Oncologists employed in district general hospitals were less likely to discuss fertility (p = 0.033). On average, 44.6% of reproductive men and 28.9% of reproductive women is referred to fertility specialists. Half of the respondents declared to possess sufficient knowledge regarding fertility preservation . Poor prognosis (53%), unlikely survival (43.1%), and high chances on fertility recovery (28.7%) were identified as barriers to discussing fertility preservation. Among oncologists, impact of cancer treatment on fertility is a well-accepted responsibility to counsel. Despite, self-reported knowledge regarding fertility preservation is strongly varying. In practice, fertility is discussed to some extent, influenced by several barriers and depending on prognosis and type of hospital. Patients benefit from knowledge improvement among oncology care providers concerning fertility effects of cancer treatment. Education during medical school, residency, and among practicing oncologists may raise awareness, together with enhancement of referral possibilities.Cancer diagnosis and treatment may influence reproductive planning and impact fertility in patients of reproductive age. Although guidelines have been established in the past decade, education, practice, and attitudes of medical oncologists regarding fertility preservation remain undecided. A nationwide survey was performed among members of the Dutch Society for Medical Oncology. Demographics, practice, knowledge, and barriers were measured regarding information provision of fertility preservation towards cancer patients of childbearing age. From 392 members, 120 oncologists completed the questionnaire (30.6%). Majority of oncologists was convinced it is their responsibility to discuss impact of cancer treatment to fertility (93.2%), yet 68.3% discussed the subject often or always (The online version contains supplementary material available at 10.1007/s13187-021-02084-1. Cancer treatments are associated with a variety of undesirable side effects; of which one of specific concern to young men and women is the effect on their endocrine health and future reproductive ability . Due to Cytostatic cancer drugs are designed to target dividing cells, implying that in addition to inhibiting cancer cell growth, proliferating primordial follicles which enfold oocytes are conjointly harmed . As for Over the last decade, we have experienced a surge of scientific reports on aspects of altered fertility in young adults with cancer; these particularly include the growing number of available preservation options  and the To date, published quantitative surveys have suggested there may be a deficiency in medical oncologists’ knowledge about FP options and that the provision of information to patients about FP may be suboptimal. The purpose of the hereby presented nationwide study was to evaluate Dutch medical oncologists’ practice patterns, knowledge, educational need, attitudes, and barriers regarding treatment-related infertility and FP among men and women of reproductive age.A questionnaire was used for collecting data in a cross-sectional postal survey. The sample consisted of 433 members of the NVMO  with several areas of expertise. Our sampling strategy aimed for representation with regard to different tumours, employment setting, level of education, years of oncology experience, type of hospital, age, and gender.The questionnaire was developed by the authors. The content of the questionnaire was evaluated by 4 oncologists working in Leiden University Medical Center through an anonymous pilot study and modified using their feedback. The final version comprised a demographic sheet, including professional background, experience in oncology practice, gender, and age. Furthermore, Likert-scale items measured practices, attitudes, content of sexual and fertility counselling, responsibility, need for education, and barriers regarding the discussing of sexual function and fertility issues. In addition, a list was made of most common medications measuring knowledge about their possible side effects to sexual function, to future reproductive ability and regarding teratogenicity. Data concerning the discussing of sexuality issues and knowledge about medication were processed separately .The questionnaires were sent to all medical oncologists who were member of the NVMO; members not practicing in the Netherlands have been excluded. After the initial mailing was finished, reminders were sent to non-responders after 6 and 12 months. An information letter concerning the study and a post-paid return envelope were added, as well as an opt-out possibility. Data were collected anonymously in order to prevent a self-reporting bias.T-test, and independent sample T-test. P-values < 0.05 were considered statistically significant.Data analysis was performed using SPSS . Frequency distribution was used to calculate demographic information. Respondents were recoded regarding age (set at median age 47: 46 years or under vs. over 46), experience (0–10 years vs. 11 years or more), knowledge (none to some vs. sufficient to a lot), and residents vs. qualified specialists. Observed differences between demographic information and specific answers were identified using the Pearson’s chi-square test, linear-by-linear association, paired In the Netherlands, studies that do not involve patients or interventions are not subject to approval from an ethical board. The ethical board was consulted for a comparable previous study, as the study did not concern information recorded by the investigator in such a manner that subjects could be identified, and as it did not compromise the study participants’ integrity, the Committee declared that no official ethical approval was needed.n = 35), a lack of interest (n = 2), a lack of experience (n = 2), the length of the instrument (n = 4), or other reasons (n = 5). Out of 392 eligible participants, 120 oncologists completed the questionnaire (30.6%). Majority of the respondents reported breast cancer (73.3%) and colorectal cancer (65.8%) as area of expertise (multiple areas of expertise possible). For extensive information on the respondents’ characteristics, see Table Of the 433 invited participants, 209 responses were received, resulting in a response-rate of 48.3%. Of the 209 responses, 26 oncologists reported to be retired, 6 physicians were not medical oncologists, and 9 were returned to sender. Forty-eight oncologists reported they were not willing to participate due to a lack of time  stated to discuss fertility often or always, 20% (n = 24) declared to discuss it in more than half of the cases, 5.8% (n = 7) in half of the cases, 3.3% (n = 4) in less than half of the cases, and 2.5% (n = 3) hardly never/never. Among oncologists working in a district general hospital, it was less usual to discuss fertility. In district general hospitals, 84.1% discussed fertility in more than half of the cases vs. 90.3% in all others hospitals . No significant differences were observed regarding gender, all different specialties, residents vs. oncologists, age through 46 years or older, experience through 10 years or more, level of knowledge, and availability of a department protocol.When it comes to discussing the impact of cancer treatment to fertility, almost seventy percent of respondents  discuss fertility. Yet, if cancer treatment has no prospect of cure, only half of the respondents  discuss fertility. When treatment is at palliative stage, a quarter of the respondents stated to discuss fertility .When cancer treatment has the prospect to cure, almost all respondents (n = 114) and on average with men until the age of 53 .Fertility is discussed with women until the age of 44 on average , menopausal symptoms , fear for premature termination of pregnancy , fear for congenital abnormalities , and heredity . With men, frequently discussed topics were a desire to start a family , erectile dysfunction , ability to ejaculate , fear for congenital abnormalities , and heredity .Topics that were reported to be discussed with women are a desire to start a family (n = 57) answered sufficient knowledge, 41.7% (n = 50) had some knowledge, 7.5% (n = 9) said they did not have much knowledge, and 3.3% (n = 4) reported they possessed a lot of knowledge. Oncologists estimated their knowledge significantly higher in comparison to residents (linear-by-linear association p = 0.004).To the question: ‘How much knowledge do you possess regarding FP for cancer patients?’, 47.5% of the respondents  would like to improve their knowledge towards fertility issues and management of fertility issues. Residents significantly more often wish to improve their knowledge (p = 0.041). Experience, however, is not of significant influence to the wish for more knowledge (p = 0.081). Almost three-quarters  of the respondents believe there is too little attention for fertility issues and management of fertility issues during residency. Respondents estimated that initial cryopreservation of semen would cost 693,15 euro  with an annual cost for cryopreservation of 103,07 euro .Three-quarters of the oncologists  of the respondents reported a protocol or a standard at their current workplace stating the routine discussing of fertility, 41.9% (n = 49) did not have such a protocol, and 19.7% (n = 23) was not aware of such a protocol. During multidisciplinary oncology meetings, according to 37.1% (n = 43), fertility is regularly discussed. Seventy-three oncologists (62.9%) reported fertility is not routinely discussed in multidisciplinary meetings. Half of the oncologists reported there is sufficient patient information available in their department regarding fertility , a quarter  reported there is not sufficient information, and the remaining quarter  did not know whether patient information is available. Seventy percent often or always registered fertility consultation in the patient’s file (n = 82), 12% (n = 14) does so in more than half of the cases, and 21 oncologists (18%) reported to register in half of the cases or less. Eighty-four percent (n = 101) never/hardly never prescribed a gonadotropin-releasing hormone agonist (GnRH–A) before starting chemotherapy, for protection of the ovaria. Twelve oncologists (10%) did so in less than half of the cases, 2.5% (n = 3) in half of the cases, and 3.3% (n = 4) did so in more than half of the cases or almost always.Approximately 40% (n = 43), responsibility for the discussion of fertility was assigned to their department, 53 oncologists (44.9%) stated there were no agreements regarding responsibility and 18.6% (n = 22) did not know if there were agreements. Majority of the participants 93.2%  was convinced that it is the responsibility of the oncologist to discuss fertility with patients of reproductive age; 5.8% (n = 7) disagreed to this responsibility. One oncologist did not know whether it is within the treatment responsibility to discuss fertility. In addition, 78% (n = 92) believed that there is also a responsibility for the oncology nurse, 17% (n = 20) did not believe that it is the oncology nurses’ responsibility to address fertility, and 5.1% (n = 6) did not know if it should be oncology nurses’ responsibility.According to 36.4% , ‘unlikely patient will survive treatment’ (43.1%), and ‘high chance on fertility recovery after treatment’ 28.7%). The three barriers most disagreed upon by respondents were ‘patient cannot afford treatment’ (91.3%), ‘patient is single’ (90.6%), and ‘no contact information available of fertility specialist’ (88.8%). A complete overview of barriers can be found in Table 8.7%. Thep < 0.001, paired T-test). The percentage of men being referred was more often by oncologists of 47 years and older  and by residents . There were no significant differences in gender or hospital type of the respondents in reference to the percentage of referred patients.When asked which percentage of all patients of reproductive age has been referred to a fertility specialist, on average 44.6% of men , and on average 28.9% of women , is referred. The percentage of women being referred is significantly lower in comparison to men (n = 56) believed this is acceptable, 39 oncologists (35.5%) believed this is not acceptable, and 15 oncologists (13.6%) were not aware of the existence of this possibility.The participating oncologists were asked to give their opinion upon post-mortem use of preserved material for assistant reproduction for the partner. Half of the oncologists  or demarcated areas, and often only investigated FP regarding female cancer or breast cancer patients as seen in Supplement Barriers most