and at the stage of instantaneous explosion pressure load was verified . The infIn the analyzed case, the destruction of the tank’s structural elements was a consequence of an explosion initiated by placing an open flame in the zone of contact with biogas. An additional factor stimulating the explosion was the limitation of the combustion space due to the failures of the safety valve ventilation system.Similar phenomena, defects in safety and control devices as well as human errors, resulted in the explosion of wood dust and the destruction of the reinforced-concrete production hall.The explosion phenomenon, presented in several examples, should be treated as an exceptional load . UncontrTechnological processes in industrial plants, using flammable materials, may constitute a potential explosion hazard. Its consequence, apart from the destruction of devices and equipment, is also damage to buildings or industrial engineering structures .The explosion of technological devices used in wood processing initiated a construction disaster of a prefabricated hall with a reinforced-concrete structure . The facBy analyzing the guidelines set out in the documentation of the technological process of chipboard production and the data recorded by the devices controlling these processes, the values of the basic parameters of the forming device, which had a significant impact on the occurrence of the explosion, were established. Immediately before the explosion, factory control systems indicated a critically dangerous increase in temperature and pressure inside the machine, but they went unnoticed by technical supervision. Devices designed to ventilate the machine were ineffective during the explosion, which was recorded by the control software. The ventilation systems inside the hall, designed to remove excessively concentrated wood dust, also did not work properly, although the information about the system’s defects was generated by devices controlling the panel production process in a 24-h mode.The lack of a proper reaction of employees supervising the technological production process and the poor technical condition of fire-fighting devices contributed to an increase in the scope of the damage to building structure elements .After the analysis of all the collected information, it was found that two more explosions occurred in the production hall. The first was caused by the spontaneous combustion of a mixture of wood dust and air supplied to the technological machine with a sharp increase in pressure inside it. The accelerator of the reaction was vapor of formaldehyde resin, which was used in the production of the plates. The self-ignition flame ignited the wood dust accumulated in the hall and triggered a secondary explosion that damaged the structure of the prefabricated reinforced-concrete walls and roof of the building.As a result of the tests and calculations carried out, it was found that the implementation of the reinforcements taking over the weight of the damaged prestressed girders was not effective. The girders were qualified for dismantling . The worAn important conclusion resulting from the conducted research is the recommendation to avoid prestressed reinforced-concrete structures in buildings exposed to internal or external fire hazards, or those under threat of an explosion. Traditional reinforced-concrete girders or steel truss girders result in minor losses in the event of an explosion. In place of the girders used so far, a light covering made of corrugated sheets based on purlins was designed to transfer the load to the steel girders. Taking into account the assembly conditions, each truss was divided into three segments, joined after stabilization on supports and previously made working platforms. The damaged parts of the gable walls made of aerated concrete blocks were replaced with light curtain walls made of corrugated sheets.The presented catastrophe could be avoided, or its effects significantly reduced, provided that the technical staff reacted correctly to the information and warnings generated by the automatic control system for the compliance of the technological process parameters and their comparison with the designed reference values. Properly coordinated actions after the explosion and damage to the building structure contributed to the reduction in the degradation process in the zones of subsequent production aisles.The explosion phenomenon has consequences in the form of an additional load with the temperature of the fire and then cooling of the structure during the firefighting operation.The environmental temperature load, often neglected at the design stage of reinforced-concrete structures, also leads to the surface degradation phenomenon caused by the appearance of uncontrolled scratches or cracks.Identification of the structure and morphology of loads in the implemented and operated structures is an important aspect of scientific research. The proper selection of research methods , the corThe underground fire pond was located in the warehouse area of the shopping center building. The rectangular-shaped reservoir, built in 1990, was made of two chambers, each of which was separated by a structural wall with two rectangular openings enabling the flow of water during emptying. The dimensions of the tank were 17.05 × 19.60 m. The bottom plate was 0.40 m thick, the thickness of the reinforced-concrete external walls and the middle wall was 0.30 m, and the thickness of the longitudinal partition walls supporting the upper plate of the tank and reducing the span of the slab was equal to 0.20 m. The structural elements of the tank were made of C25/30-class concrete and the tightness requirements were marked with the symbol W8.As a result of the visual tests, the presence of irregular scratches of the floor, located along the direction of the main reinforcement of the slab, was confirmed. Cracks with a width of 0.5–2.5 mm were located at intervals of 1.2–2.0 m . The conThe limit state of deflections was identified on the basis of leveling measurements of the actual deformation of the slab. The greatest displacements were obtained in the destruction zones over the total thickness of the slab. The type and condition of the main reinforcement and separating bars in the top slab structure and the actual concrete strength, i.e., the main parameters limiting the scratching process, were identified in the course of the research work.The upper plate of the tank absorbed the loads resulting from the fixed weight of the plate, the weight of the pallets with the stored goods, and the weight and movement of the means of transport.Since the analysis of the ultimate load capacity in the direction determined by the main reinforcement bars did not explain the cracking process, the bending state of the plate strands in the perpendicular direction was analyzed, taking into account the distributed reinforcement. It was justified computationally that the plate strips separated with successive cracks created a state of danger, especially during changes in the load caused by the dynamic impact of means of transportation with the simultaneous process of loading with warehouse materials.It was found that the flaws in the design of the distribution bars of the tank top plate reinforcement stimulated the failure condition of the structure loaded with the environmental temperature load through roof skylights, which was not taken into account at the design stage. The slab’s cross-section was classified as concrete, as the used reinforcement bars had a cross-section area smaller than required by the standards. The load-bearing capacity of the unreinforced-concrete element turned out to be insufficient, which resulted in the destruction of the concrete structure due to bending moments and the formation of cracks in the slab along a direction parallel to the direction of the main reinforcement.The underground pond located in the warehouse was made of reinforced concrete. For this reason, it was decided to also perform repair works of reinforced concrete, which involved permanently connecting structural supporting elements and restoring proper safety conditions.On the basis of the tests and identification of the deformation process, it was found that the upper plate did not lose its elastic properties despite significant damage. The consequence of the research work was the development of the concept of the reinforcing structure, and then the commencement of the reinforcement implementation after emptying two of the four compartments of the tank at the same time. Thanks to this technology, the facility still had a water reserve in case of fire. During the works, the commercial facility was in operation. The reinforced-concrete monolithic structure was made of C35/45 concrete, in the form of a four-span beam, supported in nests, profiled in the extreme gable walls of the tank and on square-section columns. The girders were connected with the upper plate of the tank with an individually designed structure of round spindles, reducing the mutual displacement of the separate plate strips.A similar reinforcing structure was used by the authors of ,37, who In the cases studied and presented in this paper, proper risk assessment after the occurrence of a disaster and efficiently carried out reconstruction works allows the elimination of the risk of degradation phenomena and ensures the fastest possible launch of broadly understood technological processes .Designed construction solutions;Current static scheme;Real, implemented design solutions;Completed repair and strengthening works;Actual physical and mechanical parameters of construction materials, including their wear and tear;Variable, operational technological parameters.If defects are found, especially those resulting from previous destructive phenomena, the structure of the facility should be secured against the possibility of intensifying the threat stage, taking into account:Restoration of the safe serviceability of the existing structure by repairing and strengthening it, taking into account the cooperation of new structural elements;Checking whether the structure can be loaded in accordance with the intended use, taking into account the possible extension of the service life;Reconstruction of a defective structure, e.g., damaged by external factors, especially random situations in terms of the effects of exceptional actions.Re-admitting a degraded structure to service should be related to the assessment of the possibility of:In each case, it is necessary to compare the design solutions with the realized state, even if the facility had been used without failure for several dozen years.As a final result of the research and design process of solutions protecting degraded structures, it is necessary to indicate to the user the period in which the structure can safely meet the limit state conditions in order to adjust the applied solutions to the planned lifetime of the facility.However, a rebuilt or reinforced structure should be carefully monitored throughout its entire lifetime. Taking into account the fact that industrial facilities are operated continuously, it is recommended to use mainly non-destructive testing, restricting the number of destructive testing and openings performed. The necessity of incurring additional costs related to the exclusion of an object, or a part of it, from operation for the time of carrying out control tests cannot be a criterion that limits the safety assessment of the structure. The results of control tests, carried out in the periods strictly defined in the recommendations of specialists, will allow for an ongoing assessment of the reliability of building structures. The periods between the dates of examinations may not exceed the periods defined in the applicable regulations.The possibilities of using real cases to assess the degradation stages of buildings are limited to the analysis of similar structures, used in the same foundation conditions, climatic zones, technological and environmental operational loads. The use of comparative analysis is justified in scientific research due to the expansion of practical knowledge. It is necessary to compare reliably obtained practical effects with the results of verifiable theoretical and computational analyzes. Consistent results make it possible to achieve a probability of the formulated conclusions to the extent sufficient to assess the state of degradation of materials and the causes of damage, and above all, to allow the facility to be operated safely within the prescribed period.The method of assessing the state of structure degradation based on experimental tests has limitations due to the possibility of the hypothetical occurrence of random phenomena, locally variable structural and material solutions, or different loads, unidentified in the research process. Only long-term monitoring of a number of facilities in which similar construction solutions were applied, and also operated in similar conditions, allows for the formulation of conclusions addressed to people involved in the investment process, from design, to construction, to the operation of the building.


