Tumour-to-tumour metastasis is very unusual and has been defined as a tumour metastasis into another histologically different tumour. It is extremely rare in bone. We report a case of lung squamous cell carcinoma metastasized to an enchondroma in the femur of a patient with Ollier disease. A 60-year-old female had a history of a poorly differentiated squamous cell carcinoma of the lung. She underwent a video-assisted thoracoscopic lobectomy, and a follow-up MRI scan showed three lesions in the left distal femur and proximal tibia, which were initially interpreted as metastasis on radiology. Resection of the left proximal tibial lesion was performed, and the pathological findings were consistent with enchondroma with no evidence of metastasis. Subsequent curettage of lesions in the distal left femur revealed metastatic poorly differentiated carcinoma with foci of hyaline cartilage, which was most consistent with metastatic carcinoma in a pre-existing enchondroma. The MRI films were re-reviewed. Characteristic MRI features of enchondroma were found in the lesion in the left proximal tibia and one of the lesions in the left distal femur, while the features of the other lesion in the left distal femur included cortical destruction and extensive oedema in surrounding soft tissue, which were consistent with a malignant tumour. In addition, the enchondroma in the lateral condyle showed blurring and irregular inner margin and adjacent bone oedema, which likely represents a co-existing metastatic tumour and enchondroma. The difference in lineage was confirmed by immunohistochemistry. The final diagnosis was metastatic poorly differentiated carcinoma of the lung into a co-existent enchondroma. The diagnosis can be challenging and could be easily overlooked both radiologically and histologically. Thorough clinical and radiological information is critical for the diagnosis, and despite a very unusual event, awareness of the tumour-to-tumour metastasis phenomenon can avoid an inaccurate diagnosis by the pathologist, therefore preventing inappropriate clinical intervention. Tumour-to-tumour metastasis is a rare phenomenon that has been described as an occurrence of distant tumour metastasis into another histologically different tumour. The metastatic tumour is usually an aggressive high-grade neoplasm, while the primary tumour is often a more indolent one. Although tumour-to-tumour metastasis cases have been reported intermittently, it is extremely rare in the bone. We herein present a case of a patient with Ollier disease with multiple enchondroma  and withA 60-year-old female was admitted to our hospital, complaining of cough and expectoration for 2 weeks. A contrast-enhanced computed tomography (CT) scan of the chest revealed a mass with an irregular margin in the posterior segment of the right upper lobe of the lung Fig. . CT-guidNearly 4 months after the surgery, the patient was admitted to our hospital for the second time, complaining of swelling, pain and loss of range of movement in the left knee joint. Magnetic resonance imaging (MRI) scan revealed tumours in the left distal femur and the left proximal tibia, which were initially radiologically interpreted as tumour metastasis Fig. . ResectiOn a retrospective review of the MRI films using the criteria of Geirnaerdt et al. , the fatImaging follow-up of the patient showed multiple metastatic tumours in the right 7th rib and bilateral frontal lobes of the brain Figs. . The patMetastases are the most common type of malignancy involving the skeleton, and lung carcinoma is the second most common malignant tumour metastasizing to the bone both in women and men . MetastaApproximately 200 tumour-to-tumour metastasis cases have been reported since 1902 . Berent In the present case, the first radiographic presentation of the patient was a pulmonary mass, which was pathologically diagnosed as a poorly differentiated squamous cell carcinoma of the lung. The follow-up MRI scan showed multiple lesions in the left femur and tibia, which were initially radiologically interpreted as metastasis, but pathologic examination revealed a diagnosis of enchondroma for left proximal tibial lesion and metastatic lung carcinoma and co-existent enchondroma for the distal left femoral lesion. Subsequent re-review of the MRI image confirmed that the left proximal tibial lesion and one of the lesions in the distal left femur were enchondromas, while the other distal femoral lesion was a malignant tumour partially “melting” with the enchondroma.In this case, with the presence of both benign cartilaginous and high-grade malignant non-cartilaginous components, a differential diagnosis would be dedifferentiated chondrosarcoma. According to the latest WHO classification of bone tumours , the lowBased on the literature, metastases to a benign tumour are more common than those to malignant tumours. A few factors have been proposed to explain the reason. The most reasonable one may be the benign tumour’s slow growth rate with low metabolic activity, which can provide prolonged exposure and a non-competitive environment for metastatic seeding and growth , 24. TheBone metastases are common in practice, while the coexistence of metastases with benign or malignant primary bone neoplasms is rare in the literature. To our best knowledge, this is the first report of a lung carcinoma metastasizing to an enchondroma of a patient with Ollier disease. The diagnosis of metastatic carcinoma in a primary bone tumour can be challenging. It can be easily overlooked both radiologically and pathologically, which may lead to misdiagnosing a benign bone tumour as malignant tumour or mislabelling the metastatic carcinoma as dedifferentiated chondrosarcoma. Thorough clinical and radiological information is critical for an accurate diagnosis. Awareness of the tumour-to-tumour metastasis phenomenon by the pathologist can prevent inappropriate clinical intervention.


Upson Professor of Chemical Engineering at Cornell University. Professor Steen was an Associate Editor of this journal for over five years, providing both scholarly oversight as well as professional advice from his experience as a world-class researcher and former associate editor for the Journal of Fluid Mechanics.The editorial board of Paul Steen graduated from John Hopkins University in 1981 and after a brief stint as a post-doctoral fellow at Stanford, joined Cornell in 1982 where he remained until his untimely passing on September 4, 2020. Paul’s contributions to the field of nonlinear fluid mechanics, hydrodynamic stability and interfacial fluid mechanics ranged from convective flows in porous media to stability of drops, liquid bridges and resonance patterns. He was particularly interested in conducting fluids research in the microgravity environment and did his research with the rare combination of mathematical acumen and great practical sense. Paul Steen was more than a researcher who published well and published wide. He guided many students who excelled in their own professions, owing much gratitude to Paul’s mentoring style. A devoted husband to Kyra Stepanoff and father to two daughters, Ana and Frances, Paul was also a loyal friend to many in the scientific community who cherish the time during which they knew him. This Collection is a token of the admiration that the community had for Paul and is presented as an honor to this wonderful person whose life was marked by dedication with dignity to duty.


S. aureus bacteremia (SAB).Bacterial bloodstream infections (BSI) are one of the most described syndromes in infectious diseases, but the presence of racial disparities in BSI is unclear. The purpose of this project was to determine if racial disparities exist in patients with S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) infections. Statistical comparisons were performed for binary variables with Fisher’s Exact test and continuous variables with Kruskal-Wallis test.Data was used from a prospective cohort of patients with SAB at Duke University Medical Center from 1995-2015. Patients were categorized as African American (AA) or White. Characteristics of interest included discharge disposition, metastatic infection, persistence of SAB, and in-hospital mortality stratified by methicillin-susceptible Among the 2396 patients with SAB, 1496 (62.4%) were White and 900 (37.6%) were AA. 1241 patients (51.8%) had MSSA bacteremia overall. Whites comprised 63.6% of MSSA and 61.2% of MRSA infections. AA were younger  and more likely to be female . AA had higher rates of diabetes, hemodialysis, HIV infection for both MSSA and MRSA, but higher rates of injection drug use for MSSA only; Whites had higher rates of neoplasm, corticosteroid use, surgery for MSSA and MRSA, but higher rates of transplant for MRSA only . AA had higher Acute Physiology Scores . AA experienced increased rates of healthcare-associated infection . Although Whites were more likely to have in-hospital mortality for MRSA , discharge disposition, metastatic infection, and persistence did not vary significantly by race.Racial disparities exist in SAB, more so for patient characteristics than for outcomes. AA patients were younger, had a different set of comorbidities, and had more acute presentations. Although Whites had higher rates of in-hospital mortality, all other outcomes were similar.Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Advanced Liquid Logics (Grant/Research Support)Affinergy Affinium (Consultant)Akagera (Consultant)Allergan (Grant/Research Support)Amphliphi Biosciences (Consultant)Aridis (Consultant)Armata (Consultant)Basilea Bayer (Consultant)C3J (Consultant)Cerexa Contrafect Debiopharm Destiny (Consultant)Durata Genentech Green Cross Integrated Biotherapeutics (Consultant)Janssen Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)MedImmune Merck (Grant/Research Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis Pfizer (Grant/Research Support)Regeneron sepsis diagnostics Tetraphase (Consultant)Theravance Trius (Consultant)UpToDate Valanbio xBiotech (Consultant)


This study was designed to monitor changes in DCE-MRI-based parameters in preclinical GBM models in response to choline kinase inhibition using a cluster analysis approach. In terms of therapeutic response in F98 rat GBMs, a sustained decrease in permeability and perfusion and increased necrosis was observed during treatment with JAS239 as compared to control animals. No significant differences in these parameters were found for the GL261 mice GBMs. The study demonstrates that region-based clustered pharmacokinetic parameters obtained using DCE-MRI can be used for detecting and assessing tumour haemodynamic heterogeneity, which may be useful in assessing therapeutic response.ep, , To investigate the utility of DCE-MRI derived pharmacokinetic parameters in evaluating tumour haemodynamic heterogeneity and treatment response in rodent models of glioblastoma, imaging was performed on intracranial F98 and GL261 glioblastoma bearing rodents. Clustering of the DCE-MRI-based parametric maps  was performed using a hierarchical clustering algorithm, resulting in areas with poor fit (reflecting necrosis), low, medium, and high valued pixels representing parameters  Glioblastoma multiforme (GBM) is the most prevalent and fast-growing primary brain tumour with poor prognosis and a median survival rate of 14–16 months after diagnosis . As surv−1) of gadolinium-based contrast agent from the intravascular compartment to tumour interstitium [ep, measured in min−1), plasma volume  or its extended version (ETM). Other models, such as the shutter speed (SSM) and two-compartment exchange model (2CXM), can provide additional physiologically sensitive parameters such as GBMs are formed by tumour cells, which differ in their morphology, genetics and biological behaviour ,19. They1H MR spectroscopy (MRS) can be used to detect a decrease in total choline (tCho) that is associated with the inhibition of choline kinase (ChoK) activity