mentioned by our respondents were a poor prognosis and unlikelihood the patient will survive the treatment. In comparison to literature, these are often mentioned barriers towards discussing fertility issues by clinicians working in oncology departments. By way of comparison, in a Swedish survey, the barrier ‘poor prognosis’ was mentioned by 78% , in a GeIn addition, we asked the clinicians to estimate costs of semen cryopreservation. Estimations of the costs of semen cryopreservation were variable; on average, the estimated costs were fairly overestimated. Specifying, costs for initial cryopreservation were estimated €693,15, actual costs are €119,82, with additional costs per sample of €62,81 (reimbursements 2018). Annual costs for cryopreservation were estimated €103,07, actual annual costs are €60,12 (reimbursements 2018). As the costs are fairly overestimated , patients may be informed incorrectly by their clinicians. In some cases, this may result in the decision to withhold from cryopreservation, an undesirable consequence.Clearly, there is a reported lack of training for fertility issues and their management during residency. Consequently, a wish for additional education is expressed by the majority of the respondents, implying a major role for the development of training courses and implementation of the subject fertility issues during residency. By these means, early referral by oncologists before initiation of chemotherapy and radiotherapy will be enabled, as this is a key factor for success in  FP .The completion rate of 30.6% is lower than the average response rate of physicians surveys , also onAwareness and sufficient knowledge among medical oncologists regarding possible toxic effects to endocrine and reproductive health is of critical importance for young men and women with cancer. Due to a lack of knowledge, referral possibilities, and counselling barriers, the ability to start or complete a family after treatment may not be extensively discussed. Subsequently, many men and women of reproductive age with cancer could be missing the opportunity to investigate their FP options. We recommend expansion of education of fertility treatment risks and preservation options starting in medical school, continued during residency training and updates when practicing as a medical oncologist. A culture of shared decision making should be pursued, through the development of clear fertility referral pathways including psychosocial support to improve care for men and women of childbearing age facing a cancer treatment.In conclusion, the results suggest that medical oncologists take responsible attitudes towards fertility preservation in oncology practice. Self-reported knowledge regarding fertility preservation is strongly varying and the majority expressed a wish for additional education. Practice attitudes remain under influence of factors like poor prognosis, a lack of knowledge, treatment-delay, and local availability of fertility specialists. Efforts to develop educational training on treatment fertility risks, communication skills, and acquaintance with fertility preservation options are highly recommended. Improvement of awareness regarding fertility preservation and in addition availability of fertility specialists in district general hospitals may increase referral of young cancer patients for fertility preservation. Timely referral to discuss preserving options for endocrine and reproductive health is crucial, before irreversible damage to the gonads is done.Supplementary file1 (DOCX 46 KB)Below is the link to the electronic supplementary material.


To determine whether unilateral chronic ankle instability (CAI) affects the kinematics of the uninjured contralateral ankle.n = 15) were compared with that of healthy individuals . Applying body photo‐reflective markers, the participant's motion during gait was measured. Biomechanical variables including overall ankle‐toe angle, linear velocity, linear acceleration, angular velocity, angular acceleration, range of motion (RoM) in dorsiplantar flexion, and inversion‐eversion at initial contact, loading response, mid‐stance, terminal stance, pre‐swing, and swing phase of the gait were measured.In this case‐control study, 15 adult patients with unilateral CAI and 15 healthy controls were studied. Both the unstable and uninjured ankles in patients with unilateral CAI . The uninjured ankles of patients showed lower ankle‐toe velocity (p = 0.01) and acceleration (p = 0.01) compared to both the left and right ankles of the controls. In addition, the uninjured ankles of the patients showed decreased ankle dorsiflexion and increased inversion during initial contact, loading response, mid‐stance, terminal stance, pre‐swing, and swing compared to the control group (p < 0.017).In patients with CAI, the injured and uninjured ankles were significantly different regarding angle‐toe angle, inversion‐eversion RoM, dorsiplantar flexion in mid‐stance, inversion‐eversion at initial contact and terminal stance as well as the pre‐swing and swing phases (The results suggest that unilateral CAI can affect gait biomechanics in the contralateral uninjured ankle. Left unaddressed, unilateral CAI may lead to increased morbidity to the contralateral uninjured side. When surgery is not preferred for the management of unilateral CAI, rehabilitation protocols should focus on both sides. Unilateral chronic lateral ankle instability affects gait biomechanics in the contralateral uninjured ankle.Mismanaged unilateral chronic lateral ankle instability may increase the risk of progressive disability to the contralateral uninjured side.When surgery is not preferred to manage chronic lateral ankle instability, rehabilitation protocols should focus on both sides.Unilateral chronic ankle instability affects the contralateral healthy ankle Ankle sprains are among the most prevalent injuries. A high percentage of individuals with ankle sprains will develop residual physical disability which may include chronic ankle instability (CAI). Accordingly, an estimated 15%–20% of the patients with acute ankle sprains may develop chronic lateral ankle instability CAI.Treatment of CAI includes conservative treatment or surgery that focuses mainly on the injured ankle with instability. Surgical treatment for these patients is usually considered after conservative treatment has failed to restore stability.Previous biomechanical research on patients diagnosed with CAI showed considerable changes in the kinematics and kinetics of the unstable ankle when compared to uninjured ankles in healthy individuals during gait.et al., patients with CAI showed inability to complete jumping and landing within 2 weeks and poorer dynamic postural control 6 months after a first‐time lateral ankle sprain. They showed that the single‐leg drop and drop vertical jump were important predictive inputs for CAI outcomes including dynamic postural control and patient self‐reported functions after 6 months.In a prospective study by Doherty Chinne and colleagues compared the ankle joint among patients with CAI and healthy controls. In this study, the authors showed that those with CAI had altered kinematics at specific points of the gait cycle.We hypothesized that the injured ankle in patients with CAI will affect the biomechanics of the contralateral uninjured ankle of these patients. The objectives of this in‐vivo biomechanical study were (i) to assess bilateral ankle kinematics in patients diagnosed with unilateral CAI, and (ii) to compare these findings with those found in healthy individuals. Accordingly, in this study, we compared the kinematics of the injured ankle joint of patients with CAI with that of healthy controls and their own contralateral uninjured ankles.The protocol of this case‐control study was approved by the Institutional Review Board of the Iran University of Science and Technology, Tehran, Iran (Registry no.: 2580373). Study participants were enrolled in three orthopaedic surgical clinics in Tehran, Iran. The protocol was explained to each participant and informed consent was obtained before entering the study. Inclusion criteria were: (i) individuals between 18 and 65 years old age; and (ii) suffering from unilateral CAI. The exclusion criteria were individuals with: (i) musculoskeletal disorders other than injuries of the lateral ligaments of the ankle complex, such as joint hyperlaxity, syndesmosis ligament injury, or deltoid ligament injury; (ii) neurological disorders such as neuropathies and lower limb paralysis; (iii) signs of pain or swelling of the lower extremity due to other injuries and not merely related to CAI; (iv) psychiatric disorders preventing appropriate cooperation; and (v) individuals who did not provide informed consent.A total of 15 individuals diagnosed with unilateral functional CAI were included in the patient group between November 2018 and October 2019. The diagnosis of CAI was made if patients had clinical symptoms of: instability, including giving way for more than 6 months on multiple occasions; a history of at least one ankle sprain within the last 12 months before referral; signs of lateral ankle ligaments injury in anterior drawer and talar tilt tests; radiographic and MRI images based on previously reported criteria.Anthropometric indices including height, weight, and body mass index (BMI) were measured. According to the Vicon™ Plug‐in‐Gait model ,2), leg absolute angle , angular velocities of the ankle‐toe (m/s), the angular acceleration of the ankle‐toe (m/s2), range of motion (RoM) in dorsi‐plantar flexion , and degree of eversion and inversion  were measured during the gait. Initially, all data were calculated in the X, Y, and Z axes. Data were extracted and classified using MatLab 7.04 .Overall ankle‐toe linear speed (m/s), overall ankle‐toe linear acceleration  was considered statistically significant.Data obtained from three‐axis measurements were analyzed using the SPSS version 21.0  and were reported as mean ± standard deviation (SD). One‐way ANOVA and Tukey's post hoc tests were used to test the hypotheses that unilateral CAI affects the kinematics of the healthy contralateral ankle during gait. Considering dorsiplantar flexion as our specific variable, as the effect size was a large number , the minimum sample size with respect to a power of 95% and type one error of 1% was estimated to be lower than 1. Decreasing the effect size to 2 and 3 resulted in a minimum sample size of 9 and 4, respectively. Thus, based on a previous publication,n = 15) consisted of eight males and seven females, with a mean age of 29.7 ± 10.5 years (range: 18–50 years) and BMI of 22.8 ± 6.9 kg/m2. The control group included nine males and six females with a mean age of 31.06 ± 7.31 years (range: 18–65 years) and BMI of 23.3 ± 2.8 kg/m2).The CAI group  as well as significant increases in inversion‐eversion RoM . Dorsiflexion position of the joint in unstable ankles decreased significantly during the midstance phase of the gait . Inversion‐eversion positioning of the ankle decreased significantly during initial contact  and terminal stance  but increased significantly during pre‐swing  and swing phases  and acceleration of movement during gait  were found to be significantly decreased in the CAI group  and left ankle of the control group . Moreover, dorsi‐plantar flexion and inversion‐eversion were significantly altered with a tendency to plantarflexion and inversion in all phases of the gait cycle including initial contact, foot flat, midstance, terminal stance, pre‐swing, and swing .There were a few limitations that should be taken into consideration. Study participants were asked to walk at their normal speed in their usual state in order to measure velocity and acceleration, which might have caused some bias in the assessment of kinematic variables as some studies have shown that kinematics could vary at different speeds of walking (walking The current study strongly suggests that unilateral chronic ankle instability can affect the kinematics of the contralateral uninjured ankle in patients with unilateral CAI. These changes may include ankle‐toe degree, the velocity of ankle movement, acceleration, and inversion‐eversion RoM. The uninjured ankles of such patients also had a significantly lower tendency towards dorsiflexion during gait when compared to individuals with bilaterally normal ankles. While early and appropriate surgical stabilization for unilateral CAI might be a rational way to prevent this issue, it is recommended that any rehabilitation protocol should include both the unstable and stable ankles.None declared.