Low-performance concrete (LPC) is characterized by its low strength and commonly by the presence of large aggregates. This type of concrete was used for construction of load carrying, commonly unreinforced walls in old buildings. The resistance of these buildings with LPC squat walls (of relatively low height-to-length ratio), to in plane horizontal loads, was experimentally investigated in this study. The low compressive strength of these walls, well below that of standard concrete, requires estimation of the relation between the actual LPC compressive strength and its tensile strength, and identification of their failure mode and corresponding shear capacity when subjected to in plane horizontal loads. In this study, compressive and splitting tensile strengths of authentic LPC specimens were measured, and based on them, a relation between the compressive and tensile strengths is proposed. Then, diagonal compression tests were performed on authentic LPC specimens, as well as specimens made of standard concrete. These tests yielded the expected mode of failure of vertical cracking and their analysis shows that their shear capacity needs to be evaluated based on their tensile strength . Thus, the load-bearing  capacity to prevent diagonal tension failure of an unreinforced LPC wall can be evaluated by comparing the LPC tensile strength to the major principal stress caused by the load. Assessment of the tensile strength can be based on the relation between the compressive and tensile strengths proposed in this work. Assessment of existing concrete buildings requires, as a first step, the knowledge of the mechanical properties of the concrete. When dealing with standard concrete, most of its mechanical properties  are related by empirical expressions to its compressive strength ,2. HowevVery few studies of the mechanical properties of LPC have been performed ,5,7. Manpecimens ,9. The fpecimens .This paper presents an experimental research of LPC mechanical properties and shear capacity of old unreinforced squat walls, made of this concrete and subjected to in plane loads. The research goals were to obtain the compressive–tensile strength relation for LPC, realizing that this relation cannot be taken from standard concrete and to evaluate the shear capacity of these walls. In order to achieve the first goal, compressive and splitting tensile tests were performed. The second goal was achieved by performing diagonal compression tests and by analyzing their results, thus providing an insight into the correlation between the concrete tensile strength and the shear capacity of unreinforced LPC squat walls. The shear capacity  is also examined analytically and against well known expressions from the literature ,9. AccorThis study dealt with non-standard concrete (LPC) of which old existing buildings were constructed. Thus, the experimental program had two main goals. The first goal was to obtain the compressive–tensile strength relation. The second goal was to evaluate the shear capacity of LPC squat walls that comprise the gravitational load carrying structural system of these buildings. Therefore, the experimental program consisted of three test types: standard tests of compressive and splitting tensile strengths were performed to obtain the first goal and for the second one, non-standard diagonal compression tests were conducted. The latter tests were adopted from a testing procedure of masonry .The study of LPC required coping with the challenge of testing specimens that would best represent the properties of this non-standard concrete. Thus, special effort was made to extract authentic specimens from old existing buildings at several different locations as illustrated in The authentic specimens were extracted from five different existing buildings and are represented in the following sections by two letters (representing the places from which they were extracted): LO , BZ , DH , TA , and SY (Sde Yaakov). The laboratory-reproduced LPC specimens are denoted PCLAB, and those of the control low strength standard concrete are denoted CON80, CON120, and CLAB. H and D are the specimen’s height and diameter, respectively). The resulted maximum measured stresses  Linear Variable Differential Transformers (LVDTs) with a gauge length of ∼500 mm for CON80, LO, and DH specimens and ∼600 mm for CON120 specimens . MoreoveThe load was applied through two steel loading shoes that were attached at the top and bottom sides of the specimens to prevent local failure b. This sAll the diagonal compression specimens failed after a vertical crack initiated at their center part and propagated both upward and downward, as expected, see The maximum load, opagated c,g. Ther acr see i.The response of the specimens was almost linear up to the maximum load . This is evident from the load–strain curves shown in Analysis of the current experimental results can be used for provision of the relation between the compressive and tensile strengths of the non-standard, low-performance concrete. Additionally, they provide information regarding the tensile strength of LPC by both splitting tests and diagonal compression tests (DCT). The DCT results also allow to assess the main mechanism that controls the resistance to horizontal loads of existing unreinforced, non-slender LPC walls, as explained in the following sections.The measured LPC compressive and tensile strengths have been used to assess the relations between them. Thus, the tensile strengths, Equation  is plottThis relationship provides a reasonable (as well as conservative) evaluation of the LPC tensile strength based on the mean compressive strength measured from the samples of existing structures. Note also that Equation  merges wion  were originally developed in order to evaluate the shear capacity of masonry walls. The failure mode of the specimens tested in DCT resembles splitting failure, where a vertical crack initiates at the specimen center and then propagates towards its upper and lower loaded edges see also . On the P is the vertical load, and h and t are the specimen’s width and thickness, respectively , which has been evaluated byrefer to  with w=hby RILEM  and by Aby RILEM  to be 0.mens see  a linearsoftware  and the In addition to confirming the observed failure and the principal stress causing it, the FEA results were used to evaluate the coefficient for the principal stress at a distance refer to i. This wEquation  the majoEquation  :VRd,c,minP were Substituting these variables and the mean compressive strength of the control specimens 17.3 MPa  in Equat17.3 MPa  yields 3pecimens . Thus, tConsidering that old LPC walls do not (or hardly) include any reinforcement, their resistance to horizontal forces, prior to an application of strengthening materials, is controlled by two main types of mechanisms: resistance which is dominated by the wall overall stability  or sliding (commonly near their base) and, in the case of squat walls, by diagonal tensile failure . Once itThen, the concrete uniaxial tensile strength has to be assessed. This can be done based on the material mean compression strength Equation , while cEquation :(6)ft=0.The resistance of old buildings with unreinforced LPC squat walls (of relatively low height-to-length ratio), to in plane horizontal loads, was investigated in an experimental study. LPC is characterized by its low strength and, commonly, by the presence of large aggregates. While some of these old buildings are demolished to allow new construction, there are many one- or two-story buildings, which are still in use and are not planned to be replaced in the foreseen future. These buildings were built with LPC walls that carry the gravitational loads. The low compressive strength of these walls, well below that of standard concrete, requires estimation of the relation between the actual LPC compressive strength and its tensile strength, and identification of their failure mode and corresponding shear capacity, in case of being subjected to horizontal loads. The actual compressive strength is commonly obtained from cylinders that can be extracted from the existing wall, yet because of the inclusion of large stones in these walls, it was not clear to what extent these results or results from splitting tensile tests can be used for this evaluation. The experimental research reported in this paper comprised testing authentic specimens that were extracted from existing buildings at different locations as well as laboratory-reproduced LPC specimens and control specimens made of standard concrete. The main findings of this study, which refer to concrete compressive cylinder strengths up to 14 MPa, are as follows.Compressive and splitting tensile strengths of authentic and reproduced LPC specimens were measured.Based on these measurements, a relation between the tensile and compressive strengths is proposed, pointing also to the range of possible scatter, which should be examined by the designer when coming to assess the capacity of an existing wall. Note that this new relation is different than that of standard concrete and therefore the findings of this study allow engineers to properly evaluate the mechanical properties of LPC.Then, based on the use of relatively large stones in LPC walls, diagonal compression tests (DCT) were performed on authentic LPC specimens, as well as control specimens made of standard concrete. These tests are usually performed on masonry specimens and here they were adopted to study the shear capacity of LPC specimens.These tests yielded the expected mode of failure of vertical cracking, caused by principal tension stresses, perpendicular to the external load line of action and corresponding to diagonal tension failure, when the DCT rhombus specimens are considered as cartesian rectangular ones acted by horizontal and normal forces.To the best of the authors knowledge, DCT was used in this research for the first time for LPC specimens. For this specimen type, it was found that major principal (tensile) stress is best evaluated by the RILEM approach or by FEM analysis.Analysis of the measured maximum load, as well as the specimen dimensions, corresponding to those of squat walls, show that their shear capacity needs to be evaluated based on their tensile strength .Thus, the load-bearing  capacity to prevent diagonal tension failure of an unreinforced LPC wall can be evaluated by comparing the LPC tensile strength to the major principal stress caused by the load. Assessment of the tensile strength can be based on the proposed compressive–tensile strength relation.