by MN58b in gliomas [There is an urgent need to evaluate new drugs for the treatment of GBMs. Recent studies have explored the possibility of altering the expression or activity of enzymes involved in choline metabolism as a novel therapeutic target for cancer treatment. A recent study demonstrated that  gliomas . The inh gliomas . Another gliomas ,29. AsseTo assess the generalizability of our methods, we performed the imaging studies on two syngeneic rodent models of GBM, the F98 GBM in rats and a GL261 models in mice, as both have been shown to recapitulate several features of human GBM and have been used previously in the DCE-MRI literature ,30,31.F344 Fischer rats (n = 34) were implanted with 50,000 F98 GBM cells and C57BL6 mice (n = 10) were implanted with 500,000 GL261 GBM cells. Intracranial tumours were developed by transcranial injection of the GBM cells in the right cortex. The rodents were secured on a stereotaxic frame, a burr hole was drilled through the skull 3 mm right for rats (1.5 mm right for mice) and 3 mm posterior for rats (2 mm posterior for mice) from the bregma, and GBM cells suspended in 5 µL serum-free medium were injected 2.5 mm into the brain for rats (2 mm for mice).2 and slice thickness = 1.16 mm, was used to acquire the pre-contrast T1 maps from a set of six F98 tumour bearing rats. A 3D FLASH sequence was used to obtain T1-weighted images with five flip angles of 2°, 5°, 7°, 12° and 15° and MRI scan parameters: FOV = 20 × 20 × 4.8 mm3; matrix size = 128 × 64 × 8; TR/TE of 15/1.5 ms, from all GL261 GBM bearing mouse brains to obtain pre-contrast T1 maps.The MR images were obtained using a 9.4 T Bruker Biospec scanner . FAIR  pulse sequence using non-selective 180° pulse and 40 inversion times varying from 100 to 7900 ms in steps of 200 ms with matrix size = 128 × 128, FOV of 30 × 30 mm3 (for rats) and 20 × 20 × 4.8 mm3 (for mice), TR/TE1/TE2 = 14/2.25/4.76 ms, and a 12° flip angle was used. A bolus of gadopentetate in saline at the standard dose of 0.1 mmol/kg for rats and 0.2 mmol/kg for mice (for better SNR) was injected through a tail vein catheter, starting at 1 min after collection of baseline images. 180 volumes were collected with a temporal resolution of 5.37 s per volume. Higher resolution anatomical T2- weighted images were also acquired using a RARE sequence  for co-registration of the DCE images and tumour volume calculation.Dynamic 3D multi-gradient-echo (MGE) sequence was used to record the kinetics of the contrast agent. For the dynamic imaging, a matrix size of 128 × 64 × 8, FOV of 30 × 30 × 9.28 mmThe tumour haemodynamic heterogeneity was evaluated on the basis of change in tumour volumes using the different pharmacokinetic models .T0, baseline), day 3 , 6  of treatment and post-treatment day 8 (T8) for rats and day 10 (T10) for mice.For therapeutic response monitoring, a separate cohort  received JAS239 treatment , or saline . Animals were imaged on day 0 (2- weighted images using rigid body registration to correct for bulk motion. The region of interest (ROI) from brain slices containing tumour and the arterial input function (AIF) from the superior sagittal sinus were drawn manually on the co-registered DCE images. The mean T1 value in the tumour ROI from the six F98 rat GBMs was chosen as an initial T1 value for conversion of signal intensity to concentration curves. The ROI was also drawn in the tumour region across every slice manually on the T2- weighted images; the number of pixels in the ROI was multiplied with the pixel dimensions to get the tumour volume. The tumour volumes ranged from 0.006–0.04 cc with a mean value of 0.015 tortions . T1 mapsep were derived from Tofts model (TM) [R2) values in the tumour ROI were within a range of 0.7–1.00. The values less than 0.7 resulted from noisy signals that did not show a pattern for contrast agent uptake in the tissues. Hence, all the parameters were set to zero in case of a poor fit (R2 < 0.7) resulting in a poor fit region or cluster reflecting necrosis.del (TM) , extendedel (TM) , shutterdel (TM) ,34, two-del (TM) ,36 and tdel (TM) , respectectively ,35,36,37ectively ,34,37. FXM model ,39. A hyXM model ,41. A poXM model ,43. The XM model ,45 and mep, , A clustering analysis was used to assess regional changes in the tumour using a hierarchical clustering algorithm, a kind of agglomerative clustering. The algorithm was implemented in MATLAB. It uses a similarity measure to compare two vectors. Initially, each vector is considered as a single cluster. The clustering method uses a strategy to merge pairs of clusters. In each step of clustering, two clusters are merged until a threshold is achieved. A Ward’s linkage method and Euclidean distance measure was used . Ward’s p ≤ 0.05. Differences between JAS239 and control group  were evaluated using Wilcoxon rank sum test. All analyses were conducted using MATLAB. The pharmacokinetic models, showing a significant increase in the number of necrotic pixels with increase in tumour volume (based on Pearson’s correlation coefficient), along with a decrease in high The goodness of fit was estimated using mean The DCE-MRI data quality was good in all cases, and the tumour data were fitted well, as shown for the SSM model in a representative case . Figure T0, T3, T6, and T8 are shown along with the treatment points marked with coloured arrows on the X-axis.Representative example images from a JAS239-treated rat and a saline control are displayed in r = 0.53, p < 0.001) and the 2CXM  model.T3 to T8 compared to control animals (T3 (p = 0.04).For F98 rat GBMs, the SSM and 2CXM models demonstrated an increasing trend in the percentage of necrotic pixels due to JAS239 treatment from  animals A. HoweveThere was an increasing trend in necrotic pixels with JAS239 treatment compared to control in GL261 cases B.KtransAs shown in p = 0.02) between T3 and T8, respectively, using the 2CXM model, as shown in p = 0.02) with a significant increase in p = 0.04) was observed on T3 in JAS239-treated as compared to control animals using SSM. A significant decrease in p = 0.02) was observed on T6 in JAS239-treated compared to control animals using 2CXM. p = 0.02) on T6 using the SSM in JAS239-treated as compared to control animals. This indicates a reduction of permeability and perfusion of the tumour with JAS239 treatment.For F98 rat GBMs, a significant decrease in No significant change or trend was noticed for the GL261 mice treated with JAS239 .ep pixels were found using any of the models  was observed on T3 and T6 in JAS239 compared to control animals using SSM. A significant reduction in mean Kep (p = 0.043 and 0.02) was observed on T3, and T6 in JAS239-treated animals using the 2CXM.For F98 rat GBMs, no significant change in No significant change or trend in any of the parameters was observed for the GL261 mice treated with JAS239.p<  0.01) and ETM , as shown in p < 0.01) and ETM  and the 2CXM  as shown in r > 0.5, p < 0.001) between A significant negative correlation between p = 0.04) between T3 and T8 using 2CXM, as shown in p = 0.04) was observed on T6 in JAS239-treated compared to control animals using 2CXM. A significant increase in mean p = 0.043) was observed on T6 in JAS239-treated as compared to control animals and a significant decrease (p = 0.045) between T3 and T8 of JAS239 treatment was found using the SSM. A significant increase in mean p = 0.02 and 0.02) was observed on T3 and T6 in JAS239-treated as compared to control group and a significant decrease (p = 0.03) between T3 and T8 of JAS239 treatment was found using the 2CXM, as shown in For F98 rat GBMs, a significant increase in No significant change or trend was noticed for the GL261 mice treated with JAS239 .vpNo significant correlation between tumour volume and clustered ny model . In termFor F98 rat GBMs, no significant change in No significant change or trend was observed for the GL261 mice treated with JAS239.No significant correlation between tumour volume and clustered ny model . In termp = 0.02) was observed on T3 in JAS239-treated as compared to control animals using 2CXM and a statistically significant decrease in p = 0.02) and p = 0.02) was observed on T3 in JAS239-treated compared to control animals using 2CXM, as shown in p = 0.028) on T3 in JAS239-treated as compared to control animals, as shown in For F98 rat GBMs, a significant increase in No significant change or trend was noticed for the GL261 mice treated with JAS239 .τiAs shown in For F98 rat GBMs, no significant change in No significant change or trend was noticed for the GL261 mice treated with JAS239.T6), the percent change with respect to baseline in tumour volumes in JAS239-treated animals was compared to control animals. For F98 rat GBMs, the control saline treated animals demonstrated a statistically significant increase (p = 0.033) in tumour volume as compared to JAS239-treated animals  within tumours can be linked to underlying tumour pathophysiology . Deep le2, the SSM and the 2CXM models were selected to detect changes in ep, , ,Correlation analysis was performed to assess the relationship between the number of pixels representing a cluster in the DCE parametric maps with tumour growth. Although we did not find any significant correlation between tumour growth and The relationship between DCE-MRI parameters  suggests therapy induced acute changes in tumour permeability and perfusion. The change in T6 with JAS239 suggests a sustained decrease in permeability and perfusion until the end of treatment. A significant increase in T6 suggests reduced cell density with JAS239 treatment and could be theoretically interpreted as increase in extracellular fluid levels due to the disintegration of tumour cell membranes. Kep calculated as a ratio between ep was observed with JAS239 treatment. No significant change in In this study, we also observed early changes in pharmacokinetic parameters in response to treatment with JAS239 in F98 rat GBMs. A significant decrease inAlthough activity , we did activity , where aactivity ,68,69,702 in the tumour ROI and a significant increase in the number of necrotic pixels with an increase in tumour volume along with a decrease in high Our results also demonstrated that the overall trend in percentage change of the pharmacokinetic parameters followed the same pattern using SSM and 2CXM, which were chosen for monitoring treatment response based on high mean R1B mapping for bias correction in estimation of the variable flip angle based T1 maps was not performed in this study (for GL261 mouse GBMs). In addition, the use of population AIF does not consider the individual variations and might lead to biased estimation of the parameters. Another limitation of the study is the low number of animals used for monitoring the treatment response and the absence of histopathological results to confirm the imaging findings. Correlating the findings from MRI with histopathological data can provide better confirmation of the findings. Future studies will focus on deteremining an optimal combination of the pharmacokinetic models to fit all the tumour pixels. In addition, we plan to perform the clustering approach based on the optimal combination of these models for better accuracy in identifying tumour haemodynamic heterogeneity.The significance levels in various parameters were different, which may have been due to the lower number of animals for the treatment studies. Some technical limitations of this work include analysing data with a fixed T1 value for which the information was obtained from a small subset (due to scan time constraints) out of the total number of F98 rat GBMs used. Moreover, due to scan time constraints, In conclusion, this study demonstrates that the clustered DCE-MRI-based pharmacokinetic parameters generated using different models correlate with tumour volume and may be used for detecting and assessing early therapeutic response. The 2CXM and SSM models were found to be best to monitor treatment response.