As the detection of non-alcoholic fatty liver disease (NAFLD) is imperative for the prevention of its complications, we aimed to explore the predictive value of platelet to lymphocyte count ratio (PLR) and white blood cell count to mean platelet volume ratio (WBC/MPV) in relation to the occurrence of NAFLD among patients with obstructive sleep apnea–hypopnea syndrome (OSAHS).This was a cross-sectional study consisting of 351 patients with OSAHS (279 with and 72 without NAFLD). The logistic regression analysis was performed to estimate associations between PLR, WBC/MPV, and NAFLD. Finally, the receiver operating characteristic curve (ROC curve) was used to analyze the efficacy of PLR and WBC/MPV in NAFLD prediction.2), WBC/MPV and PLR as predicted factors  for NAFLD in OSAHS patients. Moreover, compared with WBC/MPV, PLR, FLI, and APRI, a combination of WBC/MPV and PLR presented the largest AUC for the detection of NAFLD in BMI < 28 kg/m2 , and in age ≥ 60 years subgroup  in ROC analysis. Meanwhile, a combination of WBC/MPV and PLR presented the second largest AUC for the detection of NAFLD in all subjects , as well as in the age < 60 years subgroup , only ranked after FLI, suggesting the combination of WBC/MPV and PLR has a good predictive value for NAFLD in OSAHS patients.Compared to the OSAHS-only group, there was a rising trend in AHI and TS90% in the OSAHS + NAFLD group. And the logistic regression analysis identified average oxygen saturation (MaSO2 were closely related to the occurrence of NAFLD among OSAHS patients. Furthermore, our results highlighted the clinical combination of WBC/MPV and PLR levels could act as a simple and effective biomarker for screening NAFLD in patients with OSAHS.We confirmed that the levels of WBC/MPV, PLR, and MaSO Non-alcoholic fatty liver disease (NAFLD) is a spectrum ranging from non-alcoholic fatty liver (NAFL), to non-alcoholic steatohepatitis (NASH), to cirrhosis . NAFLD hThere is a growing body of evidence demonstrating a positive correlation between NAFLD and obstructive sleep apnea–hypopnea syndrome (OSAHS) , 5. Of nA series of studies have shown that NAFLD was closely linked to subclinical inflammation , 8, and Platelet to lymphocyte count ratio (PLR) is a novel biomarker that has been initially proposed as an ideal indicator of systemic inflammation –13. ReceThe study cohort comprised individuals who attended our sleep center because of snoring, excessive daytime sleepiness, or other related symptoms, and were finally diagnosed with OSAHS by polysomnography between January 2016 and December 2020. The exclusion criteria included the following: (1) chronic obstructive pulmonary disease, bronchial asthma, interstitial lung disease, and other chronic lung diseases; and (2) severe heart failure, stroke, and other severe cardiovascular and cerebrovascular diseases; and (3) malignant tumor or major physical or mental illness; and (4) hepatic diseases such as viral hepatitis, autoimmune liver disease, and drug-induced liver disease; and (5) immune or hematological diseases such as rheumatoid arthritis; (6) acute and chronic infections; and (7) anti-platelet drugs used in the last month; and (8) excessive drinking ; and (9) other sleep disorders, such as narcolepsy and restless leg syndrome, etc.; and (10) sleep apnea attributable to other causes, such as hypothyroidism and central and mixed sleep apnea; and (11) history of previous CPAP treatment; and (12) history of previous splenectomy. The study was approved by the First Affiliated Hospital of Fujian Medical University  and all participants gave their written informed consent after a full explanation.2). Waist circumference  and neck circumference  were measured with a tape. In addition, every subject completed an Epworth sleepiness scale (ESS) using a well-validated Chinese version with the score ranging from 0 to 24, and it was considered daytime sleepiness when ESS score was ≥ 10 [All participants completed a detailed questionnaire on history of smoking and alcohol consumption, medical history , and medications, and physical examination. Anthropometric measurements including height and body weight were obtained with the participants wearing light clothing. The body mass index (BMI) was calculated as body weight/ height squared (kg/mwas ≥ 10 .0.953×ln(triglycerides)+0.139×BMI+0.718×ln(GGT)+0.053×waistcircumference−15.745)/(1 + e0.953×ln(triglycerides)+0.139×BMI+0.718×ln(GGT)+0.053×waistcircumference−15.745) × 100 , APRI = /platelets (109/L) × 100.Venous blood was taken the morning after polysomnographic evaluation. Blood routine, liver function, triglyceride (TG), total cholesterol (TC), and fasting glucose were tested in all patients. Blood routine was detected by Hitachi H-7600 autoanalyzer produced by Japan Co., Ltd., and blood biochemistry was performed using a Modular P800 autoanalyzer . PLR measured platelet count to lymphocyte count, and WBC/MPV measured white blood cell count to mean platelet volume. Platelet-related parameters including platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), average concentration of platelet contents (MPC) were also assessed. FLI and APRI were calculated using the following formulas , 22: FLI2, MaSO2, and TS90%, were also assessed. All PSG studies were scored according to the criteria of the American Academy of Sleep Medicine published in 2012 [Overnight polysomnography  was conducted to diagnose OSAHS. Electroencephalography, electrooculography, electromyography, and electrocardiography were performed during polysomnography, and the variables assessed being as follows: oronasal airflow, thoracic and abdominal respiratory efforts, and pulse oxygen saturation. AHI was defined as the number of episodes of apnea and hypopnea per hour of sleep. ODI was defined as number of episodes of oxyhemoglobin desaturation ≥ 3% from the immediate baseline per hour of total sleep time. Other variables, including LaSO in 2012 . The sevAbdominal ultrasonography was performed by the trained sonographers using a Toshiba SSA-660A instrument  with a 2–5 MHz curved array probe. According to the revised 2018 NAFLD definition and treatment guidelines, diagnosAll statistical analyses were carried out with IBM SPSS Statistics for windows (Version 25.0 IBM Corp. Released 2017). Armonk, NY). Normally distributed data were expressed as means ± standard deviations, while skewed data were expressed as medians with interquartile range (IQR). Categorical data were expressed as proportions (percentage). Using the χ2 test for categorical data, the independent t-test for normally distributed data, and the Mann–Whitney U test for skewed data, the differences between groups with and without NAFLD were analyzed. Using Spearman's rank correlation coefficients, the relationships between platelet-related parameters and relevant factors were evaluated. An examination of the association between platelet-related characteristics and NAFLD, which served as the dependent variable, was accomplished by means of a binary logistic regression analysis. Through the use of receiver operating characteristic curve (ROC) analysis, the predictive value of PLR, WBC/MPV, and the combination of the two indices was investigated. P < 0.05 was deemed statistically significant for all two-tailed tests.2. According to the ultrasound diagnosis of NAFLD, participants were allocated to OSAHS-only group (n = 72) and OSAHS + NAFLD group (n = 279). The anthropometric and polysomnographic characteristics of the patients were summarized in Table P < 0.05), whereas gender, ESS score,and medical history, such as hypertension and diabetes did not. Furthermore, no significant differences were observed in polysomnographic parameters, including AHI, LaSO2, MaSO2, TS90% and ODI. However, the OSAHS + NAFLD group tended to have a higher AHI and a longer TS90% than the OSAHS-only group, suggesting that apnea and intermittent hypoxia were more severe in the OSAHS + NAFLD group.Our study comprised 351 OSAHS patients including 283 males and 68 females, with a mean age of 51.32 ± 13.65 years and a mean BMI of 28.2 ± 11.1 kg/m2, MaSO2, TS90%, and ODI) were presented as median (interquartile range). Categorical variables were expressed as number (percentage). NC neck circumference, WC waist circumference, BMI Body mass index, ESS score Epworth Sleepiness Scale score, AHI apnea–hypopnea index, LaSO2 lowest O2 saturation, MaSO2 average O2 saturation, TS90% the percentage of total sleep time spent with SpO2 < 90%, ODI oxygen desaturation index.Normally distributed data were expressed as mean ± SD, skewed data , while had lower HDL-C levels than the OSAHS-only group . WBC/MPV, lymphocyte count, and white blood cell count were significant higher, while PLR was lower in OSAHS + NAFLD group. Nevertheless, there was a remarkable fact that no significant differences were observed in absolute value, such as PC, MPV, PDW, PCT and MPC . And the percentage of patients with upper limit of normal lymphocyte and white blood cell count was significant higher in OSAHS + NAFLD group than in OSAHS-only group (both P < 0.05), whereas there was no significant difference in the percentage of patients with upper limit of PC and MPV (both P > 0.05).Biochemical and hematological parameters were reported in Table P < 0.001), whereas WBC/MPV was positively correlated with NAFLD . In addition, PLR was positively correlated with MaSO2 , and WBC/MPV was positively correlated with ALT . Furthermore, platelet count, as expressions of platelet activation, had a negative correlation with LaSO2 , while MPV had a positive correlation with TS90% , suggesting sleep apnea and intermittent hypoxia played important roles in platelet activation.Table P = 0.018), followed by gender , BMI , MaSO2 , ALT , HDL-C , and PLR  after adjustment, reaching 7.559 , ranked only after FLI  and APRI . In the age subgroup analysis, the AUCs for the combination of WBC/MPV and PLR of age < 60 years old and age ≥ 60 years old with NAFLD were 0.729 (95% CI 0.652–0.806) and 0.786 (95% CI 0.692–0.880), which were the highest in age ≥ 60 years subgroup and the second highest in age < 60 years subgroup, respectively. Compared with the other four parameters, the most sensitive parameter for predicting NAFLD was the combination of WBC/MPV and PLR in BMI < 28 kg/m2 subgroup, BMI ≥ 28 kg/m2 subgroup, age < 60 years subgroup, and in all subjects.The results of the ROC curve analysis of the WBC/MPV, PLR, the combination of WBC/MPV and PLR, FLI, and APRI corresponding to 95% CI were shown in Table 2 as risk factors, while PLR as a protective factor for NAFLD in OSAHS populations. In addition, a combination of PLR and WBC/MPV showed a good prediction capacity regarding NAFLD compared with WBC/MPV, PLR, FLI, and APRI. Further subgroup ROC analysis indicated a combination of PLR and WBC/MPV presented the largest AUC for the detection of NAFLD in BMI < 28 kg/m2 subgroup , and in the age ≥ 60 years subgroup .In this study, we evaluated platelet-related biomarkers as potential predictors of NAFLD among OSAHS participants. Logistic regression analysis identified WBC/MPV and MaSONAFLD has become more and more common worldwide, especially in the OSAHS populations, and it can result in a range of serious complications, including liver failure and even death , so if w2 was an independent risk factor for NAFLD, suggesting that nocturnal hypoxia played an important role in the development of NAFLD in OSAHS participants. According to previous studies, nocturnal hypoxia was linked with systemic inflammation. He et al. [Our study showed that AHI and TS90% were higher in the OSAHS + NAFLD group. Subsequent binary logistic regression analysis found that MaSOe et al.  developee et al. . Polotske et al.  studied e et al. –35.Platelets play a crucial role in liver injury and liver fibrosis. Ghafoory et al.  demonstr2, implying that PLR is linked to hypoxia in this research. Prior studies have shown that oxyhemoglobin desaturation is associated with platelet activation [PLR, a newly discovered sensitive index of the inflammation system in the body, is able to reflect the state of inflammation . PLR seetivation –41, and tivation . Furthertivation .WBC/MPV is usually used to predict thrombosis-related events, particularly in cardiovascular, cerebrovascular, and peripheral vascular diseases. There hasn't been any research done on the link between WBC/MPV, OSAHS, and NAFLD. We used WBC/MPV to predict NAFLD in OSAHS patients in a novel way since both OSAHS and NAFLD can lead to pathological changes in the blood system. Our research indicated that WBC/MPV ratio was greater in the OSAHS + NAFLD group, and the WBC/MPV ratio was an independent risk factor for OSAHS complicated with NAFLD. According to previous studies, patients with NAFLD exhibited higher white blood cell and platelet counts. The increased expression of inflammatory markers in NAFLD patients may promote thrombopoietin development, resulting in larger platelets in the bone marrow and platelet activation, which in turn causes liver damage, and creates a vicious cycle. In our research, we found that a combination of WBC/MPV and PLR can better predict the occurrence of NAFLD compared to PLR or WBC/MPV alone.2, and in the age ≥ 60 years subgroup. To be emphasized, there was no significant differences in the absolute value of platelet count and MPV. However, PLR and WBC/MPV, the composite indicator, have better performances in predicting NAFLD. We hypothesized that stress, changes in blood volume in vivo, and changes in specimen fluid volume during testing operations may affect absolute values of platelet count, lymphocyte count, white blood cell, and MPV, resulting in improved sensitivity and resistance to interference when using composite indicators for disease prediction.In this study, we also compared the efficacy of PLR, WBC/MPV, FLI, APRI, and the combination of WBC/MPV and PLR to predict the occurrence of NAFLD in patients with OSAHS. FLI and APRI were non-invasive scores widely used in the prediction of NAFLD , 22. AndThere are a few problems with this study. As a matter of fact, our study only included a limited number of patients, and each of those patients was only evaluated at a single location. Therefore, we were unable to avoid selection bias when gathering data. Second, the PLR and WBC/MPV ratios were evaluated using a single measurement at the time of admission for the preliminary diagnosis. In order to avoid interference brought on by measurement mistakes in the subsequent study, further blood procedures will be needed to carry out multiple times at a variety of time points. Third, because a liver biopsy was not possible, a diagnosis of fatty liver was made using liver ultrasonography rather than a biopsy of the liver. Despite the fact that a previous study found that ultrasonography had a sensitivity of 89% and a specificity of 93% for NAFLD, and that it was widely used in population-based studies because of its non-invasiveness and accessibility, ultrasound has limited sensitivity in individuals with an elevated BMI, and it does not reliably detect mild steatosis . Future PLR and WBC/MPV are closely related to liver inflammation in patients with OSAHS. PLR and WBC/MPC are potential risk factors for NAFLD. Furthermore, our findings highlighted the combination of PLR and WBC/MPV as an effective indicator of NAFLD in patients with OSAHS. Given the accessibility and simplicity of calculation, these indices could be widely used for screening NAFLD in individuals with OSAHS in clinical settings.