In Lebanon and many other countries where structures are vulnerable to impact loads caused by accidental rock falls due to landslides, specifically bridges with hollow core slab, it is mandatory to develop safe and efficient design procedures to design such types of structures to withstand extreme cases of loading. The structural response of concrete members subjected to low velocity high falling weight raised the interest of researchers in the previous years. The effect of impact due to landslide falling rocks on reinforced concrete (RC) slabs has been investigated by many researchers, while very few studied the effect of impact loading on pre-stressed structures, noting that a recent study was conducted at Beirut Arab University which compared the dynamic behavior of reinforced concrete and post-tensioned slabs under impact loading from a 605 kg impactor freely dropped from a height of 20 m. Hollow core slabs are widely used in bridges and precast structures. Thus, studying their behavior due to such hazards becomes inevitable. This study focuses on these types of slabs. For a better understanding of the behavior, a full scale experimental program consists of testing a single span hollow core slab. The specimen has 6000 mm × 1200 mm × 200 mm dimensions with a 100 mm cast in a place topping slab. Successive free fall drops cases from 14 m height will be investigated on the prescribed slab having a span of 6000 m. This series of impacts will be held by hitting the single span hollow core slab at three different locations: center, edge, and near the support. The data from the testing program were used to assess the structural response in terms of experimental observations, maximum impact and inertia forces, structural damage/failure: type and pattern, acceleration response, and structural design recommendations. This research showed that the hollow core slab has a different dynamic behavior compared to the post tensioned and reinforced concrete slabs mentioned in the literature review section. Lebanon is characterized by its varied terrain . With the increase in population, people moved to live in the mountain region, increasing the percentage of inhabitants there. Lebanon is one of the countries where many landslides are caused because of heavy rain falling in the winter, particularly in mountain areas, resulting in rock falls threatening lives and causing severe damage to the infrastructure and to the residential buildings. Considering the advantages of precast pre-stressed concrete structures, they were introduced in the industry for construction purposes such as covering large spans and speed of erection compared to conventional RC structures. Noting that the most commonly used bridge deck system used in Lebanon mountain areas are made up using precast hollow core units and because of the high probability of natural catastrophes that may highly cause failure for this structures, it is mandatory to study the behavior of hollow core slab under impact loading and finally provide design recommendations for manufactures and structural enhancement for a better performance under such extreme cases of loading. This complex phenomenon drew the attention of many researchers noting that structural engineers do not take into consideration such type of loading cases though the international design codes used.Numerous studies have been conducted, experimentally and numerically, on the behavior of reinforced concrete and pre-stressed structures when subjected to impact loads.Reference : The aimReference : This reReference  studied Reference  studied References ,6,7,8 nuThe current study intended to extend understanding and to get a deep insight into the structural response of pre-stressed slabs’ behavior, namely the hollow core slabs when subjected to low-velocity successive impacts.The hollow core slab unit was selected based on the thickness to span and characteristic service loads where a 200 mm hollow core slab with a 6 m long span can support 10.5 KPa according to the manufacturer.The experimental test in this paper is part of an ongoing doctoral program at the department of structural engineering in Beirut Arab University, studying the structural response of concrete structures under impact loading.-Tested SpecimenThe analyzed slab is a structure 6000 mm in length by 2400 mm (width) and 200 mm thickness as illustrated is The slab system consists of two precast hollow core units. As illustrated in The topping slab is made of concrete with a 45 MPa compressive strength and includes steel reinforcement bars as illustrated in Construction materials properties were grouped in The bars are of 12 mm diameter spaced at 200 mm in both directions with no use of shear connectors or any other type of shear reinforcement. They have an average modulus of elasticity and tensile strength of 200 GPA and 515 MPa, respectively.-Drop WeightThe mass of the drop-weight used in the experimental program is 600 kg . The droThe impact loads were generated by what was essentially a free-fall condition of the drop weight. The cable of the moving crane attached to the steel ball ran through the center of the drop-weight and was used to guide the weight during the fall.The hollow core slab was tested under successive impact loading at three different locations: Slab center, edge, and near the support as illustrated in The hollow core slab was mounted by four electronic accelerometer fixed at different positions as shown in The experimental analysis consists of simulating a slab subject to a series of successive impacts. The tests involve dropping a steel ball of 600 kg as illustrated in The drop weight is lifted to the dropping height by a crane as shown in The generated accelerations with respect to time were recorded and the data were saved through the data acquisition system. Then these values were used to derive the displacements and calculating the impact force, as discussed in the following section. The structural assessment of the specimen response to the impacts such as damaged zones, failure pattern, cracks detections, and propagation were registered after each impact, and results were then analyzed.Several measurements have been made on the analyzed slab. We present in this paper the results related to the (i) damage analysis, (ii) dynamic behavior in terms of acceleration response, and damping ratio, (iii) shear strength, inertia force, and impact force grouped in --Impact crater diameter 28 cm;-No cracks in the topping slab;-No punching with a 2 cm impact penetration through the slab thickness.Concrete topping slab damage assessment:-No global failure in the hollow core units;-Local damage directly beneath the impact represented by the spalling of the 25 mm concrete cover from the bottom side as illustrated in the figure below;-Overall damages were concentrated in the lower unreinforced flange of the hollow core unit;-No damage in the upper flange of the hollow core unit was assessed (Topping slab and hollow core unit worked compositely);-There is no separation between the concrete topping and the hollow core unit;-No de-bonding between the embedded strands and the concrete host.Hollow core slab damage assessment:First Impact Experimental Observations :Concrete--Concrete fracture at the impact location with damaged zone;-Transversal crack passing through the depth was initiated in the topping slab and the hollow core unit;Concrete topping slab damage assessment:-Severe shear damage normal to the slab caused a cut off for the first three cores of the hollow core unit;-Total concrete facture of the web, top, and bottom flanges of the hollow core unit;-Normal and transversal contact separation between the concrete topping and the hollow core units;-The first three tendons were de-bonded from the hollow core unit because of the concrete facture of the web, top, and bottom flanges of the hollow core;-The total stiffness of the hollow core unit was highly reduced by the loss of three of its cores with their strands;-The composite behavior between the concrete topping and the hollow core unit in terms of flexural rigidity was highly reduced because of the surface contact separation;-As expected, the edge impact caused a much higher damage in both the concrete topping and hollow core unit as compared to the one done by the first impact at the center.Hollow core slab damage assessment:Second Impact Experimental Observations :Concrete--Impact crater diameter 35 cm;-No cracks in the topping slab;-Concrete topping was punched through its depth (high shear force near the support);Concrete topping slab damage assessment:-Large damage distributed along the whole parts of the hollow core units;-Major concrete facture of the web, top and bottom flanges of the hollow core unit;-The brittle damage in the top and bottom thin flanges connecting the webs leads to a total loss of hollow core slab stiffness;-The brittle damage in the web connecting the two flanges leads to a total loss of hollow core slab stiffness mainly when the lower part where the pre-stressing strands are embedded separates from the gross the section of the slab;-The brittle failure of the top and bottom thin flanges governs the global behavior of the slab.Hollow core slab damage assessment:Third Impact Experimental Observations :ConcreteThe structural damage in the concrete topping and in the hollow core slab was assessed as following:Experimental results of the three impacts are summarized in Damping ratio was calculated by the use of the first two peak accelerations and according to the Equation (3):Equation (4) from the PCI code was used to calculated the shear strength of the composite slab and found to be equal to 121.27 KN.And Equations (5) and (6) were used to calculate the maximum impact force and the dynamic magnification factor respectively for each impact.This paper studied the behavior of single span hollow core slab under successive impact load at three different locations: center, edge, and near the support under a 600 kg free falling steel ball from a height of 14 m. The structural response of the slab in terms of damage assessment, acceleration response, damping, and impact force has been studied. The results thus obtained were mentioned and the following conclusions were drawn:-Structural damages in hollow core units cannot be repaired or strengthened.-Voids, thin web, and thin flanges are considered the weak points of the hollow core slab.-The presence of strands has no participation in the section load resistance if the continuity of the webs is lost by the facture of one or both flanges.-The slab system (HC + Topping) showed a lower capacity in terms of damage and acceleration response for impact at the edge compared to the impact at the slab center.--The severe damage in the slab body led to a vibration with a low acceleration amplitude directly after the impact;-The concrete topping as solid section and the hollow core units as voided section vibrate in a different manner under impact loading;-The concrete topping and the hollow core units vibrate independently from each other under vertical excitation because of the absence of any type of connectors enforcing the total thickness to work as one unit;-The reduction in slab capacity to resist impact can be demonstrated by the ratio of the maximum acceleration response between the first and the third impact The decaying function of the acceleration response represented by the accelerometers readings indicate an unconventional damped vibration. This response can be explained by the following reasons:-The reinforced concrete topping with high compressive strength (45 Mpa) helped the hollow core slab section to carry more impacts.-Concrete solid section behaves in a much better way than the hollow section in terms of structural damage and cracks generation.-Adding shear connectors can enhance the structural response of the slab system (Topping + HC unit) to avoid the contact separation specially in the case of impact at the slab edge.-Code limitations must be provided to select the minimum flange and web thicknesses in addition to the maximum void diameter in hollow core units.-Filling material such as foam can be used to absorb a part of the energy induced in the body of the hollow core unit to mitigate the brittle fracture of the thin flanges, therefore enhancing the structural performance of the slab system.-The presented damping ratio showed the vulnerability of the impact load location in the hollow core slab.-The reduction in slab impact capacity after successive impacts can be measured by the ratio of impact resistance factor = F1/(F2) = 13,868/1600 = 8.67.