Retraction Note: J Exp Clin Cancer Res 37, 181 (2018)https://doi.org/10.1186/s13046-018-0857-5Figure panels 2a-f, labeled as the brain cancer cell line GBM U118, appeared to be falsified and/or fabricated, and were also used in multiple NIH grant applications as the brain cancer cell line GM139 or as the IMR90 cell line.Figure 3 appeared to be produced by cutting out and reusing three lanes from a heatmap that was previously used in a 2014 NIH grant application. The heatmap lanes in the grant application were labelled as iOPCs, WT  and OPC (Ctrl), while the lanes in Figure 3 in this publication were labeled as iN, GBM cells and Ctrl neuron.Figure 4c, labeled as iN cells in the 2018 this publication, appeared to be falsified and/or fabricated, and was also published in [Figure panel 4d, labeled as GBM U18 cells, appeared to be produced by reusing, manipulating, and relabeling photographs from Figure 1c labeled as IMR90 cells in .An additional concern identified as part of the investigation is extensive overlap between this publication and .The Editor-in-Chief has retracted this article. An investigation by the Office of the Vice Chancellor for Research at Washington University in St. Louis concluded that:In addition, the authors have been unable to provide any records of ethics approval for the animal study to the Editor. Limeng He and Zhen Zhang have stated that they were not aware of their inclusion in the author list of this study.Dennis Hallahan, Zhen Zhang, Liming He and Ling-gang Wu agree to this retraction. Jie Yuan, Fan Zhang, Meng You and Qin Yang have not responded to any correspondence from the editor or publisher about this retraction.


Main concern of current research is to develop a novel mathematical model for stagnation-point flow of magnetohydrodynamic (MHD) Prandtl–Eyring fluid over a stretchable cylinder. The thermal radiation and convective boundary condition are also incorporated. The modeled partial differential equations (PDEs) with associative boundary conditions are deduced into coupled non-linear ordinary differential equations (ODEs) by utilizing proper similarity transformations. The deduced dimensionless set of ODEs are solved numerically via shooting method. Behavior of controlling parameters on the fluid velocity, temperature fields as well as skin friction and Nusselt number are highlighted through graphs. Outcome declared that dimensionless fluid temperature boosts up for both the radiation parameter and Biot number. It is also revealed that the magnitude of both heat transfer rate and skin friction enhance for higher estimation of curvature parameter. Furthermore, comparative analysis between present and previous reports are provided for some specific cases to verify the obtained results. In biology, a blood-flow in the blood vessel at the branch/ sub-branch separates into two or more directions and corresponds to the stagnation-point flow2. Hiemenz3 in 1911, first proposed an exact solution for the stagnation-point flow in a static-rigid surface. In this study, Hiemenz utilized appropriate transformation to transform the steady two dimensional (2D) Navier-Stokes equations into non-dimensional highly ODEs. After the remarkable work of Hiemenz3, many investigators considered the stagnation-point flow phenomena by means of different physical features7. Recently, Vaidya et al.8 examined the steady 2D oblique stagnation-point flow on a stretching plate. They have solved analytically dimensionless highly non-linear ODEs using the Optimal Homotopy Analysis Method (OHAM). Further, it has been shown there8 that axial fluid velocity declines with a rise in the viscosity while the dual effect of viscosity is found on the transverse fluid velocity. Meanwhile, Hayat et al.9 discussed the steady 2D stagnation-point flow with both heat generation and thermal radiation. They noticed in9 that variations in the radiation variable and Biot number improve the dimensionless fluid temperature. Further, Aly and Pop10 have obtained unique and dual solutions for a steady 2D stagnation-point flow associated with dynamic hybrid nanofluid. They showed that dual and unique solutions exist for a certain estimations of magnetic parameter and revealed that the behavior of hybrid nanofluid velocity field and temperature are different along the three regions of stability. Additionally, Wain et al.11 comprehended the analysis for incompressible stagnation-point flow in a shrinking/stretching plate, admitting growth of skin friction and heat transfer due to the melting parameter.In fluid dynamics, the phenomenon of stagnation-point flow has got considerable attention of various researchers in the recent past due to its significant applications in natural and industrial phenomena. The former includes a flow of fluid over the tips of various objects, e.g., ships, submarines, aircrafts, rockets etc27 to describe the complex nature of non-Newtonian fluids phenomena. Prandtl–Eyring model is a particular type of non-Newtonian fluid which indicates that shear stress is proportional to the sine hyperbolic function of strain rate to the fluid. Recently, Khan et al.28 proposed the combined impacts of Brownian and thermophoresis diffusion on 2D Prandtl–Eyring nanofluid with entropy generation through a heated stretchable plate. They revealed that for greater estimations of Brinkman number and material parameter, the entropy generation rate rises. Further, the influences of heat source and thermophoresis on steady incompressible MHD flow of Prandtl–Eyring nanofluid in a symmetric channel was analyzed by Akram et al.29. They analyzed that Brownian and thermophoresis parameters have opposite behavior on both the temperature gradient and heart transfer rate. Meanwhile, Uddin et al.30 examined numerically the impact of activation energy on dynamical 2D MHD Prandtl–Eyring nonofluid due to the Joule heating effect. Additionally, Rehman et al.31 studied scaling group transformation method for steady incompressible Prandtl–Eyring fluid through a 2D semi-infinite stretching sheet. With the help of scaling transformation they obtained new similarity transformations for the analysis of Prandtl–Eyring fluid flow. Abdelsalam et al.32 used the Eyring-Powell fluid model as the base fluid to investigate the behavior of a microorganism swimming through a cervical canal. Moreover, Shankar and Naduvinamani33 carried out the numerical solution for magnetized squeezed unsteady 2D Prandtl–Eyring fluid flow through a horizontal sensor sheet. From their investigation it has been noticed that fluid velocity boosts with magnetic parameter while the fluid temperature diminishes in the flow region with magnetic parameter.Non-Newtonian fluids flow phenomena plays a pivotal role in numerous natural, industrial, geophysical and engineering processes. Some common examples of these fluids are drilling mud, lubricating oils, liquid crystals, paints, silly putty, polymeric liquids, biological fluids and many others. The properties of such fluids are hard to define as a single constitutive equation but many attempts have been made by the investigators to characterize the rheological characteristics of fluids containing non-Newtonian fluid behavior. Non-Newtonian fluid models are evidently more complex and have a highly nonlinear behavior. Various investigators presented different fluid models34 was the first researcher who presented the aspect of thermal radiation on steady 2D flow. Later on, the influence of thermal radiation on fluid temperature and heat transfer in an emitting/absorbing medium flowing on a wedge was explored by Viskanta and Grosh35. Recently, Raza et al.36 numerically elaborated the impacts of MHD and thermal radiation on unsteady 2D molybdenum disulfide nanoparticle through a porous channel. They revealed that the heat transfer rises by enhancing the solid volume fraction for various shapes of nanofluids. Gireesha et al.37 analyzed the preparation process of hybrid nanomaterials on a porous longitudinal fin with thermal radiation. Wakif38 scrutinized the impact of incompressible MHD flow of Casson fluid on a horizontal stretched plate with thermal radiation and they show that with radiation parameter the nanofluid temperature increases. Additionally, the characteristics of heat transfer and MHD nanoparticle on a stretching plate with thermal radiation and Joule heating impacts was scrutinized by Dogonchi and Ganji39. They observed that with an increase in the volume of nanofluid turn out a linear rise in the Nusselt number, whereas, this number shows inverse behavior with thermal radiation. Khan and Alzahrani40 proposed the combined effects of thermal radiation and viscous dissipation on 2D nanofluid with entropy generation through a stretched surface. Raza et al.41 studied the thermal radiation impacts on the convective flow of a non-Newtonian fluid through a curved surface. Moreover, Ullah et al.42 numerically studied the flow pattern followed by hybrid nanoliquids  using an infinite disk in the presence of thermal radiation. Furthermore, the authors suggested that Nusselt number shows direct behavior with thermal slip and radiation parameters where reverse effect was noticed for large Eckert number.The influence of thermal radiation plays an essential role in space technology and in processes with high temperatures. The study of heat transfer characteristics on a stretched sheet with radiation was studied by a number of researchers. Smith44 Prandtl–Eyring fluid flow near the stagnation-point induced by stretching cylinder. Energy expression is characterized with thermal radiation. Suitable transformations are utilized to convert the set of non-linear PDEs into a system of highly non-linear ODEs. The reduced dimensionless system is then solved by Shooting method. The influence of various controlling parameters and dimensionless numbers, like curvature, magnetic, radiation and fluid parameters, Prandtl and Biot numbers on the fluid velocity, temperature as well as skin friction and heat transfer are reported via graphs and investigated. The present results of skin friction and heat transfer rate are compared with the previous published work in the limiting cases which are found to be satisfactory.In view of aforementioned literature survey, it is concluded that Prandtl–Eyring fluid in the cylindrical geometry is not addressed yet. Therefore our intention here is to develop a novel mathematical modeling for incompressible MHDx, r)-coordinates are presumed in cylinder and normal to it 14) are aentclass1pt{minimaHere significance of different control physical parameters of the projected problem on the flow velocity A and M, curvature parameter K and ratio of velocities B over velocity gradients. Figure A on the fluid velocity for both cases (A causes boosts up A tend to diminish the viscosity and this overcomes the resistance offered to the liquid. Therefore, boundary layer thickness enhances. It is further remarked that M shows larger value compared to the velocity field in the presence of M. The similar trend was also reported by Hussain et al.45. Figure M shows lesser