The nasal histopathology of HTLV-1 carriers with chronic rhinitis is unknown.To describe the histopathological features of HTLV-1 carriers with chronic rhinitis.Biopsies of nasal mucosa of ten HTLV-1 carriers with chronic rhinitis  were studied using a light microscope. Samples from ten patients with allergic rhinitis not infected with HTLV-1 were used as controls.p=0.01), while the basement membrane thickness was greater in controls (p=0.03). There was a trend towards less eosinophilia and edema among those infected with HTLV-1, without statistical significance (p=0.2). For the lymphocytic infiltrate, there was no difference between infected and not infected patients with allergic rhinitis (p=1.0). Subepithelial fibrosis associated to moderate or small number of lymphocytes were found in the two HTLV-1 carriers with non-allergic rhinitis.Subepithelial fibrosis was more pronounced in patients with allergic rhinitis infected with HTLV-1 (This study suggests HTLV-1 may modify the histopathology of allergic rhinitis, especially by promoting subepithelial fibrosis, and may be related to chronic non-allergic rhinitis with lymphocytic infiltrate. The Human T-lymphotropic Virus Type 1 (HTLV-1) is a human retrovirus with tropism for T-cells. Diseases such as adult T-cell leukemia and myelopathy are strongly associated with HTLV-1 infectionWhile HTLV-1 infection is associated to lymphocytic infiltration in the involved tissues, rhinitis allergic – the most common type of chronic rhinitis – and asthma are characterized by eosinophilic infiltration of the nasal and bronchial mucosa respectivelySome HTLV-1 carriers present respiratory symptoms suggestive of chronic rhinitis, but the characteristics of the nasal mucosa of these patients are unknown. To know them, therefore, is most desirable, even more so in the city of Salvador in the Brazilian Northeast, where HTLV-1 seroprevalence is the highest in the nation: 1.76%This study was approved by our institution's Ethics Committee and given permit number 09/2002; all participants signed an informed consent form.Eight asymptomatic HTLV-1 carriers diagnosed with untreated perennial allergic rhinitis were recruited at the Multidisciplinary HTLV-1 Ward to undergo nasal biopsy. The diagnosis of perennial allergic rhinitis was produced from the analysis of each patient's history and physical examination, supported by skin tests for local relevant aeroallergens. Additionally, two HTLV-1 carriers with chronic rhinitis of unknown etiology were analyzed; they were negative for local aeroallergens and their prevailing symptoms were nasal obstruction and coryza.Patients with intestinal parasites, deviated nasal septum, nasal polyps, viral hepatitis, mycobacterium infection, smokers, and subjects taking steroids and/or immunosuppressants were excluded.Surgical specimens from elective turbinectomy patients with allergic rhinitis and negative serology for HTLV-1 were used as controls. Therefore, this was a sample of convenience. According to the institution's procedures, the patients in this group used nasal topical steroids for three months before surgery and combined oral antihistamines for three weeks. These patients were kept on nasal steroids for ethical reasons, the same reason why patients without nasal complaints did not undergo nasal biopsy.The biopsy samples for HTLV-1 carriers with chronic rhinitis were obtained through the Fokkens modifiedBiopsy samples were fixated in 10% buffered formalin and embedded in paraffin. The 5μm slices were dyed in H&E, periodic acid-Schiff (PAS), and Sirius red, and were then observed in the light microscope by an experienced pathologist in a blinded fashion (EAR). Samples were categorized based on the method described by Shioda & Mishima (1966)Immunohistochemistry testing of inflammatory cells was done in two HTLV-1 carriers whose allergy tests were negative. The paraffin-embedded slices were analyzed using a panel of antibodies and the standard technique using streptavidin-biotin-peroxidasep<0.05.The Mann-Whitney test was used to compare mean ages, presence of lymphocytes, eosinophils, subepithelial fibrosis, basement membrane thickening, and nasal mucosa edema among HTLV-1 carriers with allergic rhinitis (case group) and patients with allergic rhinitis and negative serology for HTLV-1 (control group). Fisher's test was used to analyze gender differences. For all tests statistical significance was attributed when Three males and five females with allergic rhinitis and infected by HTLV-1 had ages ranging between 25 and 55 years (mean 44.5). One 55-year-old female patient also had asthma. In the group of allergic rhinitis patients not infected by HTLV-1 (control group), five patients were males and five were females. Their ages ranged between 22 and 56 years (mean 38.9). There was no statistically significant difference for gender and age among the patients with allergic rhinitis either infected or not by HTLV-1.The two non-allergic rhinitis patients infected by HTLV-1 were males aged 36 and 42 years.p=0.01), as seen in the comparison between p=0.03). HTLV-1 carriers tended to have less eosinophilia and edema, but the difference lacked statistical significance (p=0.2). There was no difference in terms of lymphocytic infiltrate between infected patients with allergic rhinitis and uninfected subjects (p=1.0). Epithelial lining alterations were similar for infected and uninfected patients.Nasal mucosa histology findings can be seen on Allergic rhinitis combined with HTLV-1 infection was associated with nasal mucosa subepithelial fibrosis in our study. Basement membrane thickening was observed at a greater degree in allergic rhinitis patients not infected by HTLV-1. Nasal mucosa subepithelial fibrosis was greater in HTLV-1 carriers with allergic rhinitis when compared to uninfected allergic rhinitis patients. The difference in the intensity of subepithelial fibrosis observed between the two groups cannot be explained solely by the antiinflammatory effect of the topical nasal steroids used by the control group, as such association is not established in the literature and the therapy was of short duration. For the patients with allergic rhinitis infected by HTLV-1, one must consider that both allergic rhinitis and HTLV-1 infection may be potentially associated with the fibrosis of the involved tissues. On the other hand, it is not clear why subepithelial basement membrane thickening was lesser in the allergic rhinitis patients not infected by HTLV-1.Montero et al. (2003) described basement membrane thickening and nasal mucosa subepithelial fibrosis in 92.3% and 92.4%, respectively, of individuals with allergic rhinitisThe chronic inflammation associated with HTLV-1 infection causes fibrosis to set in on the involved tissues. Patients with HTLV-1-related myelopathy have early leptomeningeal fibrosisHTLV-1 infection stimulates the production of GM-CSF, interferon gamma (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor (TNF-α), immune response type 1 cytokines, aside from IL-4, IL-5 and IL-10Concomitant HTLV-1 infection is associated with the scarce eosinophilia seen in the nasal mucosa of allergic rhinitis patients. This study showed a trend of less nasal eosinophilia in allergic rhinitis patients infected by HTLV-1 when compared to uninfected allergic rhinitis patients treated with steroids. Therefore, this study indicates that HTLV-1 infection may affect nasal eosinophilia to the extent that the findings in this group is, at least, similar to the findings seen in some individuals who were supposedly affected by the therapeutic effect of steroids. Contrary to subepithelial fibrosis, the nasal eosinophilic infiltrate seen in patients with allergic rhinitis may be reduced after only four weeks of treatment with steroidsSouza-Machado et al. (2005) found prevalence rates of atopy in HTLV-1 carriers of 14.9% against 29.7% in uninfected controlsThe two HTLV-1 carriers with allergic rhinitis had mononuclear infiltrate with a predominant presence of T-cells as confirmed by immunohistochemistry. Considering the thesis of the single airwayThis study indicates that HTLV-1 infection may modify the nasal histopathology of allergic rhinitis. This paper indicates that the coexistence of allergic rhinitis and HTLV-1 infection on one same individual may be associated with increased subepithelial fibrosis, less thickening of the subepithelial basement membrane, and a trend towards scarce eosinophilia. Nonetheless, the role of allergy and HTLV-1 infection concomitant to fibrosis on nasal mucosa cell counts require better characterization in future studies. We do not know if fibrosis and nasal lymphocytic infiltrate seen in HTLV-1 carriers are a new entity within the realm of rhinitis.