This paper shows a theoretical model for predicting the moment–curvature/load–deflection relationships and debonding failure of reinforced concrete (RC) beams externally strengthened with steel reinforced geopolymeric matrix (SRGM) or steel reinforced grout (SRG) systems. Force equilibrium and strain compatibility equations for a beam section divided into several segments are numerically solved using non-linear behaviour of concrete and internal steel bars. The deflection is then obtained from the flexural stiffness at a mid-span section. Considering the appropriate SRGM-concrete bond–slip law, calibrated on single-lap shear bond tests, both end and intermediate debonding failures are analysed. To predict the end debonding, an anchorage strength model is adopted. To predict intermediate debonding, at each pair of flexural cracks a shear stress limitation is placed at concrete–matrix interface and the differential problem is solved at steel strip–matrix interface. Based on the theoretical predictions, the comparisons with experimental data show that the proposed model can accurately predict the structural response of SRGM/SRG strengthened RC beams. It can be a useful tool for evaluating the behaviour of externally strengthened RC beams, avoiding experimental tests. In the last four decades, the need for repair and rehabilitation of existing reinforced concrete (RC) structures has become an increasingly important challenge for civil engineering community. Among the various methods developed, externally bonded-fibre reinforced polymer (EB-FRP) systems have been widely accepted as an effective and suitable system for the strengthening and retrofitting of RC members ,2,3. EB-Within the broad category of inorganic composite materials, polymer-based inorganic systems (SRGM) have received growing interest in recent years. The experimental investigations on the flexural strengthening of RC beams by Menna et al. , KatakalThe bond behaviour between the external strengthening system and the concrete substrate is an issue that concerns and generally controls the ultimate capacity of strengthened members. It is affected by a high level of uncertainty due to the complex interaction of several phenomena, such as concrete cracking, steel yielding in longitudinal bars, interface adhesion properties, the type of components and the matrix composition. As a result of this partial understanding, different analytical approaches have been proposed within the scientific literature for FRP systems and adopted by the most common codes, standards and guidelines to perform the required safety checks ,2,3. HowIn the present study, a theoretical procedure was developed for the prediction of the moment–curvature relationship and, hence, the load carrying capacity and deflections of RC beams strengthened with steel strips and inorganic matrices (SRGM/SRG systems). In the proposed procedure, a sectional analysis is firstly carried out, where the cross-section of strengthened RC member is divided into a number of concrete segments. The model is able to predict both the end debonding in the un-cracked regions, and intermediate debonding at SRGM–concrete and fibre–matrix interfaces in the cracked regions of the strengthened beams. To this end, an appropriate bond–slip law, calibrated on SRGM–concrete shear bond tests, was used in the numerical model. Finally, to check the reliability of the model experimental and theoretical comparisons were carried out.In this section, the theoretical procedure is presented. Specifically, the constitutive law of materials, the evaluation of the moment–curvature/load–displacement curves and the end/intermediate debonding predictions are described. Computer code using MATLAB R2020a  has beenSimilar numerical techniques were used by ,32,33 foThe well-known stress–strain relationships of concrete, internal steel, and external reinforcement implemented in the model are showed in A bi-linear stress–strain relationship b is usedFinally, the stress–strain relationship of external strengthening system d is assucf and cε are the compressive stress and strain of the concrete, respectively; c’f is the cylinder compressive strength; cE is the initial tangent modulus; c0ε (=0.002) is the strain in concrete at maximum stress; c50uε is the strain corresponding to 0.5 c’f; cuε is the ultimate strain of concrete; and Z is a factor controlling the rate of compressive strength decay.In tf and tε are the tensile stress and strain of the concrete, respectively; tuf and ctε are the tensile strength and corresponding tensile strain, respectively; tE is the tensile modulus, assumed to be the same as cE; and μ is a factor controlling the rate of tensile strength decay. The tension stiffening effect is taken into account in the model.In sf and sε are the stress and strain of the internal steel bars, respectively; syf and syε are the yield strength and corresponding strain, respectively; suf and suε are the ultimate strength and corresponding strain, respectively; sE  is the elastic modulus; and s’E (=sE/100) is the hardening modulus.In ff and fε are the stress and strain of the reinforcing strip, respectively; fE is the elastic modulus; fuf and fuε are the ultimate tensile strength and strain, respectively.Finally, in n, of segments. The analysis starts by assuming a small value of strain at the concrete extreme compression fibre. For each strain cε at the top level of concrete section, the neutral axis depth (x) is iteratively obtained when equilibrium of the forces is satisfied. According to the assumption that the section remains plane after bending, the strain in each compressive or tensile concrete segment can be expressed as:cε is the strain at the top compression level and iε is the concrete compressive or tensile strain at mid-depth of ith segment. Assuming perfect bonds between all materials the strains can also be obtained as follows:d′ and d are the top and bottom steel reinforcement depths, respectively; t is the distance between bottom internal steel and external reinforcement, that is equal to d′/2 and d′ for the IRS and EB strengthening techniques, respectively.cif is the concrete compressive or tensile stress at the centroid of the ith segment, ih (=h/n) is the thickness of the ith segment and b is the beam width. This summation extends over all compressive and tensile segments of concrete section. The forces in the top steel bars, bottom steel bars and external strengthening strip can also be calculated as:s′f, sf, and ff are the stresses in top steel, bottom steel, and external strip, respectively. By considering the equilibrium of forces, the neutral axis depth x is the only unknown parameter, and it can be determined.The total concrete force includes the contribution of compressive and tensile concrete and is calculated by the following relationship:M is then calculated by taking moments of internal forces about the neutral axis:The bending moment φ can also be determined from the strain distribution as follows (The beam curvature  follows :(6)ϕ=εcxeffEI) of member at the location of the maximum moment is firstly determined from the moment-curvature relationship at each loading as:In order to obtain the load–midspan deflection curve, the flexural stiffness  or the concrete strain in the extreme compression fibre reaches the ultimate compressive strain (c = εcuε).The midspan deflection (Δ) is then calculated using the elastic deflection formula of simply supported beams loaded with two-point loads, each P/2:In the theoretical procedure presented above, the full composite action is assumed and the debonding failures are not taken into account. The debonding load is evaluated by means of calculations presented in the next sections.The general opinion among researchers is that the debonding failure is initiated by high interfacial shear and normal stresses at external strengthening–matrix or matrix–concrete interfaces, when the strength of the weakest element is exceeded ,36,37.In general, for externally strengthened RC members there are two types of debonding: end debonding and intermediate debonding ,36. End On the other hand, intermediate debonding failure starts either from a flexural crack (flexure crack delamination) or an inclined flexure-shear crack (shear crack delamination) and propagates to the end-side of the reinforcing strip. The flexural delamination occurs when large vertical cracks take place, whereas the shear delamination has been found to be the most critical due to the brittleness of failure . HoweverIn order to evaluate the debonding load, an incremental procedure was developed. rms) after yielding until failure, is assumed. In fact, it is well-known that few cracks appear after yielding thanks to the steel bars. Most cracks occur before yielding increasing their width until failure. According to Fib 14 [smτ) and external (fmτ) reinforcements, as follows:crM is the cracking moment, calculated by cross-section analysis; sd is the diameter of ith bottom steel bar; h is the number of bottom steel bars; and mz is the mean level arm determined taking into account the axial stiffness of different layers of reinforcement:To simplify the calculations, a constant crack spacing  is required. To this purpose, twelve single-lap shear bond tests on SRGM–concrete joints by varying the bonded length  were carried out [fb) was bonded to the two faces of 150 mm × 600 mm. The mechanical properties of the concrete substrate were similar to those of the EB/IRS-SRGM strengthened RC beams briefly described in the next section [effl) of 200 mm was defined.The load carrying capacity of externally strengthened RC members is affected by debonding of the external strengthening layer. In order to evaluate the interfacial bond failure mechanisms, an appropriate local bond–slip law , exists a unique bond–sτ relationship and a unique relationship between the strain of FRP sheets (fε) and interfacial slip (s) as expressed below:A and B are two parameters evaluated by means of non-linear regression analysis. The mean values of A and B, calculated for the specimens with b ≥ leffl, were equal to 7.82‰ and 6.46 mm−1, respectively [bond-sτ) and interfacial fracture energy (fG) can be derived:ft is the equivalent thickness of external strengthening strip. By substituting the values of A and B, the expression of the bond–slip law and the value of fracture energy (0.54 N/mm) are obtained [In order to calibrate an analytical bond–slip law for SRGM system, the approach proposed by Dai et al.  for FRP ectively . By consobtained .A represents the analytical maximum strain of the stainless-steel strip for end debonding. This strain value was used in the proposed model to predict the end debonding failure of RC beams strengthened with either EB or IRS technique.According to the failure mode detected for the single-lap shear bond tests , EquatioFurther details regarding the test set-up of