velocity than the absence of magnetic field. The influence of curvature parameter K over dimensionless velocity field in both cases (K in the absence of M. In fact K varies inversely with radius of cylinder. Thus larger estimation of K decays the cylinder radius and hence contact zone of the cylinder with fluid diminishes. Hence less resistive force occurs for the fluid and consequently velocity field improves. Behavior of velocity ratio parameter on the dimensionless fluid velocity in the presence/absence of M is sketched in Fig. B values due to higher free stream velocity. Furthermore, when B It is also noted from Fig. M with and without fluid parameter M values causes a rise in both the velocity and thickness of momentum layer. It holds physically that a rise in M causes an increase in Lorentz force, thus M when Figures entclass1pt{minimaentclass1pt{minimaentclass1pt{minimaR, magnetic parameter M, Prandtl number Pr, curvature parameter K and Biot number Bi, over dimensionless temperature field are plotted in Figs. Pr on the temperature against R. It is evident that temperature down with improvement in Pr. Because by enhancing Pr, the fluid thermal diffusion declines, which accordingly drops the temperature and corresponding thermal layer. Additionally, the temperature field with R shows more heat transfer compared to the temperature field without radiation. The significance of Biot number Bi over the temperature for both cases (M and Bi. Higher values of Bi results in higher heat transfer coefficient which consequently boosts the temperature field. The influence of curvature parameter K in the presence/absence of magnetic parameter M over dimensionless temperature field is witnessed in Fig. K near the surface thickness of thermal layer declines whereas it rises far away from the surface with M. It holds physically that rise in K causes an enhance in heat transfer due to which temperature distribution falls adjacent to the surface, on the other hand, it is the reason for rising the ambient temperature distribution. Figure B. However, opposite behavior is found for magnetic parameter M on fluid temperature (see Fig. M and consequently more heat is added which gives rise to temperature field. More improvement is observed when radiation parameter R is presented. Similarly, Fig. R in the presence/absence of M. It is witnessed from the graph that an increase in R causes a boost in the temperature distribution of the flow. This is because a rise in R generates the heat energy to the flow, as a result, the thermal layer thicknesses enhances. Also, fluid acquires high temperature in the presence of M.The effects of radiation parameter see Fig. a. BecausM are sketched in Figs. M. This is because M creates an opposing force which diminishes the fluid velocity and consequently, the skin friction rises for larger values of M. The results investigated in Fig. A and K boosts the B. Similarly, the behaviors of curvature parameter K, Prandtl number Pr, radiation parameter R and Biot number Bi in the presence/absence M on Nusselt number are witnessed in Fig. M. It is further explained in Fig. K. It is evidently analyzed that for higher K near the surface thickness of thermal boundary layer declines. From this Figure, it is investigated that with rise in Pr heat transfer rises. This is because Pr declines the fluid temperature which enhances the gap between fluid and surface temperature. Finally, it is revealed from Fig. Bi and radiation parameter R.The skin friction coefficient (M while the fluid temperature enhances.It is investigated that fluid velocity decays for higher values of magnetic parameter A, curvature parameter K and ratio of velocities B; while decreasing function of fluid parameter B.Velocity field improves for fluid parameter K, Biot number Bi and radiation parameter R; while decreasing functions of Prandtl number Pr and ratio of velocities B.Further, it is revealed that dimensionless fluid velocity and related layer thickness are enhancing functions of curvature parameter A, curvature parameter K and magnetic parameter M.It is concluded that the skin friction boosts by enhancing the fluid parameter Bi, radiation parameter R, Prandtl number Pr and curvature parameter K.The heat transfer rate is boosted for Biot number Comparative study shows that current outcomes have better relevance with existing results.Here the numerical simulation of a 2D stagnation-point flow of MHD Prandtl–Eyring fluid over a stretching cylinder has been inspected. Further, convective boundary condition and radiation effect are also considered in this study. The computations of converted set of non-linear ODEs are performed successfully by Shooting method numerically using Mathematica software 11. The following are some of the significant findings from the present work:


To explore the relationship between retinal fluid status and best-corrected visual acuity (BCVA) in patients treated with intravitreal aflibercept (IVT-AFL) treat-and-extend (T&E) in the ALTAIR study.Outcomes were investigated according to overall fluid status at week 16 (predefined) and the relationship between any fluid, intraretinal fluid (IRF), subretinal fluid (SRF), or pigment epithelial detachment with BCVA at baseline, and weeks 16, 52, and 96 (post-hoc). The analyses involved treatment-naïve patients (N = 246) with exudative age-related macular degeneration (AMD), aged ≥ 50 years with BCVA of 73–25 Early Treatment Diabetic Retinopathy Study letters, who participated in the ALTAIR study.The mean (standard deviation) change in BCVA from baseline to week 52 was + 10.6 (10.9) and + 6.5 (16.0) letters in patients without and with fluid at week 16, respectively; and to week 96 was + 9.1 (14.3) and + 4.3 (16.1) letters in patients without and with fluid at week 16, respectively. The last injection interval was 16 weeks in 33.6% and 2.0% (week 52), and 62.9% and 17.6% (week 96) of patients without or with fluid at week 16, respectively. At baseline, 35.7% of patients had IRF and 85.2% of patients had SRF, which decreased to 11.8% (IRF) and 31.7% (SRF) of patients, 8.5% (IRF) and 18.7% (SRF), and 6.5% (IRF) and 20.7% (SRF) at weeks 16, 52, and 96, respectively. Presence of IRF at all timepoints was associated with poorer BCVA than if IRF was absent, while the presence of SRF was not associated with poorer BCVA compared with the absence of SRF.IVT-AFL T&E dosing was effective at clearing fluid regardless of fluid type in ~ 80% of patients with exudative AMD. Patients without fluid at week 16 had numerically better BCVA than those with fluid at week 16. Over 60% of patients without fluid at week 16 achieved the maximum treatment interval of 16 weeks by study end, compared with < 20% of patients with fluid at week 16. IRF , although evident in a small number of patients, was associated with poorer BCVA, whereas SRF was not.ClinicalTrials.gov Identifier: NCT02305238 Exudative age-related macular degeneration (AMD) is characterized by abnormal growth of new blood vessels in the macula  and is tTreat-and-extend (T&E) is a proactive, individualized dosing strategy whereby the treatment interval is gradually extended or shortened based on physician decision regarding the maintenance of functional and anatomic stability . The fleIncreasing evidence suggests that consideration of fluid, and the role of the different compartments, may be important in determining the impact of anti-VEGF treatment on functional outcomes in patients with exudative AMD –8. An anThis article reports predefined and post-hoc exploratory analyses of data from ALTAIR, a 96-week, randomized, open-label, phase 4 study  that was conducted to investigate the efficacy and safety of repeated doses of IVT-AFL with two different T&E approaches in patients with exudative AMD ) of 9.4 (1.7) and 11.8 (2.8) injections, respectively Table  and 17.6At baseline, mean (SD) BCVA was 55.5 12.4) and 54.5 (12.8) letters for patients without and with fluid at week 16, respectively. For patients without fluid at week 16, the mean (SD) change in BCVA from baseline to week 52 was + 10.6 (10.9) letters, and to week 96 was + 9.1 (14.3) letters. For patients with fluid at week 16, the mean change in BCVA was + 6.5 (16.0) letters and + 4.3 (16.1) letters from baseline to weeks 52 and 96, respectively  CRT was 370.8 (137.9) µm and 390.0 (145.1) µm for patients without and with fluid at week 16, respectively. For patients without fluid at week 16, the mean (SD) change in CRT from baseline to week 52 was − 132.0 (135.3), and to week 96 was − 134.5 (133.8) µm. For patients with fluid at week 16, the mean change in CRT was − 127.8 (138.9) and − 118.9 (144.4) µm from baseline to weeks 52 and 96, respectively , or who did not have a subretinal hemorrhage were more likely to have retinal fluid at week 16 Table . Mean  was 57.1 at baseline (n = 16), 66.1 at week 16 (n = 149), 65.4 at week 52 (n = 181), and 64.1 at week 96 (n = 179) for patients without any fluid Fig. .1 The prSRF was not associated with lower BCVA values, unless IRF was also present . Overall, 33 patients had new and/or persistent SRF both at weeks 16 and 52. Of these, 30 patients did not have coexisting IRF at week 52, and, in this group, the mean BCVA was maintained from week 16  to week 96 . Of the 33 patients with new and/or persistent SRF both at weeks 16 and 52, 3 patients had coexisting IRF at week 52, and, in this group, the mean BCVA decreased from week 16  to week 96 .In this predefined fluid analysis of data from the ALTAIR study, IVT-AFL T&E dosing was effective at clearing fluid and improving vision by week 16 in treatment-naïve patients with exudative AMD. The mean BCVA was similar between groups at baseline, and the mean change to week 52 was + 10.6 letters and + 6.5 letters in patients without and with fluid at week 16, respectively, with outcomes maintained to week 96. The mean change in CRT from baseline to week 96 followed a similar pattern; however, at baseline, there was a slight difference between groups . Regarding the last treatment interval up to week 96, over 60% of patients without fluid at week 16 achieved the maximum treatment extension interval of 16 weeks, compared with 17.6% of patients with fluid at week 16. From baseline to week 96, patients without and with fluid at week 16 received a mean of 9.4 and 11.8 injections of IVT-AFL, respectively. The post-hoc evaluation of baseline features suggested that patients with relatively thinner CRT and a lower PED height at baseline were more likely to have no fluid at week 16. A higher proportion of patients without fluid at week 16 had PCV and subretinal hemorrhage at baseline than those with fluid at week 16. Previous studies involving patients with PCV have reported comparable visual outcomes to those with typical AMD following treatment with IVT-AFL fixed or T&E dosing [Overall, the fluid compartment analysis showed that IVT-AFL T&E dosing was effective at clearing fluid in ~ 80% of patients with exudative AMD over the 96-week treatment period and led to improved BCVA, regardless of the fluid type. Over 70% of patients had no new or