Secreted frizzled-related protein 1 (SFRP1) is a member of secretory glycoprotein SFRP family. As a primitive gene regulating cell growth, development and transformation, SFRP1 is widely expressed in human cells, including various cancer cells and fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA). Deletion or silencing of SFRP1 involves epigenetic and other mechanisms, and participates in biological behaviors such as cell proliferation, migration and cell pyroptosis, which leads to disease progression and poor prognosis. In this review, we discuss the role of SFRP1 in the pathogenesis of RA-FLS and summarize different experimental platforms and recent research results. These are helpful for understanding the biological characteristics of SFRP1 in RA, especially the mechanism by which SFRP1 regulates RA-FLS pyroptosis through Wnt/β-catenin and Notch signaling pathways. In addition, the epigenetic regulation of SFRP1 in RA-FLS is emphasized, which may be considered as a promising biomarker and therapeutic target of RA. Rheumatoid arthritis (RA) is an autoimmune-mediated chronic progressive disease and the synovium is the main target tissue. The main pathological features are persistent synovial hyperplasia and inflammation, which eventually lead to joint injury, cartilage destruction, and bone erosion , 2. FibrThe Notch and Wnt/β-catenin signaling pathways are two highly conserved and functionally closely related pathways that coordinate and regulate cell growth, differentiation, and proliferation in various tissues and are involved in the development of various diseases . SecreteOne gene may act on different signaling pathways, and the regulatory role of SFRP1 in Wnt/β-catenin and Notch signaling pathways may be related to the pathological mechanisms of different diseases and may be associated with the process of pyroptosis. Functional connections among genes, signaling pathways, and pyroptosis may also exist in RA-FLS, and the crosstalk between different pathways may play an important role in the pathology and development of RA. In this review, we have added a new section on the pathological mechanisms of RA. This manuscript focuses on the relationship between SFRP1, Wnt/β-catenin signaling pathway, Notch signaling pathway, and pyroptosis, and their involvement in the pathogenesis of RA-FLS. The epigenetic regulation of SFRP1 could be a promising RA biomarker and a therapeutic target.The Wnt signaling pathway is a complex signal transduction network that plays an important role in maintaining a balance between human growth and development . The Wntvia siRNA to exert therapeutic effects , and Gasdermins (GSDMs) protein families, accompanied by the release of a large number of pro-inflammatory factors, such as IL-1β and IL-18 . PyroptoSFRP is a protein that can be folded into two independent domains, the N-terminal and C-terminal domains. The N-terminal cysteine-rich domain region (CRD) can bind to FZD receptors through disulfide bonds; therefore, SFRP1 can act as a regulator of the Wnt/β-catenin signaling pathway , 69. GivThere is also a relationship between the Wnt/β-catenin and Notch signaling pathways and cell pyroptosis. Studies have shown that β-catenin interacts with NLRP3 and promotes its binding and that of ASC, thus activating the NLRP3 inflammasome and initiating the subsequent process of cell pyroptosis. When siRNA was used to inhibit β-catenin expression, activation of the NLRP3 inflammasome was also observed . This reIn summary, although the regulation of NLRP3-mediated cell pyroptosis by the Wnt/β-catenin and Notch signaling pathways has not been carried out in RA-FLS, its key role is based on observation in other diseases. We propose the following hypothesis: in RA-FLS, SFRP1 participates in NLRP3-mediated cell pyroptosis by regulating the Wnt/β-catenin and Notch signaling pathways Figure 4Tripterygium wilfordii Hook F, or methylation inhibitors and further develop drugs that potentially target SFRP1 to fill in the gaps related to RA-FLS therapy.FLS have always been considered an attractive therapeutic target for RA. However, no treatment that directly targets FLS has been approved. In this review, we systematically explain how SFRP1, Wnt/β-catenin signaling, Notch signaling, and cell pyroptosis independently affect the development of RA-FLS. Based on these theories, we propose that in RA-FLS, SFRP1 participates in NLRP3-mediated pyroptosis by regulating the Wnt/β-catenin and Notch signaling pathways, thereby affecting the progression of RA. Moreover, a preliminary study showed that SFRP1 was hypermethylated in RA synovial tissues. Thus, SFRP1 may serve as a potential target for RA treatment. Through the promotion of SFRP1, it is highly expressed in RA-FLS, so as to observe whether it can inhibit the activation of Wnt/β-catenin and Notch signaling pathway and the occurrence of pyroptosis, whether it can improve the inflammatory microenvironment of joint synovium and alleviate the symptoms of RA, which will be our main research work. In addition, to verify this hypothesis, our team is also planning to use traditional Chinese medicine, PJ and KW was responsible for the collection, collation of data, and writing of the original manuscript. CC, JZ, RZ, LXX, YJ, LSX, and YS were accountable for collection of data. SG, SS and DH were responsible for concept development and manuscript revision. All authors reviewed and accepted the final version of the manuscript. All authors contributed to the article and approved the submitted version.This work was funded by the National Natural Science Funds of China (82074234 and 82071756), Shanghai Chinese Medicine Development Office, National Administration of Traditional Chinese Medicine, Regional Chinese Medicine  Diagnosis and Treatment Center Construction Project-Rheumatology, State Administration of Traditional Chinese Medicine, National TCM Evidence-Based Medicine Research and Construction Project, Basic TCM Evidence-Based Capacity Development Program, Shanghai Municipal Health Commission, and East China Region-based Chinese and Western Medicine Joint Disease Specialist Alliance.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Prediction of bull fertility is critical for the sustainability of both dairy and beef cattle production. Even though bulls produce ample amounts of sperm with normal parameters, some bulls may still suffer from subpar fertility. This causes major economic losses in the cattle industry because using artificial insemination, semen from one single bull can be used to inseminate hundreds of thousands of cows. Although there are several traditional methods to estimate bull fertility, such methods are not sufficient to explain and accurately predict the subfertility of individual bulls. Since fertility is a complex trait influenced by a number of factors including genetics, epigenetics, and environment, there is an urgent need for a comprehensive methodological approach to clarify uncertainty in male subfertility. The present review focuses on molecular and functional signatures of bull sperm associated with fertility. Potential roles of functional genomics  on determining male fertility and its potential as a fertility biomarker are discussed. This review provides a better understanding of the molecular signatures of viable and fertile sperm cells and their potential to be used as fertility biomarkers. This information will help uncover the underlying reasons for idiopathic subfertility. There is an urgent need to increase the efficiency and sustainability of animal food production in the face of an ever-increasing world population . With liin vitro embryo production and embryo transfer), estrus synchronization protocols, and various feed additives  is a systematic method to assess the reproductive potential of a given bull, and current standards of BSE were adopted by STF . AccordiThere is ongoing research focused on the identification of new markers to estimate bull fertility. Evaluation of arterial blood flow to the testes through an ultrasonography is one of the potential methods to contribute to proper assessment of male fertility . BatissaBased on the current literature, it becomes clear that scientists have significant knowledge about male reproductive physiology but there is no single method or parameter that can precisely estimate bull fertility. This scenario indicates, therefore, that novel fertility markers are required, as well as more comprehensive methodologies and updated techniques for assessment of sperm quality and viability. Novel biomarkers  coupled with computational analyses can be used as integrated approaches to better understand spermatogenesis and sperm quality, and to predict male fertility. High throughput screening methods combined with traditional protocols could be a better approach to understand molecular, cellular, and physiological underpinnings of bull fertility. Better understanding of sperm molecular and functional signature associated with bull fertility using systems biology approach along with systems physiology concepts is expected to enhance both the fundamental science of reproduction and assisted reproductive technologies (ART).Sperm are formed in the seminiferous tubules after a complex series of mitotic and reductional divisions, starting from a reservoir of spermatogonium stem cells. In the process of spermatozoa formation, the structure of sperm chromatin changes in such a way that most histones are replaced by protamines, and sperm are thought to become transcriptionally inactive . This alResearchers have dedicated significant efforts to the task of mapping the complete proteome of sperm cells. Proteomic studies are more advanced in humans, where nearly 6,200 sperm proteins have been described so far, from the universe of estimated 7,500 proteins . It is dFor the bovine species, coverage of the global proteome of sperm has reached significant milestones but it is still limited, with almost 3,000 proteins being identified so far . As mentBos indicus vs. Bos taurus) and as such there is a need for discovering definitive biomarkers of bull fertility or sperm freezability based on sperm proteins. Such variations in studies about biomarkers of bull fertility have been also noticed when fertility-associated proteins of the seminal plasma were recently analyzed in a comprehensive review  . ProteinOver many years, scientists supposed that the great majority of the genome that is noncoding part of DNA was “junk” because no noticeable function had been identified for this portion . In receWhile there is no common consensus about the origin of RNAs in sperm, it is generally accepted that RNAs are left over molecules from spermatogenesis . The exaLipids are building blocks of cell membranes and consist of a large group of heterogeneous chemical compounds with varying structure and biological functions . NumerouThe bilayer of the sperm plasma membrane is predominantly made of phospholipids and fatty acids, and saturation levels of fatty acids could be a potential indicator for sperm parameters . PolyunsMetabolomics is an emerging technology for the discovery of biomarkers and provides a snapshot of biological processes through the measurement of metabolites and investigation of metabolomic pathways . Since m1H NMR) and revealed that taurine, isoleucine, and leucine of seminal plasma are potential biomarkers of bull fertility. Similarly, Initial metabolomics studies in reproductive studies were focused on the detection of oxidative stress markers  in human sperm, oocyte, and embryo . More reThe chromatin structure of spermatogonia consists of nucleosomes and each nucleosome is made of DNA wrapped around nuclear histones comprised of H2A, H2B, H3, and H4 . Such hiDuring the meiotic and post-meiotic stages of spermatogenesis, spermatids undergo a chromatin remodeling process to protect the paternal genome . This rePost-translational modifications of histones include acetylation, methylation, phosphorylation and ubiquitylation . Such moH3f3a and H3f3b genes. Their findings revealed that H3.3 is a potential marker for gametogenesis and fertilization. An inverse correlation was also reported between expression levels of testis-specific histone 2B (TH2B) and bull fertility  to protamine 2 (PRM2) in mature sperm is associated with DNA fragmentation, sperm motility, and sperm morphology . In addiThe technological advances achieved in the last decades in the areas of proteomics, metabolomics, transcriptome, and genomics, have allowed the identification of possible biomarkers related to bull fertility. All these have contributed to drawing a profile, or signatures of bull sperm associated with fertility that is of extreme importance to the cattle industry since many losses are related to low rates of return after insemination of cows. However, there is still a great divergence in the results obtained, mainly due to the methodology employed and the differences between Bos Taurus and Bos indicus. Therefore, high resolution mapping of semen from bulls with reliable fertility phenotypes using advanced techniques is needed for the discovery of sperm biomarkers of fertility for precision livestock reproduction and agriculture.