single-lap shear bond tests, experimental results and calibration of bond–slip laws are given in Bencardino et al. .In order to predict the end debonding failure mode, different approaches were proposed in the literature for FRP systems. The existing models can be generally classified into four categories, namely: shear capacity models , concretIn this study, an anchorage strength model calibrated on single-lap shear bond tests is adopted. It assumes that, at the end uncracked regions of EB/IRS strengthened RC beams , the intb ≥ leffl, the maximum axial strain in strengthening strip for end debonding , at first crack (see A (=7.82‰); whereas, for b < leffl, f,EDε is reduced according to the following parabolic relationship suggested by CNR-DT200R1/2013 [For rack see , is equaee A =7.8‰; whereabl) and, consequently, the maximum axial strain in the reinforcing strip as obtained from Equation (16).The first crack position along the beam, for each load step, is determined based on the cracking moment evaluated by means of the cross-section analysis presented in EDSF), at each load step, is computed as follows:Ed,EDM and Rd,EDM  are the bending moment and bending strength at first crack, respectively. If EDSF is greater than one, end debonding failure occurs and the analysis is stopped.The safety factor for end debonding th and ith crack, respectively.ith concrete tooth is equal to the difference of the steel strip force between two flexural cracks divided by the bonding area between them:With reference to concrete–matrix interface , the bonlimτ) at concrete–matrix interface is assumed different for EB and IRS techniques. The experimental data [lim = τfmτ) [The equation above defines a mean global value for shear stress that results from a change in bending moment along the beam. The stress limitation  . Insteadm = τfm) ,17. Therm = τfm) . AdoptinTwo different safety factors for intermediate debonding at concrete–matrix interface, The values of ith concrete tooth s is the steel strip–matrix slip at ith concrete tooth. Equation (21) is obtained considering the equilibrium in the horizontal direction at steel strip–matrix interface and assuming that the concrete substrate is rigid compared with external strengthening layer (f (x) = ds (x)/dxε). By substituting the expression of local bond–slip law (Equation (14)), Equation (21) gives:With reference to steel strip–matrix interface, it assumes that in the cracked regions of EB/IRS strengthened RC beams, the interface behaviour between external reinforcement and te tooth  is similrms into k (=150) segments th and wth segment in ith concrete tooth (rm/k= s), respectively.Equation (22) is integrated using the finite difference method, dividing segments . To solv follows :(23)τ2b,ID,SMSF) of ith concrete tooth is computed as follows:The debonding occurs when there is no strain variation in the strengthening strip and then the bond stress at interface is about zero. In the proposed procedure, safety factor for intermediate debonding at steel strip-matrix interface (If the bond stress maxΔfσ) within the strengthening system, which can be transferred by means of bond stresses between two subsequent flexural cracks. This increase can be compared to the actual increase, due to the loading condition, calculated assuming full composite action (Δfσ). The model assumes that debonding occurs if Δf > maxσΔfσ. However, the simplified relationships proposed in Fib 14 [maxΔfσ were derived assuming a bi-linear bond–slip law at FRP–concrete interface. This assumption is not consistent with SRGM exponential bond–slip law, presented in fG = 0.54 N/mm), maximum bond shear stress (maxτ = 1.76 MPa) and corresponding slip (maxs = 0.12 mm). Furthermore, approach 2 [fΔσ = 0 (fmaxΔσ ≥ 0). The experimental studies highlight that in many beams tested under four-point bending, intermediate debonding at steel strip–matrix interface in constant bending span occurs before the debonding in constant shear span.The procedure presented above, for predicting debonding at steel strip–matrix interface, is similar to approach 2 proposed by Fib 14  for FRP n Fib 14  to evaluproach 2  assumes Finally, it should be noted that the debonding at the interface between external strengthening strip and matrix is a typical failure mode of inorganic-based composite systems. In fact, all the analytical models available in literature for FRP systems ,2,3 do nIn order to have a better understanding of the algorithm used in the analysis the flowchart of the code developed is presented in To properly implement the numerical procedure, the first experimental work considered in this study refers to a specific set of RC beams strengthened with EB-SRGM and IRS-SRGM systems tested by Bencardino and Condello ,17. The fE = 188,360 MPa; ultimate tensile strength, fuf = 1470 MPa; equivalent thickness, ft = 0.24 mm), embedded in a polymer-based inorganic matrix. By using both the EB and IRS techniques, the RC beams were strengthened with a single layer of stainless-steel strip having f x lfb  equal to 100 mm × 2600 mm and 150 mm × 4400 mm for groups A and B, respectively. Complete details of the experimental investigation including capacity, ductility and failure modes, can be found in Bencardino and Condello [To simulate a wide range of existing RC structures built in the 1960s and 1970s, the specimens were made using low concrete strength and both corroded smooth (12 mm diameter bars) and ribbed steel bars (8 mm and 16 mm diameters). The average values of the material properties were: concrete compressive strength of 16.8 MPa, concrete tensile strength of 1.7 MPa, steel yielding strength of 543.8 MPa, 367.1 MPa and 492.0 MPa for the 8 mm, 12 mm, and 16 mm diameters, respectively. The external strengthening system included a unidirectional reinforcing strip, made of stainless-steel cords  systems were collected. The experimental works show that the failure modes of SRG-strengthened RC beams ,22,23 arThe main geometrical and mechanical properties of the specimens are given in Barton et al.  experimePecce et al.  tested sMenna et al.  investigBencardino and Condello  analysedNapoli and Realfonzo  tested tThe comparisons between theoretical results and experimental data, in terms of failure mode and ultimate load value, are given in tuf) that affected the bond shear strength of concrete–matrix interface, calculated according to Equations (19) and (20). In fact, the beam A-EB had the lowest concrete tensile strength (lim =τ 0.75 MPa) occurred before the debonding at steel strip–matrix interface, which is not affected by the properties of the concrete substrate (Equation (24)). This highlights the role of the concrete substrate on the structural effectiveness of the external strengthening system applied in the EB technique. Further experimental and theoretical research is needed on this topic. The average and standard deviation of the ratio between the proposed model and experimental failure loads are 1.02 and 7% . This is mainly due to the interaction between the two ends of the strengthening strip , because the available bonded length is insufficient to equilibrate the applied force (eff > srm/2l) and therefore the two parts “hook” to each other.As regards to steel strip–matrix interface, the bond stresses/SRGM strains for all strengthened beams (groups A and B) in the shear and half bending spans are given in In general, the failure modes predicted by the proposed numerical technique are consistent with experimental ones. In fact, the unstrengthened RC beams failed, both experimental and theoretical, by concrete crushing. The RC beams strengthened with EB-SRGM system failed experimentally by end debonding, whereas numerical predictions were end debonding for beam B-EB and intermediate debonding at concrete–matrix interface for beam A-EB. Beams A-IRS and B-IRS failed experimentally by intermediate debonding at steel strip–matrix interface and concrete crushing, respectively; whereas, the theoretical failure modes were debonding at steel strip–matrix interface for both strengthened beams.cuε is equal to 0.0035 and 0.003 according to Eurocode 2 [However, for beam B-IRS, the theoretical strain at concrete extreme compression fibre was 3.67‰. This value is higher than the conventional ultimate strain suggested by the main standards/codes  has been developed and presented. The moment–curvature relationship is numerically obtained by considering force equilibrium and strain compatibility. The beam deflection is then calculated from the midspan curvature. Failure modes and loads involving end debonding and/or intermediate debonding at steel strip–matrix and concrete–matrix interfaces are also predicted.The end debonding failure, for bonded lengths equal to or greater than effective bonded length, can be predicted by limiting the strain in the external strengthening strip, at first flexural crack, to the maximum analytical strain calibrated on single-lap shear bond tests. For bonded lengths lower than the effective bonded length a parabolic relationship can be used for reducing the maximum strain.The maximum strain value in the strengthening system for intermediate debonding at steel strip–matrix interface is about 1.30–1.40 times the end debonding strain (7.82‰). As a result, the load carrying capacity of strengthened RC beams for debonding failure at fibre–matrix interface can be predicted by limiting the average axial strain in the strengthening strip to 10–11‰.The brittle intermediate debonding at concrete–matrix interface can be predicted by limiting the maximum shear bond stress to the interface shear strength.Approach 2 proposed by Fib 14 for FRP systems provides conservative values of failure load compared with the values calculated according to the proposed model.The assumption of a perfect bond between materials leads to slightly stiffer behaviour of the numerical curves in the first stage . In any case, the yielding and failure loads are accurately predicted by the calculation procedure. Further development of the code could take into account a suitable bond–slip law between reinforcing steel bars/concrete and external composite material/concrete.The accuracy of the model is examined by comparing theoretical results with experimental data available in literature. A reasonable agreement between the failure modes and failure loads from the current analysis and those from experiments is achieved. Based on the results obtained some concluding remarks can be drawn:The developed model is a useful tool for the prediction of structural behaviour of RC beams strengthened with steel strips embedded into inorganic matrices. Furthermore, varying the interface bond–slip law, the procedure can be adjusted to predict the flexural response of RC beams externally strengthened with other composite materials, both inorganic and organic based systems. This topic needs to be addressed in future works.