persistent IRF or SRF at any measured timepoint after week 8, following the three initial doses of IVT-AFL. The role of the different fluid compartments in determining the impact of anti-VEGF treatment on functional outcomes in patients with exudative AMD is a growing area of interest . IRF accIn our analysis, conducted in patients treated with IVT-AFL, new or persistent SRF  was not associated with lower BCVA, consistent with previous reports –8. HowevThe present analysis explored the relationship between fluid status at week 16 after initial dosing and BCVA following treatment with IVT-AFL in a T&E regimen over 2 years, suggesting that absence of fluid at week 16 was predictive of good outcomes. In the ALTAIR study , patientThe main strength of this study was that the data were obtained from a large randomized trial with a strict protocol, offering the opportunity to explore the relationship between fluid status and BCVA/anatomic outcomes in patients with exudative AMD. Furthermore, to our knowledge, this was the first CATT-like fluid analysis in patients treated with IVT-AFL. We should acknowledge that the CATT analysis identified various other factors  as beinA limitation of these analyses was the differing definitions of fluid between the predefined analysis, which was based on the presence or absence of new or persistent fluid, and the post-hoc analysis, which was based on the presence or absence of any fluid . Furthermore, the original study was not designed to determine the relationships between compartment fluid status and impact of disease outcomes after IVT-AFL treatment, and as the specific volume of fluid was not evaluated, quantitative fluid analysis could not be conducted. Limitations in relation to SD-OCT techniques and SD-OCT scan analysis for the determination of fluid status must also be acknowledged. Although there was no reading center involved in the ALTAIR study, SD-OCT machine and image settings for OCT were the same throughout the study at each site. The SD-OCT images were not read by the same observer nor were they checked by another individual, but were guided by a specific OCT manual.In conclusion, this analysis of data from the ALTAIR study demonstrated that IVT-AFL T&E dosing was effective at clearing fluid in over 70% of treatment-naïve patients with exudative AMD and improving vision. Findings from the predefined analysis demonstrated that patients without fluid had better BCVA than those with fluid at week 16. In patients with exudative AMD, baseline features such as CRT and PED height may play a role in determining the initial response of retinal fluid to treatment with IVT-AFL; further research is required to investigate predictive factors for response. The post-hoc analysis showed that IRF, although evident in a small number of patients, was associated with lower BCVA, whereas foveal SRF was not. Further quantitative analyses are required to confirm these findings.


Trojan horse technology institutes a potentially promising strategy to bring together a diagnostic or cell-based drug design and a delivery platform. It provides the opportunity to re-engineer a novel multimodal, neurovascular detection probe, or medicine to fuse with blood-brain barrier (BBB) molecular Trojan horse. In Alzheimer’s disease (AD) this could allow the targeted delivery of detection or therapeutic probes across the BBB to the sites of plaques and tangles development to image or decrease amyloid load, enhance perivascular Aβ clearance, and improve cerebral blood flow, owing principally to the significantly improved cerebral permeation. A Trojan horse can also be equipped with photosensitizers, nanoparticles, quantum dots, or fluorescent molecules to function as multiple targeting theranostic compounds that could be activated following changes in disease-specific processes of the diseased tissue such as pH and protease activity, or exogenous stimuli such as, light. This concept review theorizes the use of receptor-mediated transport-based platforms to transform such novel ideas to engineer systemic and smart Trojan detection or therapeutic probes to advance the neurodegenerative field. The defective blood-brain barrier (BBB) function  MAb (against β-amyloid (Aβ) and TfR), conjugated to a fusion drug that should have at least three components: (i) an Aβ disaggregating component, (ii) an Aβ clearing component to eliminate the disaggregated Aβ from the brain to the blood, and (iii) a vascular component for healing the vascular endothelium  after absorbing external light, could also be fused to the Trojan horse. Singlet oxygen then could effectively disintegrate the Aβ plaques locally. Here, we also proposed a mechanism to eliminate the dependency of these photosensitizers on an external light source; instead, they could be designed to carry their own light source. Such activatable, switchable, smart Trojan probes could assure the safe passage to the site of injury without causing any harm to the healthy tissues/cells on their way. Besides, such probes offer an external spatial and temporal control over their activities. Moreover, as an additional feature, the use of CdSe/ZnS quantum dots (QDs)  TfRMAb with known pharmacokinetics, (ii) a high yield coupling and cleavable linker that attaches TfRMAb to the drug and finally (iii) the fusion protein (for detection or treatment) that is unable to cross BBB at its own .To make a BBB crossing probe it is essential to synthesize a recombinant molecular Trojan horse as described in detail  to the Trojan horse either via genetic engineering or by employing chemical linkers. These chemical linkers could be of any type, such as non-cleavable strong bonding (amide or biotin) linkers, cleavable stimuli-responsive temporary bonding (disulfide or hydrophobic) linkers or PEGylated linkers  propionate (SPDP) in a controlled reaction ethyl methacrylate) linker molecule (pKa 6.4) ethyl phosphorylcholine], which constitutes only pH-labile functional moieties, has demonstrated sensitivity to both pH and temperature  and the  avidin-labeled TfRMAb  that could be re-engineered for fusing to the genetically engineered molecular Trojan horses. New chemical entities could also be created that will allow cerebral drug delivery to short circuit cerebral drug discovery programs for the diverse nature of brain disorders. In the case of proteins, several multiple protein/genetic engineering methodologies can be employed to develop TfRMAb-fusion protein complexes to let through the BBB.in vivo phage panning to assist in endothelium-specific delivery of genes  that could prove to be an attractive biomarker for diagnostic purposes.in vivo. Beside virtual screening  could also be used  could also be developed based on the unique structural properties or functions of Aβ (just like Aβ-oligomer targeting probes) using DOFLA or combinatorial chemistry approach   are also an interesting example of a theranostic PDT agent  for AD treatment is still in its infancy and is not considered a mature therapeutic method. Nevertheless, photosensitizers, such as meso-tetra (4-sulfonatophenyl) porphyrin  are biocompatible organic compounds that, upon illumination, produce reactive oxygen species, such as 1O2  permits a certain level of control over photosensitizer selective activation. Conversely, PDT application is not possible in multifarious anatomical locations, such as the thoracic, abdominal cavities, or nervous tissue. Also, in circumstances where the selectivity and the short radius of action (0.01–0.2 µM in cells) of 1O2 in a non-photochemical reaction  in their native state, but stimulus-mediated activation should prompt the prodrug to produce Since the pH of the plaque region is slightly more acidic (∼pH 5.8) than the pH of the healthy regions (∼pH 7.4)  activated peptide-based probes could also be developed as potent suppressors of Aβ aggregation to prevent its buildup effectively. This concept exploits the fact that capillary basement membranes and connecting tissues are degraded during the Aβ invasion process Inoue, . Many prThere has not been much research done on distinct proteases found in the milieu of plaque formation and invasion. However, amyloid plaque-associated proteases should supposedly function at multiple stages of plaque progression, affecting plaque seeding, growth, neovascularization, and intravasation. Prior reports have shown the Aβ-induced up-regulated expression of various proteases  backbone specific for a targeted protease and coupled with multiple fluorescent chlorin e6 (Ce6) molecules is attached to the carboxyl-terminal of a prodrug to synthesize protease activatable probe  and thrombin-sensitive photosensitizers have been used for increased selectivity in atheromata and thrombin-rich synovial sites of rheumatoid arthritis  (PEO-b-PMAA) via hydrazine formation (Zhuang et al., The specificity of prodrug activation could be increased significantly by synthesizing a prodrug with dual cross-linked architecture, such as both pH- and redox-sensitivities contained in a central micelle (Wang et al., 1O2 upon blue light irradiation (Markovic et al., 1O2 quantum yield. In neurodegenerative PDT research, instead of photosensitizers, stimulus-activated GQDs could be synthesized, as described above. However, the translation of these probes into clinics is somewhat hampered due to their cytotoxic nature (Xiao et al., In PDT, many researchers have prepared conjugates between QDs and various photosensitizers (Zhou et al., 1O2 production internally; the biggest limitation of light-activated therapies including optogenetics. We also briefly highlighted the feasibility of photosensitizer use for future AD treatments, and to overcome the limitations of existing photosensitizer nanoparticle delivery and targeting. Last, the novel concepts presented here could be potentially beneficial to provide an advanced therapeutic platform for the treatment or diagnosis of other amyloidogenic neurodegenerative conditions, such as Parkinson's disease, Huntington's disease, lysosomal storage disease, and stroke, as well as type-II diabetes, epilepsy, and cancer, with minimal invasiveness.In conclusion, the engineering of a superior molecular Trojan probe is predestined, and scientists will undoubtedly continue working on it. TfRMAb-conjugated molecules, targeted across the BBB should greatly increase the penetration of detection probes or multi-functional neurovascular medicines in cerebral parenchyma to the sites of plaque deposition/development with a resulting greater reduction in the load of cerebral amyloid plaque while leaving normal cells unharmed. This should ultimately result in early diagnosis as well as the improvement in CBF (Yang et al.,