Meanwhile, we found much more greater autophagosomes in overexpressed-Wnt5A nasopharyngeal carcinoma cells by electron microscopy. Further mechanism exploration revealed that Beclin1 is the main target of Wnt5A, and knocking down Beclin1 can partially reduce Wnt5a-induced radiation resistance. By studying Wnt5A-mediated protective autophagy in promoting radiation resistance in nasopharyngeal carcinoma cells, we hope that the Wnt5A and Beclin1 can become effective targets for overcoming radiation resistance in the future.Wnt signaling pathways and autophagy play an essential role in tumor progression. Canonical Wnt signaling pathways in radiation resistance have been studied in the past, but it remains unclear whether the noncanonical Wnt signaling pathways can affect tumor radiation resistance through protective autophagy. Nasopharyngeal carcinoma, a particular subtype of head and neck squamous cell carcinoma, relies on radiation therapy. In this study, we found that radioactive rays could significantly promote the expression of Wnt noncanonical signaling pathways ligands in nasopharyngeal carcinoma, among which Wnt5A was the most markedly altered. We have demonstrated that Wnt5a can reduce the radiation sensitivity of nasopharyngeal carcinoma  Head and neck squamous cell carcinoma (HNSCC) is the seventh-largest tumor globally Radiation therapy plays a significant role in the radical and comprehensive treatment of head and neck squamous cell carcinoma. Nasopharyngeal carcinoma is sensitive to radiation therapy, the most crucial treatment method in premetastatic tumors The Wnt signaling pathways are divided into canonical and noncanonical signaling pathways. The non-canonical signaling pathways include the β‐catenin-independent WNT signaling pathways, planar cell polarity (PCP) signaling pathways and the Wnt/Ca+ signaling pathways 2+, Wnt5a can also function through canonical Wnt signaling pathways under certain conditions In addition to acting on noncanonical Wnt signaling pathways such as PCP and the Wnt/CaIn 1963, Christian de Duve first proposed autophagy, and in 2016, Yoshinori Ohsumi won the Nobel Prize for his research on the mechanism of autophagy. Autophagy is ancient and highly conserved catabolism that can form two-membranous vesicles (autophagosomes), engulfing cellular proteins and organelles, transporting them to lysosomes, and allowing cells to quickly adapt to a stressful or hostile environment. Autophagy is controlled by highly regulated signaling events at various cellular states and is induced by different signals and cellular stress. It is often thought that autophagy can prevent tumor progression; increased autophagy flow can promote tumor survival and growth once the tumor is formed. Autophagy enhancers have been reported to prevent tumor progression Earlier, we conducted in-depth research on the canonical Wnt/β‐catenin signaling pathways. We found that Wnt3a, as a canonical ligand of the Wnt/β-catenin signaling pathways, can be used as a biomarker for head and neck squamous cell carcinoma 2 incubator, and both were passaged and experimented with at the exponential phase.Nasopharyngeal carcinoma cell lines 6-10B, and CNE2 were purchased from the Cell Center of Central South University . The media were supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin, cultured in a 37 °C 5% COTo overexpress Wnt5a, we infect cells with lentivirus , stable cells are screened with puromycin for two weeks, and the efficiency of gene regulation is assessed by Western blotting. An empty vector was used as a control. For Beclin1 knockdown, three siRNA were used, and target sequences were as follows: siRNA 1:5′‐GGA GAT CTT AGA GCA AAT GAA‐3′, siRNA 2:5′‐GGA CAC GAG TTT CAA GAT CCT‐3′, siRNA 3:5′‐CCA ACG TCT TTA ATG CAA CCT‐3′. The siRNA 1, which is the most efficient, was used to design an shRNA and package lentiviral vector pLKO.1 (Addgene).The linear accelerator  offers a 6‐MeV electron beam of 300 cGy/min. A 1.5 cm compensation gel is covered in a cell culture vessel 100 cm from the radioactive source.After cells are irradiated with a gradient radiation dose, their radiation resistance is assessed by clonal survival. 6-well plates are inoculated with 600 cells per well, and different plates correspond to different radiation doses. After irradiation, the cells were cultured for 14 days, and the clonal survival rate (a colony with > 50 cells) was counted, as before We spread crawlers (12 mm) in a 24-well plate to seed cells. After six hours of incubation under 4Gy irradiation and non-irradiation control, the foci of γ-H2AX were compared. Statistical method for foci of γ-H2AX refers to the previous report 3, receive two doses of radiation for a total of 8 Gy. The control group was made sham‐irradiated. Then, we measured the mice's body weight and basic condition during the experiment. Tumor volume measured every 2-3 days (volume = length × width2/2). All rats were executed two weekends after the first radiation. All xenograft tumors were dissected, and weight was measured for statistical analysis.Athymic male nude mice were purchased from Hunan SJA Laboratory Animal Co., Ltd. . Animal Ethics Committee of Central South University . Inoculate the right hip back at 5-7 weeks, respectively (cells overexpressing Wnt5a and control), 2 million cells each. To be grown to 100 mmhttps://www.cbioportal.org/), immunohistochemistry from The Human Protein Atlas (https://www.proteinatlas.org/). The data were made using the mean ± SD, and a student's t-test was performed to calculate the statistical significance of differences between groups using GraphPad Prism. Survival curves were used by the Kaplan Meier method, and analyzed by the log-rank test. Correlation of gene expression (Wnt5a and Beclin1) was assessed using Pearson Correlation Coefficient. P‐value < 0.05 in a two‐tailed test makes sense.mRNA expression data from TCGA-HNSC  and Wnt non-canonical signaling pathways (represented by Wnt5A). Meanwhile, they all can mediate Beclin1, which improves autophagy levels and leads to radiation resistance. Still, it may have something to do with the environment the cells are in, the functions of the Wnt canonical signaling pathways and Wnt noncanonical signaling pathways in autophagy and radiation resistance are the independent effect is necessary to study further.There are 19 Wnt signaling pathways ligands in the human genome, and Wnt5A was the most strongly expressed ligand in the tumor center in early studies of head and neck squamous cell carcinoma Autophagy plays a vital role in induction of tumor development, stemness maintenance and therapy resistance At present, many reports have confirmed the feasibility of targeted therapy sensitization radiotherapy Supplementary figures.Click here for additional data file.


Giardia duodenalis, Cryptosporidium parvum, and Entamoeba histolytica. Thus, in the present work, an analysis was carried out looking for the components of the rRNA transcription machinery that are conserved in intestinal parasites and if these could be used to design new treatment strategies.Ribosome biogenesis is a key process in all living organisms, energetically expensive and tightly regulated. Currently, little is known about the components of the ribosomal RNA (rRNA) transcription machinery that are present in intestinal parasites, such as The different components of the rRNA transcription machinery were searched in the studied parasites with the NCBI BLAST tool in the EuPathDB Bioinformatics Resource Center database. The sequences of the RRN3 and POLR1F orthologs were aligned and important regions identified. Subsequently, three-dimensional models were built with different bioinformatic tools and a structural analysis was performed.C. parvum is the parasite with the fewest identifiable components of the rRNA transcription machinery. TBP, RRN3, POLR1A, POLR1B, POLR1C, POLR1D, POLR1F, POLR1H, POLR2E, POLR2F and POLR2H subunits were identified in all species studied. Furthermore, the interaction regions between RRN3 and POLR1F were found to be conserved and could be used to design drugs that inhibit rRNA transcription in the parasites studied.Among the protozoa examined, The inhibition of the rRNA transcription machinery in parasites might be a new therapeutic strategy against these microorganisms.The online version contains supplementary material available at 10.1007/s11686-022-00612-7. Giardia duodenalis and Cryptosporidium parvum are the most common pathogenic intestinal protozoan parasites with an annual incidence of about 10,000 cases each in the United States and Europe alone, whereas for Entamoeba histolytica, a worldwide annual incidence of 100 million cases is estimated [Intestinal protozoal infections are a major health problem, especially in developing countries, where poor household hygiene practices, inadequate sanitary facilities, and low socioeconomic conditions favor their spread . In partstimated . In genestimated . One aspstimated , 5, 6.G. duodenalis, C. parvum, and E. histolytica. Furthermore, special emphasis was placed on the interaction between RRN3 and POLR1F, which is a key step to link Pol I with the rest of the components of the transcriptional machinery and where anti-parasitic drugs might be designed.On the other hand, the efficient growth and proliferation of parasites require a balanced production of ribosomes for protein synthesis –10. NotaG. duodenalis (Assemblage A_isolate_WB), C. parvum (Iowa II) and E. histolytica (HM1-IMSS) were examined in the corresponding databases of the EuPathDB Bioinformatics Resource Center [Saccharomyces cerevisiae and the genome of Entamoeba dispar were also analyzed for comparative purposes.The amino acid sequences of the proteins involved in the initiation of rRNA transcription in humans were obtained from the UniProt Knowledgebase (UniProtKB)  using the Center  and usine Center  with defThe structural domains of rRNA transcription machinery proteins present in all organisms were predicted and analyzed using InterPro . MultiplG. duodenalis, two in C. parvum and three in both E. histolytica and E. parvum. Since TAFII12 orthologs were identified only in E. histolytica and E. dispar, G. duodenalis and C. parvum were the species with the fewest identifiable subunits of the SL1 transcription factor. RRN3 orthologs were found in the genome of all