Solanum tuberosum to a non-significant effect on biochemical activity in Oryza sativa and Hordeum vulgare. Various regulatory functions, e.g., phosphorylation, protein–protein interactions, and redox modulation, have been reported to affect the starch phosphorylase functions in higher plants. This review outlines the current findings on the regulation of starch phosphorylase genes and proteins with their possible role in the starch biosynthesis pathway. We highlight the gaps in present studies and elaborate on the molecular mechanisms of phosphorylase in starch metabolism. Moreover, we explore the possible role of PHO1 in crop improvement.Starch phosphorylase is a member of the GT35-glycogen-phosphorylase superfamily. Glycogen phosphorylases have been researched in animals thoroughly when compared to plants. Genetic evidence signifies the integral role of plastidial starch phosphorylase (PHO1) in starch biosynthesis in model plants. The counterpart of PHO1 is PHO2, which specifically resides in cytosol and is reported to lack L80 peptide in the middle region of proteins as seen in animal and maltodextrin forms of phosphorylases. The function of this extra peptide varies among species and ranges from the substrate of proteasomes to modulate the degradation of PHO1 in  Solanum tuberosum [Ipomoea batatas [Solanum tuberosum maintains its intact structure in young tubers but steadily degrades into smaller peptides as the tubers become mature [Vigna radiata. Interestingly, both forms were identified to make active catalytic complexes [Oryza sativa [Zea mays [Hordeum vulgare [Triticum aestivum [Phosphorylase EC 2.4.1.1), designated as starch phosphorylase (PHO) in plants and glycogen phosphorylase (gPHO) in animals, has been studied for decades due to its multiple functions. Phosphorylase was first discovered in the liver tissue of mammals in 1939 and was reported to work in the reversible transfer of the glucosyl unit from glucose-1-phosphate to glycogen with the release of inorganic phosphate .1, desig. The aliuberosum . In addi batatas . The PHOe mature . Both thomplexes . In conta sativa ,17, Zea Zea mays , Hordeum vulgare , and TriOryza sativa and is restricted to amyloplast stroma [Zea mays is the second most abundant protein in amyloplast stroma after SBEIIb (an isoform of the subgroup of starch branching enzyme (SBEII)) [PHO1 accounts for 96% of total phosphorylase activity in t stroma . The PHO(SBEII)) . Moreove(SBEII)) ,20,21. THordeum vulgare [Arabidopsis thaliana [Triticum aestivum [Oryza sativa [Starch is an important component of plants and has been subjected to profound research; however, understanding its granule synthesis remains obscure. Amylose and amylopectin are the major components of starch . Some mi vulgare ,34, Arabthaliana , Triticuaestivum , and Orya sativa  has india sativa ,36.Based on biochemical evidence, it was assumed that phosphorylase was involved in the initiation and amplification of glycogen and starch biosynthesis in animals and plants, respectively ,16,37,38sta4) lacking the PHO1 displayed reduced levels of starch with abnormally shaped granules with high amylose content, arguing for a role of PHO1 in starch biosynthesis in Chlamydomonas [Shrunken 4 (sh4), a mutant of Zea mays with no activity of phosphorylase resulted in the reduced starch accumulation and shrunken morphology of maize kernels [There can be two possible routes for starch synthesis , either ydomonas . Shrunke kernels , suggestOryza sativa. The phosphorolytic reaction of PHO1 was stimulated by DPE1 in Chlamydomonas [Increasing evidence supports that starch biosynthesis does not consist of some simple and isolated reactions. The protein–protein interaction and regulatory coordination among starch biosynthetic enzymes have been reported as the key features in starch biosynthesis ,14,53. Aydomonas . It has ydomonas . These oSeveral starch-degrading enzymes have been identified ,56 and cOryza sativa [− (lacking in PHO1) mutant (bmf136) of rice was reported to have different PSI activity and exhibited lower photosynthetic performance in comparison to wild type [bmf136 was rescued to normal when it was complemented with the PHO1. However, when these plants were complemented with the PHO1∆L80 (PHO1 with excised L80 region) instead of typical, enhanced photosynthetic activity was observed. These findings suggest that PHO1 also acts as a modulator of photosynthesis, and the L80 domain is a controller in the photosynthesis modulation.Besides storage starch synthesis in non-photosynthetic cells, it is stated that PHO1 may have an additional role in modulating the photosynthetic activity by interacting with the PsaC region of Photosystem-I (PSI) in photosynthetic cells of a sativa ,36. It cild type ,45. The Zea mays has shown that it stimulates the reaction in the phosphorolytic direction with MOs [Oryza sativa PHO1 showed a preferable role in the synthetic direction over degradation even with the high level of Pi [Tetraselmis subcordiformis  preferred a two-fold higher affinity in the synthetic direction over phosphorolytic direction [Solanum tuberosum [Both PHO1 and PHO2 can catalyze the phosphorolysis of glucans to generate Glc-1-P and Pi in a reversible reaction. Since the reaction is reversible, the appropriate catalyzing direction under physiological conditions is still in debate . In the with MOs ,62, and el of Pi ,47. Phosirection . Furtheruberosum . PHO1 acuberosum ,50,65,66uberosum ,36.Zea mays PHO1 at various developmental stages and reported that PHO1 remains active throughout the endosperm development and showed synthetic activity. At 22 days after anthesis (DAA), PHO1 showed both synthetic and phosphorolytic activity when tested on native affinity zymograms [Hordeum vulgare, PHO1 also confirmed the synthetic activity in developing endosperm, which was highest at 12 DAA and gradually decreased afterward, but the activity does not correlate with the expression level, possibly because of substrate preferences. The preference of substrate by PHO1 has been intensively investigated in various plant species [Ipomoea batatas showed low binding affinity toward starch (high molecular weight) and high binding affinity towards MOs (low molecular weight) [Zea mays showed high binding affinity toward high molecular weight compounds and low binding affinity toward low molecular weight compounds [Zea mays [Solanum tuberosum [Spinacia oleracea [Solanum tuberosum L80 insertion was reported to block the binding affinity of PHO1 with high molecular weight compounds [Further, to elaborate the synthetic and phosphorolytic activity of phosphorylase , Subsingymograms . In Hord species ,69,70,71 weight) . In contZea mays , Solanumompounds . In cerePHO) and interpreted the gene structure, identity, localization, conserved regions, and the expression in wide range of species including maize  [Brachypodium distachyon; XP_003559211.1) [Hordeum vulgare; KAE8783983.1) [Oryza sativa; XP_015631420.1) [Triticum aestivum; ACC59201.1) [Solanum tuberosum; NP_001275215.1) [Ipomoea batatas; M64362.1) [Citrus clementina; NW_0062622139.1), mung bean  [Gossypium Arboreum; LOC108456840) [Panicum hallii; LOC112876003), tomato  [Solanum habrochaites; MG962532.1) [PHO in animals has been investigated comprehensively as compared to PHO1 in plants. Only PHO1 of Zea mays, Oryza sativa, and Hordeum vulgare has been investigated comprehensively in main cereal crops. PHO1 for Triticum aestivum, Setaria italic, and Ipomoea batatas has not been demonstrated and characterized yet and should be the target of future research.During the past few years, great efforts have been made to sequence the whole genomes of plants. The availability of data is important in answering the biological questions in comparative studies ,73. In p96783.1) ,74, brom59211.1) , barley 83983.1) , rice O31420.1) ,47,52, w75215.1) ,77, swee20.1 ,47,6770459) , cotton 8456840) , bunch g34848.1) , and wil62532.1) . gPHO inPHO1 in a wide range of species  of PHO1 are highly conserved among species. It can clearly be seen that two exon–intron junctions are very much conserved among species. One is from exon–intron-2 to exon–intron-4, and the second is from exon–intron-6 to exon–intron-12. Alignments of exon–intron junctions among PHO1 of Oryza sativa, Zea mays, Hordeum vulgare, Solanum tuberosum, Arabidopsis thaliana, and Brachypodium distachyon have revealed an identity of 56% (exon 2) to 90% (exon 12) with an average of 55%, while their intron showed the identity of 29% to 62.1% with an average of 48%. Multiple motifs have also been predicted in the 2 kb upstream region of the transcription start site in PHO1 [PHO1, which can be influenced by abscisic acid (ABA), salt, and drought conditions  suggestnditions .PHO1 transcripts in various tissues and seed developmental stages among Hordeum vulgare (GSE10328), Oryza sativa (GSE6901), and