FDA approval was extended in 2015 to treat patients with SSSI and CABP who developed bacteremia. Moreover, ceftaroline has also been used off-label to treat other infection types. We evaluated the S. aureus isolates were consecutively collected from 33 US medical centers in 2018-2020 and susceptibility tested by broth microdilution method against ceftaroline and comparators. Results were stratified by infection type and resistance profile. A total of 9,268 50/90, 0.25/1 mg/L) susceptibility (S) ranged from 98.5% (SSSI) to 95.4% . Ceftaroline retained potent activity and broad spectrum against methicillin-resistant S. aureus , with S rates varying from 96.3% (SSSI) to 89.2% . Overall S rate to erythromycin (ERY), levofloxacin (LEV), tetracycline (TET), and trimethoprim-sulfamethoxazole (TMP-SMX) were 44.0%, 67.9%, 94.1%, and 97.5%, respectively. Ceftaroline retained good activity against S. aureus resistant to ERY (94.8%S), LEV (91.4%S), TET (92.3%S), and/or TMP-SMX (98.7%S). Among the resistant subsets, ceftaroline S rates were generally highest among isolates from SSSI (93.1-100.0%), followed by other infections (81.8-100.0%), bloodstream infections , and pneumonia (86.6-98.1%); overall susceptibility was highest among TMP-SMX-R isolates (98.7%), followed by ERY-R (94.8%), MRSA (93.4%), TET-R (92.3%), and LEV-R (91.4%) isolates. Dalbavancin , teicoplanin , and vancomycin  exhibited complete activity (100.0%S), whereas daptomycin  and linezolid  were active against >99.9% of isolates.Ceftaroline  Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors  Involved: Self): Research Grant or Support; Allergan  Involved: Self): Research Grant or Support; Amicrobe, Inc  Involved: Self): Research Grant or Support; Amplyx Pharma  Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc.  Involved: Self): Research Grant or Support; Astellas  Involved: Self): Research Grant or Support; Basilea  Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center  Involved: Self): Research Grant or Support; BIDMC  Involved: Self): Research Grant or Support; bioMerieux Inc.  Involved: Self): Research Grant or Support; BioVersys Ag  Involved: Self): Research Grant or Support; Bugworks  Involved: Self): Research Grant or Support; Cidara  Involved: Self): Research Grant or Support; Cipla  Involved: Self): Research Grant or Support; Contrafect  Involved: Self): Research Grant or Support; Cormedix  Involved: Self): Research Grant or Support; Crestone, Inc.  Involved: Self): Research Grant or Support; Curza  Involved: Self): Research Grant or Support; CXC7  Involved: Self): Research Grant or Support; Entasis  Involved: Self): Research Grant or Support; Fedora Pharmaceutical  Involved: Self): Research Grant or Support; Fimbrion Therapeutics  Involved: Self): Research Grant or Support; Fox Chase  Involved: Self): Research Grant or Support; GlaxoSmithKline  Involved: Self): Research Grant or Support; Guardian Therapeutics  Involved: Self): Research Grant or Support; Hardy Diagnostics  Involved: Self): Research Grant or Support; IHMA  Involved: Self): Research Grant or Support; Janssen Research & Development  Involved: Self): Research Grant or Support; Johnson & Johnson  Involved: Self): Research Grant or Support; Kaleido Biosceinces  Involved: Self): Research Grant or Support; KBP Biosciences  Involved: Self): Research Grant or Support; Luminex  Involved: Self): Research Grant or Support; Matrivax  Involved: Self): Research Grant or Support; Mayo Clinic  Involved: Self): Research Grant or Support; Medpace  Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd.  Involved: Self): Research Grant or Support; Melinta  Involved: Self): Research Grant or Support; Menarini  Involved: Self): Research Grant or Support; Merck  Involved: Self): Research Grant or Support; Meridian Bioscience Inc.  Involved: Self): Research Grant or Support; Micromyx  Involved: Self): Research Grant or Support; MicuRx  Involved: Self): Research Grant or Support; N8 Medical  Involved: Self): Research Grant or Support; Nabriva  Involved: Self): Research Grant or Support; National Institutes of Health  Involved: Self): Research Grant or Support; National University of Singapore  Involved: Self): Research Grant or Support; North Bristol NHS Trust  Involved: Self): Research Grant or Support; Novome Biotechnologies  Involved: Self): Research Grant or Support; Paratek  Involved: Self): Research Grant or Support; Pfizer  Involved: Self): Research Grant or Support; Prokaryotics Inc.  Involved: Self): Research Grant or Support; QPEX Biopharma  Involved: Self): Research Grant or Support; Rhode Island Hospital  Involved: Self): Research Grant or Support; RIHML  Involved: Self): Research Grant or Support; Roche  Involved: Self): Research Grant or Support; Roivant  Involved: Self): Research Grant or Support; Salvat  Involved: Self): Research Grant or Support; Scynexis  Involved: Self): Research Grant or Support; SeLux Diagnostics  Involved: Self): Research Grant or Support; Shionogi  Involved: Self): Research Grant or Support; Specific Diagnostics  Involved: Self): Research Grant or Support; Spero  Involved: Self): Research Grant or Support; SuperTrans Medical LT  Involved: Self): Research Grant or Support; T2 Biosystems  Involved: Self): Research Grant or Support; The University of Queensland  Involved: Self): Research Grant or Support; Thermo Fisher Scientific  Involved: Self): Research Grant or Support; Tufts Medical Center  Involved: Self): Research Grant or Support; Universite de Sherbrooke  Involved: Self): Research Grant or Support; University of Iowa  Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics  Involved: Self): Research Grant or Support; University of Wisconsin  Involved: Self): Research Grant or Support; UNT System College of Pharmacy  Involved: Self): Research Grant or Support; URMC  Involved: Self): Research Grant or Support; UT Southwestern  Involved: Self): Research Grant or Support; VenatoRx  Involved: Self): Research Grant or Support; Viosera Therapeutics  Involved: Self): Research Grant or Support; Wayne State University  Involved: Self): Research Grant or Support Leonard R. Duncan, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Shionogi (Research Grant or Support) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)


Patients with Crooke cell tumours present with features of Cushing syndrome or mass effect. There are few reports of patients with Crooke cell tumours presenting due to apoplexy. All of them had silent tumours. Patients with Cushing syndrome caused by Crooke cell tumours have not been reported to present with apoplexy.A 35-year-old female presented with sudden onset headache and visual loss for 1 week. She had secondary amenorrhoea for 10 years. There were features of Cushing syndrome including central obesity, multiple monomorphic acne, dorso-cervical and supraclavicular fat pads, hypertension, proximal weakness, pigmentation and refractory hypokalaemia. She was found to have markedly elevated serum cortisol, central hypothyroidism and hypogonadotropic hypogonadism. There was a mass in the sellar region (4.7 cm × 1.9 cm × 5.3 cm) suggestive of a pituitary tumour extending to the suprasellar region. Imaging showed evidence of bleeding and compression of the optic chiasm. She underwent urgent trans-sphenoidal excision of the tumour. Histology was compatible with a pituitary neuroendocrine tumour. There was margination of ACTH reactivity to the cell periphery and ring like positivity in most of the cells in the cytokeratin stain. Features were in favour of a Crooke cell tumour. After surgery she improved gradually and became eucortisolaemic.This is a unique presentation of an apoplexy of Crooke cell tumour causing Cushing syndrome. Delayed health seeking behaviour of this patient despite severe Cushing disease could have led to this presentation which has not been reported before. Crooke cell tumour is a rare type of pituitary neuroendocrine tumour containing Crooke’s hyaline material in the cytoplasm of more than 50% of the tumour cells , 2. ThesPituitary apoplexy is haemorrhagic infarction of a pituitary tumour presenting with headache, visual disturbances and sometimes haemodynamic instability . This coA 35-year-old Sri Lankan female presented with sudden onset painless visual loss leading to complete blindness in the left eye and partial visual loss in the right eye accompanied by sudden onset bilateral frontal headache for 1 week.On questioning, multiple features of Cushing syndrome were revealed including recent onset weight gain, darkening of skin, widespread acne and difficulty in getting up from the squatting position over several months. She had not sought any medical advice. There was secondary amenorrhoea for 10 years. During the few medical consultations she had for mild acute illnesses, the possibility of Cushing syndrome had not been considered.Personal medical and family history was unremarkable. There was no history of exposure to any psychoactive substances or glucocorticoids. She was single; and a preschool teacher.2. She had pigmentation, multiple monomorphic acne over the face and upper chest  extending to the suprasellar region with high T1 fluid level. The pituitary gland was not seen separately . The patient was satisfied with her clinical outcome. The timeline of events are summarised in Table Apoplexy in patients with Cushing disease is rare and limited to case reports. Patients with Crooke cell tumours present with Cushing disease or due to mass effects when they are hormonally silent. We did not come across any report of a patient with Crooke cell tumour causing Cushing syndrome presenting due to apoplexy. There are few case reports of apoplexy in Crooke cell tumours. All of them are in the background of silent tumours. In a 49-year-old female with pituitary apoplexy, subsequent histology was suggestive of Crooke cell tumour. Patient did not have clinical or biochemical evidence of Cushing disease . A 64-yeIn a case report of a 45-year-old male, authors describe the interesting finding of apoplexy and two intracranial pseudoaneurysms in a patient with Crooke cell tumour. Clinical and biochemical features were in favour of a silent pituitary adenoma . In anotOur patient’s clinical picture is quite different from the patients described above. She had obvious features of Cushing syndrome which resolved after surgical resection of the tumour. These included refractory hypokalaemia and multiple discriminatory features such as dorsocervial and supraclavicular fat pads, proximal weakness, multiple monomorphic acne, round face and pigmentation. Therefore this is likely to be the first reported case of apoplexy in a patient with active Cushing disease due to a Crooke cell tumour. This unique presentation could have been partly contributed to by the delayed health seeking behaviour.There were few limitations we had to face in our setting. We could not arrange ACTH assay or overnight dexamethasone suppression test prior to surgery. She underwent surgery soon after referral to the neurosurgical and endocrine teams as a sight saving measure. We used AE1/AE3 stain as the cytokeratin stain. More specific stain recommended to identify Crooke hyaline is Cam 5.2 [Our case report brings out a unique presentation of a rare Crooke cell tumour developing apoplexy in the background of progressive Cushing disease. Delayed presentation leading to lack of timely intervention might have resulted in this consequence which has never being reported before.