Arabidopsis thaliana (GSE9646). All studied PHO1 and PHO2 are proposed to have the regions (in promotors) that have functions in ABA-induced expression, but a study on PHO1 of Hordeum vulgare suggested no effect of ABA on the expression of PHO1 but up-regulation of PHO2 [Arabidopsis thaliana significant down-regulation for both isoforms were detected. In contrast, the ABA can up-regulate the expression of both the PHO1 and PHO2 in Zea mays [PHO has not been determined for various crops and could be worthy of investigation.Microarray-based data have indicated the uniform pattern of  of PHO2 . HoweverZea mays . The effZea mays [Hordeum vulgare is the only plant in which the 3D structure of PHO1 has been established completely [The comparison of the PHO1 of Zea mays  with othZea mays . In addiZea mays . The PLPmpletely .Zea mays showed a closer relationship with the PHO1 in Panicum hallii and Setaria italica. Hordeum vulgare showed a closer relationship with the PHO1 of Triticum aestivum than those in Zea mays and Oryza Sativa. All of the mentioned phosphorylases are likely to be evolved from a single species.In relation to evolution, a highly divergent phylogenetic pattern has been observed among the phosphorylases . PHO1 ofZea mays, suggesting that phosphorylation does stimulate the AGPase activity in the starch metabolism [Hordeum vulgare [Zea mays PHO1 including threonine 537, serine 547, serine 556, serine 565, and serine 566 [Zea mays PHO1 was also reported as a modifiable phosphorylation site. However, the exact fate of these phosphorylation sites has not been characterized yet.In plants, modification through phosphorylation was first reported in the major starch biosynthetic enzyme by ,66 when tabolism . Similartabolism ,66. Phostabolism ,88. A sttabolism . Phosphotabolism . In high vulgare , and varrine 566 . InteresZea mays, Oryza sativa, Hordeum vulgare, and Triticum aestivum  with PHO1 [ae−1 of maize, in which the amyloplast lacks SBEIIb, a novel protein–protein interaction complex was reported among or with SSI, SSIIa, SBEIa, and SBEIIa [ae−2, the inactive form of SBEIIb was found to be involved in complex formation with SSI, SSIIa, and SBEI both in the granule and stroma. Interestingly, PHO1 is not involved in complex formation in ae−2 as seen in the ae−1 [Solanum tuberosum have identified DPE1 as a potential interacting protein of PHO1. These (PHO1 and DPE1) might form a metabolon and contribute to amylopectin biosynthesis [Phosphorylation-dependent protein–protein interaction occurred in the amyloplast stroma among or between SBEI and SBEII of wheat plants harvested at mid-to-late stages of endosperm development . The samith PHO1 . In ae−1d SBEIIa ,51. In athe ae−1 ,19. No dthe ae−1 ,53. The the ae−1 . Experimthe ae−1 . Interesynthesis .Arabidopsis thaliana [Oryza sativa [Zea mays [Hordeum vulgare [Triticum aestivum [All these protein–protein interactions may serve as a regulatory network that is essential for the appropriate function or regulation of enzymes. Repression or loss of function of a single protein in a complex displays up- or down-regulation of other interacted proteins and affects the functional behavior of the complex in parallel ,93,94,95thaliana ,97, Oryza sativa ,98, Zea Zea mays , Hordeum vulgare , and Triaestivum , severalOryza sativa [Triticum aestivum [Hordeum vulgare thioredoxin system in Hordeum vulgare, suggesting that PHO1 is not a redox-sensitive protein [Starch biosynthetic enzymes were found to be sensitive to the redox status of the cell ,101,102.a sativa  and Tritaestivum  proposedaestivum . These f protein . The act protein . It is r protein , and thiOryza sativa [Triticum aestivum [Zea mays [Zea mays, ZmEREB156 was found to actively modulate the SSIII [Arabidopsis thaliana. Moreover, ZmZIP91 was found in direct association with the promoters of various starch-synthesis-related genes including AGPS1, SSI, SSIIIa, and ISA1. OsbZIP33 interacts with the ACGT element in the promoter region of SBEI and Wx (promoter), which suggests its role in the regulation of starch synthesis [Triticum aestivum and TubZIP28 of Triticum urartu bind to the promoter region of cytosolic AGPase to increase its activity [Oryza sativa [Starch synthesis and starch-associated proteins have been intensively investigated, as these two components limit the value of grain in cereal crops, but transcription factors to regulate the starch synthetic enzymes remain mainly unknown. A limited set of transcription factors have been identified to date  that cona sativa ,108, Triaestivum , and ZeaZea mays ,111,112.Zea mays ,114, whiZea mays . Based ohe SSIII ,116. Zmbynthesis . Recentlactivity . Apart factivity ,120,121.a sativa  suggestiSolanum tuberosum, the activity of PHO1 still remains intact, suggesting the irrelevance of the L80 domain in the function depiction. A possible reason for L80 domain insertion in the PHO1 could be to restrict the activity of the enzyme to starch only. Recent technologies of enzyme assays and native affinity zymograms can be used to test this hypothesis.In plant cells, PHO1 and PHO2 are precisely localized in amyloplasts and cytoplasm, respectively. Both isoforms share a similar mechanism of enzyme activity. The physiological functions of gPHO, maltodextrin phosphorylase, and PHO2 of plant starch phosphorylase were found to be quite similar in phosphorolytic degradation of the storage sugar moiety. However, PHO1 is a major active form of phosphorylase in plants and functions in both synthetic and degradative directions, but its role varies among different species. The possible reason for differential behavior is the presence of a unique L80 domain and the variable N-terminus sequence. The N-terminus of the protein was found to consist of targeting peptides, signal recognition peptides, and possible phosphorylation sites, suggesting a unique regulation pattern in the plants. The L80 domain was reported to be derived from an intron . Even thZea mays, which can undergo phosphorylation. However, the fate of these modifications has not been completely characterized yet. It has been reported that PHO1 activity can be regulated by phosphorylation [The L80 domain was found to consist of the PEST motif, and comparative analysis has suggested that the PEST motif is missing in PHO1 of some crops. Proteolytic cleavage is conditional and depends upon the availability of the PEST motif and/or environmental conditions. So far, studies have not been reported in cereal crops in which PHO1 can undergo proteolytic degradation. Ample work is required to determine the factors that help the PHO1 protein to remain intact and which mechanisms have been adopted to avoid cleavage. The L80 domain is found to be rich in phosphorylation sites, and it has been reported that phosphorylation of L80 at a single serine residue increases the susceptibility of the PHO1 to proteolytic degradation . Determirylation . A studyIn relation to starch metabolism, we cannot understate the importance of PHO1. It was determined to be an integral part of starch metabolism primarily in non-photosynthetic cells, maybe because of regulating the activity of various enzymes through protein–protein interactions. Most of the isoforms of DBEs, SSs, and DPEs are reported to form complexes with PHO1; however, the exact fate of complex formation is still unclear. The classical view of starch degradation is based on the non-regulatory degradation of starch. However, recent findings have suggested critical starch degrading enzymes  that make PHO1 an indirect-acting or regulatory candidate that can influence the activity of another participating enzyme. Although PHO was discovered over 75 years ago, its precise role is still in debate. Based on biochemical evidence we can suggest that the generation of various mutant lines (lacking in PHO1) and metabolite comparison among mutants may help to elucidate its main role in the starch biosynthetic pathway.Phosphorylases have broad potential in crop improvement due to their versatile function and structure. Various thermotolerant variants of AGPase showed thermostability in maize cultivars during heat stress. This suggests that other variants of starch enzymes can be also tested for their potential to breed high-yielding cultivars during heat stress. A few phosphorylases have already been exploited in biotechnology and industrial research due to their glycosyltransferase activity and thermostability. PHO gene can be genetically manipulated to increase the calorific value of silage feed from legumes, grasses, and cereal crops. Storage reservoirs of starch in the form of seeds can also be genetically modified to achieve early emergence and in obtaining the optimum period of seed dormancy. The quality improvements of starch phosphorylases in many crops, like wheat, potato, rice, and maize will contribute greatly to food security.