Cytotoxic T lymphocytes (CTLs) play an important role in controlling tumours, and an improved understanding of how they accomplish this will benefit immunotherapeutic cancer treatment strategies. Stimulation of CTLs by targeting their CD137 receptor is a strategy currently under investigation for enhancing responses against tumours, yet so far only limited quantitative knowledge regarding the effects of such stimulation upon CTLs has been obtained. Here, we develop mathematical models to describe dynamic in vivo two-photon imaging of tumour infiltrating CTLs, to characterise differences in their function either in the presence or absence of a CD137 agonist antibody. We showed that an increased antiproliferative effect and a more sustained presence of CTLs within the tumour were the most important effects associated with anti-CD137 treatment.Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation. Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities. We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. Moreover, we found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation. The global immuno-oncology pipeline grew by 67% between 2017–2018 ,4,5. Alt+ T cells including enhanced proliferation and resistance to apoptosis [One immunomodulator which has received much recent attention is CD137: in 2017 there were nine trials with therapies targeting CD137; in 2018 there were 36 , the mecpoptosis ,13,14. AWe previously quantified the effect of CTLs on solid tumours, considering both cytotoxicity through direct cellular interactions ,15 and pThe experimental data we have used derives from a previously published study where mice were inoculated with B16F10 melanoma tumours, which were then studied over a period of up to 15 days post-inoculation through dorsal imaging windows, by means of two-photon microscopy . In totaThe dataset comprises estimates of tumour volume measured at days 1, 3, 6, 9, 13 and 15 in all mice. Moreover, for the mice treated with ACT on day 3 and bearing OVA expressing tumours, statistics were available for the number of CTLs and tumour cells, as well as their mitosis and apoptosis rates, on either day 6 or day 9 after tumour inoculation (days 3 and 6 after CTL transfer). These statistics are samples from imaging volumes of size 0.35 × 0.35 × 0.1 mm which were imaged for 1–3 h  in the absence of CTLs, based on growth rates for tumours in the data for conditions either without ACT or periods before CTL transfer in the ACT treated groups. This corresponds to a doubling time of 1.4 days for the tumour cell population, and it is approximately consistent with doubling times in the region 1.7–2 (day−1) reported for B16F10 tumours growing up to 100 mm3 in another study, where B16F10 cells were implanted into the ears of mice [The available tumour growth data derives from B16F10 murine melanoma tumours recorded for 15 days after their implantation . We opte applied ,19,20,22E, and the number of tumour cells, T, so the parameter −1 day−1). An advantage of this simplification is that the killing rate We consider the following model for the killing rate of tumour cells by CTLs:on model . Similaron model ,25,26, tur cells .T in Equation (2) is the total number of tumour cells in the tumour. Our quiescent state is motivated by observations of an IFNγ-dependent cell-cycle arrest in B16F10 melanoma after ACT [−1 day−1). CTLs secrete IFNγ upon encounter with antigen presenting cells [−1). The dynamics of proliferating and quiescent tumour cells can thus be described as in Equations (3) and (4):In our data the frequency of tumour cell apoptosis was low, so in addition to the killing we included an antiproliferative effect of CTLs on the tumour in our models. For this, we denote separately fter ACT , which wfter ACT . In our ng cells , therefofew days . In our Note that the killing rate is shared between proliferating and quiescent tumour cells in accordance with their fraction in the tumour.Our model considers only transferred CTLs (since only these could be seen with the fluorescent reporter system), therefore neglecting any endogenous response. Although endogenous CTLs may have been present, robust tumour control in the presence of ACT was still achieved in RAG −/− mice  for app3), therefore any distortion in tumour shape due to the presence of the imaging windows should be minimal. To take the CTL population dynamics into account, the second term of Equation (5) includes two additional variables I and R to describe the dynamics of CTL proliferation and apoptosis inside the tumour. The variable I represents an auto-inductive response of CTLs upon encounter with antigen expressing cells and is based on other models which have included Interleukin-2 as a driver of CTL mitosis [+ T cells by means of quorum regulation [+ T cells. Our model accounts for either possibility:The first term represents the net movement of transferred CTLs into the tumour. Since we have no measurements directly pertaining to CTL infiltration of the tumours, we opted for a simple model where the net movement of CTLs across the tumour boundary occurs at a constant rate pherical . We cons mitosis ,21. Suchgulation  or from E:T ratio, as the frequency of CTLs among tumour cells should determine the strength of the auto-inductive mechanisms.Thus, CTLs induce their own mitosis at rate us model  where thR represents a resistance acquired by the tumour in response to infiltrating CTLs, leading to an increase in the rate of CTL apoptosis over time. This variable rate of CTL apoptosis represents a difference between our model and previous models in the literature which assume a constant apoptosis rate for CTLs [The second variable for CTLs ,21,25. Ifor CTLs . HoweverE:T ratio inside the tumour at a constant rate I and R in terms of their effects on the mitosis or apoptosis rates of CTLs. Thus, I and R have units of events CTL−1 day−1 and additional scaling parameters in the second term of Equation (5) are unnecessary.Similar to the auto-inductive effect of CTLs, in Equation (7) CTLs induce resistance proportional to the T = 1200, E = 0, I = 0, R = 0. Since our model only describes the adoptively transferred CTLs, we set the infiltration parameter s = 0 until the day of CTL transfer (either day 3 or day 7). On the day of CTL transfer, the parameter s was immediately set to the best fitting value thus allowing CTLs to begin infiltrating the tumours.Models were initialized on day 0, corresponding to the day of tumour inoculation in the mice. The initial conditions were g) which was fixed to the same value for both ACT-only and ACT + mAb conditions before fitting. For each group we varied all the parameters to simultaneously minimise the errors for all available data points, for both day 3 and day 7 treated conditions together. This simultaneous fitting improves identifiability of the model by supplying additional constraints. For example, the intravital process dynamics are constrained by the requirement for the model to also describe the tumour volume progression (for which more time points are available). The intravital dynamics within the day 7 treated conditions (for which few measurements were available) are also constrained by the requirement for the model to describe the intravital dynamics within the day 3 treated tumours. Minimisation was performed using a differential evolution algorithm with the DEoptim [−1) for parameters ke, ki, kq, kr, di, and dr. For the parameter s we searched within bounds of 0–5 (TC−2/3 day−1). Each parameter estimation attempt was performed with 5 repeats, using different randomly selected starting parameter values for each repeat. Individual repeats had population sizes of 200 and ran for 500 generations.Models are fit by minimising the Root Mean Square Error between model prediction and all individual data points. “Individual data points” are considered to be either one volumetric growth estimate, or one statistic estimated from one intravital position. Thus, a single mouse where the tumour volume was measured on days 1, 3, 6, 9, 13 and 15 and where intravital data was recorded at four positions on days 6 and 9 would produce 5 volumetric growth estimates, plus 8 estimates for each intravital process rate  and a further 8 E:T ratio estimates. The correspondence between the intravital process rates determined from the experimental dataset and those determined from the ODE model is given in  DEoptim  package In this work our aim was to integrate dynamic two-photon imaging and volumetric tumour progression data , to creaBesides mitosis and apoptosis rates A,B, the The number of either CTLs or TCs per position was similar between ACT-only and ACT + mAb groups, although CTL numbers were slightly higher in ACT + mAb conditions E. This r−1). We estimated that the growth rate of the untreated tumours was approximately 0.5 day−1  ratio to develop our ODE model. A further advantage of utilising the dimensionless E:T ratio for fitting is that it prevents the physical size of the imaging windows unduly influencing our results. Our ODE model (E) either killing tumour cells (T) or preventing them from proliferating, which in our model happens via transfer of proliferating (pT) tumour cells into a quiescent state (qT). To describe the population dynamics of CTLs we considered CTLs to infiltrate across the tumour boundary at a constant rate s per unit area of boundary. Additionally, since CTL mitosis and apoptosis measurements within the tumour were available we included these processes in our model as well via incorporation of two loops. The first loop considered a factor stimulating CTL proliferation (Induction/Interleukin: I), whereas the second loop described a tumour resistance factor (R). The resistance factor increased over time spent with CTLs inside the tumour and led to an increase in CTL apoptosis (see −1). Overall we varied 7 parameters for either the ACT-only or the ACT+mAb condition (In order to probe the relative contributions of these two effects (antimitotic or killing) we elected to develop an ODE model to combine all the disparate measurements together and check them for internal consistency and with other reports in the literature. The absolute number of tumour cells per field in the imaging data depended strongly on the location of the imaging windows which were sometimes located in the centre of the tumour but other times near the periphery or contained large features like vessels A. TherefDE model B featureosis see . We fit ondition  to obtaiondition . Indeed,ondition . In conce, abrogation of killing  could be of greater therapeutic benefit than strategies aiming to further enhance the antimitotic effect (kq).We studied our best fitting models to gain insight into the dynamics and activities of the transferred CTLs. When we took best fitting parameter sets for either ACT-only or ACT+mAb conditions and varied the killing rate k kq > 1; B. Note temployed . Neverthe = 0 had no substantial impact on tumour volume progression (e = 0.75 day−1) were even somewhat higher than for the ACT+mAb condition (ke = 0.5 day−1)  was substantially larger for the ACT-only condition than for the ACT+mAb condition  was negative in almost all videos, the overall dynamics of the anti-CD137 stimulated CTL populations appeared different to their unstimulated counterparts. Specifically, the peak rate of CTL mitosis occurred later in the ACT+mAb treated group, which together with a delayed onset of apoptosis led to a more sustained presence in the tumour. In summary, after anti-CD137 treatment CTLs were able to rapidly shut down mitosis of tumour cells, but also remained present in the tumour for longer, both contributing to the improvement in tumour control.Importantly, we also sought to understand mechanistically what caused the improved tumour control after treatment with anti-CD137. Killing per CTL was unchanged after anti-CD137 stimulation and hence still contributed little to tumour control, so the improvement in tumour control was largely due to an enhanced antimitotic effect after anti-CD137 treatment. Our model suggested that this enhanced antimitotic effect could be explained either by an increased per-capita ability of CTLs to exert an antimitotic effect, or simply by a numeric increase of CTLs inside the tumour (each with similar antimitotic effects to unstimulated CTLs when considered per-capita). In our model these effects were difficult to separate, since increased mitotic effect of CTLs (on a per-capita basis) should also have the effect of increasing Our results fit well with other reports about the effects of anti-CD137 stimulatory effects on CTL function in the literature. To our knowledge, there are no clear reports that CD137 enhances the cytotoxicity of CTLs. Instead, in agreement with our findings, studies which have directly measured CTL cytolytic activity have found similar killing after blockade of CD137 signalling , and CAROne limitation of our model is that there is no representation of space, so the tumour is treated as homogeneous throughout. The B16F10 melanoma tumours are highly invasive  and evenOur model predictions can be tested in various ways. Although we included the tumours treated on day 7 in our analysis, we were not able to determine the number of TC apoptosis events or the apoptosis/mitosis of CTLs. That was because, whilst absolute cell numbers or TC mitosis events were relatively easy to detect, the other events were ambiguous. Nevertheless, our model does make predictions for these values which could in principle be checked. Moreover, our model predicts the arrival rate of new CTLs into the tumours which could be checked against time-lapse images. In our data CTL apoptosis increased over time, so we introduced a resistance variable R to account for this. This is consistent with recent reports that long range IFN-γ signalling can cause upregulation of PD-L1 in cells across distances of up to 800 μm ; or thatIn future, our modelling approach could be extended to include human data. For such an extension, it is a prerequisite that the model should be defined in terms of variables and parameters that can feasibly be measured in human patients. For certain variables this is already possible, for example the frequency of tumour infiltrating CTLs can be obtained from tumour biopsies using immunofluorescence techniques  or from Overall, our modelling study provides insights into the mechanisms CTLs use to control tumours, as well as insights into how these mechanisms may have changed upon costimulation with agonist antibody targeting the CD137 receptor. We found that the cytolytic activity of transferred CTLs against tumour cells was low, with an antiproliferative effect exerted upon tumour cells being a more important factor in tumour control. Moreover, our model suggested that a stronger antiproliferative effect together with a more sustained presence of CTLs inside the tumour were the main effects of costimulation via the CD137 receptor, which together led to improved tumour control. The results of our model identify specific directions for future experimental work which would help elucidate the effect of CD137 stimulation upon CTLs.


Dear Goncalo C Almeida,This article was absorbing to read and it is fascinating to consider the breadth of mysterieswithin the macula that we have to elucidate. Upon reading your article, I had a number ofcomments with which I hoped to gain some clarity.The study did not detail if there was accumulation of fluid throughout life in the patientcohort studied. Is there any data from your patient cohort regarding this? there could be scope to look into this since despite this principle there is a patientof 37 years old that challenges this principle and is affirmed by the Mesnard et al. studywhich showed that type 2 is plausible even in young children.Although this goes against the principles of old age leading to type 2, outer retinalcavitation present due to torpedo maculopathy, as stated by Wong et al This proves the point on the matter that there may be fluid accumulation later in life.A study by Hamm et al. have found that abnormal choroid circulation could be a cause for it. They too were perplexed by the notion of the cause, is it due to a longterm dysfunction or a primary change causing it? The paper did show that there ishypo-fluorescence with fundus auto-flourescence which atrophy or missing RPE as stated. Asmentioned in your paper, is that these areas of atrophy give opportunity for fluidaccumulation and this could be due to the changes in circulation around the choroid. One ofthe figures in their study goes to show less vessels in the sub retinal cleft but a higherchoroidal vasculature which may be where the fluid could be accumulating from.The question relating to accumulation of fluid throughout life may prove to be true as therehas been a case by Su and Gurwood A where it has caused neurosensory retinal detachment.it ismore likely to be a congenital aetiology. This is due to the study showing that in the 77 cases majority were near the temporalmacula and many were very young which is suggestive of an embryological foundation to whichthe disease is occuring. Long term follow up cases did not note any clinically significantchanges suggesting that torpedo maculopathy is a progressive condition is less likely.Contrastingly, a literature review conducted by Williams et al showed that Instead, there may be multiple conditions people acquire throughout the ageing process whichmay be leading to the progressive accumulation of fluid rather than torpedo maculopathy. The serous fluid build up could be due to different causes and would need to beinvestigated further but it need not necessarily be the torpedo maculopathy that causes theprogressive accumulation of fluid throughout life. Shields C et al has noted that there is apersistent defect in the RPE in the fetal temporal bulge. This gives more evidence towards a congenital potentially static view of torpedomaculopathy.A case study in India has shown multifocal central serous chorioretinopathy, the authorclearly states this may not be linked to torpedo maculopathy.


The link between the migration of cancer cells and the spread of cancers has been established for many years. Tumour invasion and metastasis was labelled as one of the original Hallmarks of Cancer in the seminal paper written by Hanahan and Weinberg at the turn of the century . The defThe tumour microenvironment (TME) is made up of complex mixture of tumour cells and stromal derived cells but also containing a modified extracellular matrix (ECM). The ECM is the major structural component of the body comprised of proteins, glycoproteins, glycosaminoglycans and other polysaccharide in a network which would be able to host tumour cells (seed and soil theory) and control whether the tumour will be able to grow and metastases or not be able to move freely through a tissue ,4. ModulModulation of the ECM can also initiate the release of cytokines and growth factors that can stimulate pathways that allow for cells to migrate whether in single cells or as sheets . Growth n = 279 where 172 have a tumour of the oral cavity and most likely to be oral squamous carcinoma) indicates several signalling pathways such as Akt/PI3K that are up-regulated in these patients [Growth factors and ECM can both modulate cell signalling pathways. Analysis of genomes from Head and Neck Cancer patients  and how this translates into the clinical environment. We are also interested in research involving the studies of novel therapies or novel therapeutic approaches which may block cell migration and leading to possible new treatments.


Staphylococcus aureus (MRSA) present significant treatment challenges and can cause serious morbidity and mortality. Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced cephalosporin approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Ceftobiprole is currently in phase 3 clinical development to support a New Drug Application in the United States for acute bacterial skin and skin structure infections and S. aureus bacteremia. Here, the activity of ceftobiprole and comparators was evaluated against recent MDR S. aureus and MRSA clinical isolates.Multidrug-resistant (MDR) and methicillin-resistant S. aureus isolates were collected from patients with various infection types at 34 US medical centers from 2016–2020. Susceptibility to ceftobiprole and comparator agents was tested by CLSI methods. Current CLSI and EUCAST interpretive criteria were applied (Table). Isolates were categorized as MDR if they were non-susceptible  to ≥3 of the following antimicrobials: clindamycin (CM), daptomycin (DAP), erythromycin (ERY), gentamicin (GM), levofloxacin (LEV), linezolid (LZD), tetracycline (TET), tigecycline (TGC), trimethoprim-sulfamethoxazole (TMP-SMX), or vancomycin (VAN). Isolates displaying oxacillin MIC values ≥4 mg/L were categorized as MRSA.13,868 Ceftobiprole was more active than ceftaroline (CPT) against MRSA  (Table). Ceftobiprole maintained activity against 88.0% of the CPT-NS isolates, but CPT was only active against 6.5% of the ceftobiprole-NS isolates. Ceftobiprole was also highly active (97.7–100.0% S) against isolates NS to CM, DAP, ERY, GM, LEV, LZD, TET, TGC, or TMP-SMX. No VAN-NS isolates were detected. Importantly, ceftobiprole was more active (97.7% S) than CPT (83.0% S) against the subset of MDR-MRSA isolates.Conclusions: Ceftobiprole was highly active in vitro against MRSA and MDR S. aureus collected at US medical centers during 2016–2020. These results support the further development of ceftobiprole to treat S. aureus infections in the US.Leonard R. Duncan, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Shionogi (Research Grant or Support) Kamal Hamed, MD, MPH, Basilea Pharmaceutica International, Ltd (Employee)Department of Health and Human Services  Jennifer Smart, PhD, Basilea Pharmaceutica International, Ltd. (Employee)Department of Health and Human Services  Michael A Pfaller, MD, Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Department of Health and Human Services Pfizer, Inc. (Research Grant or Support) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)