Head and neck cancer is the sixth most common cancer across the globe. This is generally associated with tobacco and alcohol consumption. Cancer in the pharynx majorly arises through human papillomavirus (HPV) infection, thus classifying head and neck squamous cell carcinoma (HNSCC) into HPV-positive and HPV-negative HNSCCs. Aberrant, mesenchymal-epithelial transition factor (c-MET) signal transduction favors HNSCC progression by stimulating proliferation, motility, invasiveness, morphogenesis, and angiogenesis. c-MET upregulation can be found in the majority of head and neck squamous cell carcinomas. c-MET pathway acts on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K), alpha serine/threonine-protein kinase (Akt), mitogen-activated protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. c-MET also establishes a crosstalk pathway with epidermal growth factor receptor (EGFR) and contributes towards chemoresistance in HNSCC. In recent years, the signaling communications of c-MET/HGF in metabolic dysregulation, tumor-microenvironment and immune modulation in HNSCC have emerged. Several clinical trials have been established against c-MET/ hepatocyte growth factor (HGF) signaling network to bring up targeted and effective therapeutic strategies against HNSCC. In this review, we discuss the molecular mechanism(s) and current understanding of c-MET/HGF signaling and its effect on HNSCC. The process of development is a journey beginning through embryogenesis, where cells bud off from developing tissues and move outwards to form shape and patterns that make up the complex architecture of a living organism. Certain cellular activities such as motility, survival and proliferation follow invasive growth pattern which is mostly triggered by extracellular stimuli. This may also regulates the activity of several transcription factors to modulate the expression of proteins such as cytoskeletal, cell-cell junctional components, cell cycle regulators and anti-apoptotic effectors. Mesenchymal-epithelial transition factor (c-MET) function has been reported to be vital in various morphogenetic events in both embryonic and adult stages . c-MET iCooper et al. were the first to identify the MET oncogene in 1984. They chemically transformed human osteosarcoma cell line by transfection analysis in NIH/3 T3 cells and mapped the MET oncogene . MET oncHGF activates c-MET receptor in a paracrine manner by exerting its pleotropic effects through controlling several transmission cascades such as the mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K)/AKT, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways . c-MET nHNSCCs originate from the mucosal epithelium in the oral cavity, pharynx and larynx and are most common malignancies that arise in head and neck. This has been correlated to lifestyle factors such as tobacco smoking, excessive alcohol consumption, or both. Tobacco related carcinogens undergo metabolic activation with the help of detoxifying enzymes and pathways promoting excretion . These rThere is no such screening strategy available that proves effective rather careful physical examination that has been a primary approach for early detection. A proportion of pre-malignant lesions are present as either leucoplakia (white patches) or erythroplakia (red patches) which can progress to advanced stage of HNSCC. HNSCC in the oral cavity is primarily treated through surgical resection followed by adjuvant radiation or chemotherapy plus radiation depending on the disease stage . Howeverc-MET is a receptor tyrosine kinase primarily located on melanocytes, endothelial cells, and epithelial tissues, including those of the liver, gastrointestinal tract, kidney and other organs. In normal cells, the primary MET transcript produces a peptide of 150 kDa, which is partially glycosylated to produce a precursor protein of 170 kDa . The recHGF is the main ligand to c-MET receptor to activate its biological function. HGF is produced as a single-chain inert precursor. Cleavage by extracellular proteases converts the precursor into a two-chain functional heterodimer. HGF is majorly distributed in the extracellular matrix of most tissues in its inactive form where it is cleaved by heparin-like proteoglycans to its mature form . HGF larActivation of HGF/c-MET signaling requires phosphorylation of several elements in the c-MET receptor. Once HGF binds to the c-MET receptor autophosphosphorylation of several tyrosine residues takes place in the intracellular region. The activation of intracellular kinase activity of c-MET takes place via phosphorylation of Y1230, Y1234 and Y1235 . Y1313 iHNSCC is the sixth most common cancer worldwide , 40. It The increased cases of malignancies in oropharynx have been associated with prior infection with oncogenic strains of HPV, primarily of HPV-16 and HPV-18 , 46. HPVINK4A and ARF encoding p14 which is a stabilizer of p53. The accumulation of altered key tumor suppressor genes such as TP53 and CDKN2A, which encode p53 and p16INK4A, respectively is associated with the onset, progression and poor prognosis of HPV-negative HNSCC. Progression of HNSCC from hyperplasia to dysplasia is marked by the loss of 3p21 and 17p13. Further transition into tumor involves the loss of 11q13, 13q21 and 14q32 .Fi.Fi (Table 1).c-MET has a major contribution towards compensating for inhibition of RTK pathways that help in proliferation and metastasis in HNSCC. Therefore, targeting c-MET along with other receptor tyrosine kinases can bring effective therapeutic strategies. There are few c-MET inhibitors already in use for combination therapies against HNSCC Fig.   had been proposed for advanced non-small cell lung cancer therapy with activation of either c-ros oncogene 1 (ROS-1) or ALK . CrizotiThe second clinical trial was meant to determine the efficacy of golvatinib treatment in conjunction with capecitabine and cisplatin (NCT01355302). Unfortunately, this trial did not pass Phase I with five of the seven enrolled patients experiencing serious adverse effects, including supraventricular tachycardia, convulsion, and pulmonary embolism. Foretinib is a class II inhibitor targeting c-MET, VEGFR2, Recepteurd’ Origine Nantais (RON), kinase insert domain receptor (KDR), and Fms related tyrosine kinase 1 (Flt-1) with potent inhibition of c-MET kinase activity (enzymatic IC50 1.16 nM) . In HNSCConsidering c-MET in aspects of cell signaling network through cross-talking with EGFR, VEGFR-2 and other signaling molecules, it is necessary to develop antibodies that are able to inhibit simultaneously two signaling cascades to achieve maximal therapeutic activity , 119. ThThe incidence of HNSCC continues to rise and is predicted to rise by 30% by 2030. HNSCC has been characterized by genetic instability with frequent loss or gain of chromosomal regions. In addition to genetic alterations, epigenetic changes also have a role in driving HNSCC oncogenesis. Multiple pathways and processes contribute to the invasion and metastasis of HNSCC tumor cells. c-MET has been an important target against HNSCC because of its involvement in metabolic dysregulation, tumor-microenvirment and immune modulation. Dysregulation in HGF/c-MET signaling leading to uncontrolled proliferation, motility, invasiveness, and angiogenesis can play an essential role in the development, progression, and survival of cancer including HNSCC. Its association with several other major downstream pathways contributing towards cancer proliferation and metastasis has made it to be explored more and find suitable targets against it. Importantly, c-MET has also been associated with chemoresistance by bypassing traditionally clinically inhibited signals such as EGF. Gefitinib along with c-MET inhibited demonstrated additive synergetic effect in cell line models. Numerous investigations on c-MET aberrant signaling provide a strong rationale for exploring the therapeutic potential of specific receptor antagonists. Consequently, a crucial task will be to select the more active agents and integrate them effectively in well-designed clinical trials incorporating predictive biomarkers such as gene mutations, amplifications, and immunohistochemical c-MET overexpression. The complex crosstalk in cellular control networks opens new avenues for combination treatment protocols involving EGFR inhibitors and possibly also other targeted agents. There are abundant possibilities for bringing c-MET inhibitors to the clinic as a targeted therapeutic drugs fostering checks through metabolic signaling, tumor-microenvironment and immune modulations in HNSCC.


Page 14: The first sentence of Acknowledgments should be replaced with the following.Volume 92, no.14, e00141-18, 2018, This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 681137, from the Deutsche Forschungsgemeinschaft , and through the Collaboration on AIDS Vaccine Discovery (CAVD) by the Bill & Melinda Gates Foundation.