organisms, but the sequences of E. histolytica and E. dispar orthologs diverged widely. Regarding the UBF transcription activator, two orthologs were identified in G. duodenalis and three in both E. histolytica and E. dispar. No orthologs for this protein were found in C. parvum. The summary of the results is presented in Tables The only component of the TBP-TAF complex SL1 that was found in all the organisms analyzed was TBP, with one ortholog in G. duodenalis and C. parvum, but not in E. histolytica and E. dispar. Interestingly, no orthologs were found for the POLR2L subunit in E. dispar. In this way, E. dispar is the organism with the fewest identifiable components of RNA polymerase I. The summary of the results is presented in Tables Ortholog search for the 14 major subunits of RNA polymerase I was also performed. Thus, it was found that for the subunits POLR1A, POLR1B, POLR1C, POLR1D, POLR1F, POLR1H, POLR2E, POLR2F and POLR2H there is at least one ortholog in each species. In contrast, for the POLR1E, POLR1G and RPA3 subunits, no orthologs were found in any of the analyzed parasites. Orthologs of the POLR2K subunit were identified in C. parvum, the RRN3 orthologs had between 14.6% and 28.4% fewer amino acids than the human protein, but RRN3 HEAT repeats are conserved in all species studied. POLR1A orthologs in G. duodenalis and C. parvum had between 4.9% and 24.5% more amino acids than the human protein, but for the E. histolytica and E. dispar orthologs the number of amino acids was between 4.9% and 19.8% less than the human counterpart. Meanwhile, POLR1B orthologs from G. duodenalis and C. parvum were proteins with 6% to 13.4% more amino acids than human protein, but almost all orthologs from E. histolytica and E. dispar had similar amounts. In contrast, POLR1C orthologs in G. duodenalis and C. parvum maintained a similar number of amino acids as human protein, but orthologs in E. histolytica and E. dispar were proteins with 15.9% to 18% less amino acids. Most of the identified orthologs of POLR1H, POLR2E, POLR2F, and POLR2H in parasites were very similar in size to human and yeast proteins. A schematic representation of these data appears in Supplementary Fig. 1.Figure Despite poor sequence conservation Table , sequencC. parvum, a UBF ortholog was not found. UBF is not essential for the initiation of transcription in vitro, but it is essential for the formation of PIC in vivo and functions in the pre- and post-initiation steps [C. parvum exhibits other proteins with HMG (high mobility group) boxes whose specific function has not yet been characterized. Almost all the core subunits of Pol I were identified in intestinal protozoan parasites, only in E. histolytica no orthologs of POLR2K were found and in E. dispar orthologs of POLR2K and POLR2L. These last two mentioned subunits are shared with the other two DNA-directed RNA polymerases (RNA Pol I and RNA Pol III). Notably, the heterodimer POLR1E-POLR1G, which is required for RNA elongation by Pol I [E. histolytica [G. duodenalis and C. parvum, but not in the genomes of E. histolytica and E. dispar. However, previously Srivastava et al. [E. histolytica ortholog of RRN3 and of which there is a homologue in E. dispar. Differences in the components of the rRNA transcription machinery may be due to differences in the promoter, how the rDNA is organized in the genome of the parasites, and the number of copies, among other things. The way in which rDNA is organized in intestinal protozoan parasites varies between species, for G. duodenalis and C. parvum the classical conformation of repeats in tandem is maintained [E. histolytica, these genes are located on extrachromosomal circular DNA molecules [G. duodenalis has approximately 86 copies [C. parvum 5 copies [E. histolytica approximately 200 copies [G. duodenalis and C. parvum have not been identified, but that of E. histolytica has [G. duodenalis, the presence of binding sequences for TBP and TAF in the intergenic region of the rDNA were identified [Transcription of rRNA by Pol I is the key regulatory step in ribosome production and is tightly controlled by an intricate network of signaling pathways and epigenetic mechanisms . The traon steps , 27. Howby Pol I , was notby Pol I . In the by Pol I . For protolytica . Using ta et al.  reportedintained , 33, butolecules . Regardi6 copies , C. parv0 copies . Furthertica has . InteresThe interaction between RRN3 and the A43 subunit (POLR1F in humans) is essential for the recruitment of Pol I into the preinitiation complex in the rDNA promoter , 38. ImpSupplementary file1 Size and domains organization of conserved subunits in intestinal parasites of the rRNA transcription machinery. TBP (A), RRN3 (B), POLR1A (C), POLR1B (D), POLR1C (E), POLR1D (F), POLR1F (G), POLR1H (H), POLR2E (I), POLR2F (J), and POLR2H (K) (TIF 2638 KB)Below is the link to the electronic supplementary material.


Atypical chronic myeloid leukemia (aCML) is a rare disease that is currently classified under the myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) disease spectrum. MDS/MPN diseases are characterized by the absence of the Philadelphia (Ph) chromosome and the overlap between bone marrow fibrosis and dysplastic features. The Ph chromosome, resulting from BCR-ABL1 translocation, helps to distinguish aCML from chronic myeloid leukemia (CML). The currently reported incidence of aCML is imprecise because aCML is diagnosed primarily based on morphological features and other unspecified laboratory findings, and there is an especially high chance of under-diagnosis of aCML and other MDS/MPN diseases. Recent advances in next-generation sequencing (NGS) have allowed a greater understanding of the nature of aCML, providing better opportunities to achieve higher diagnostic accuracy and for the use of more targeted treatment to achieve better outcomes. Herein, we present a case of a 68-year-old woman who came to our hospital complaining of shortness of breath, fatigue, and weakness, who was found to have significantly increased leukocytosis, hepatosplenomegaly, and was negative for the Ph chromosome. Further investigations with NGS revealed mutations in ASXL1, GATA2, NRAS, and SRSF2 but not CSF3R. In addition to this, peripheral smear and bone marrow aspiration findings were suggestive of aCML based on specific morphological findings. Since the patient was ineligible for a stem cell transplant (SCT), symptomatic treatment was started with cell transfusion; however, the patient continued to have symptomatic anemia that required multiple transfusions. A trial with trametinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, was later started as a targeted therapy based on one of her genetic mutations. Interestingly, the patient’s blood counts stabilized, she reported feeling better, and she did not need any blood transfusions for four consecutive months during treatment with trametinib. Unfortunately, our patient later died from sepsis resulting from secondary infections. In light of the significant advancements in NGS, clinicians should always consider utilizing it as a helpful tool to not only establish a rare diagnosis of aCML but also to offer the best available targeted therapy when applicable. This might alleviate the burden associated with the poor prognosis of aCML. Chronic myeloid leukemia (CML) that is negative for the Philadelphia (Ph) chromosome has historically been considered a subtype of CML with a poor prognosis. In 2016, the World Health Organization released a new classification of myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) diseases that are negative for the Ph chromosome, including atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), and MDS/MPN-unclassified (MDS/MPS-U). The reported incidence of aCML is as low as one to two per 100 cases of confirmed CML, which are positive for the Ph chromosome . The mosOur patient was a 68-year-old female with multiple comorbidities, including but not limited to chronic obstructive pulmonary disease (COPD), hypothyroidism, asthma, diabetes, osteoarthritis, peptic ulcer disease, hypertension, obstructive sleep apnea, and previous history of grade 2 endometrial adenocarcinoma status following total abdominal hysterectomy, bilateral salpingo-oophorectomy, and radiation in 2008. She presented to our hospital with shortness of breath and reported feeling weak and fatigued, having dyspnea upon exertion, palpitations, chest heaviness upon exertion, night sweats, hot flashes, and unintentional weight loss of 23 lb over the past three months prior to presentation. The physical examination was positive for splenomegaly. The initial complete blood count (CBC) was significantly positive for leukocytosis with a total white blood cell (WBC) count of 495.36 TH/µL, hemoglobin of 9.1 g/dL, and a platelet count (PLT) of 95 TH/µL. Subsequent manual differential revealed 48% neutrophils, 2% blasts, 0% eosinophils, 0% basophils, 0% monocytes, 31% myelocytes, 11% metamyelocytes, 7% promyelocytes, and 1% lymphocytes. Biochemical analysis was positive for elevated uric acid and lactate dehydrogenase at 15.4 mg/dL and 4882 IU/L, respectively  revealed mutations in ASXL1, GATA2, NRAS, and SRSF2 without CSF3R or SETBP1 mutations. The patient was sent for evaluation by a local bone marrow transplant center. She was deemed not a good candidate for an allogeneic stem cell transplant due to a lack of social support and access to a 24-hour caregiver.2, Monday to Friday, was initiated in addition to continuation with hydroxyurea. Despite receiving a total of four cycles of decitabine in addition to hydroxyurea, she continued to have persistent anemia requiring blood transfusions. Repeated bone marrow biopsy showed dysmyelopoiesis and fibrosis with 13% blasts and, therefore, venetoclax was added to the regimen. The patient remained on venetoclax, hydroxyurea, and decitabine for approximately four months. The decision was made to discontinue venetoclax and hydroxyurea due to the patient’s worsening anemia thrombocytopenia, increasing blasts, and development of cardiac toxicity from venetoclax in the form of pericardial effusion and non-ischemic cardiomyopathy. Following six cycles of decitabine, and considering she harbored NRAS mutation based on the NGS result, she was ultimately started on a mitogen-activated protein kinase kinase (MEK) inhibitor, trametinib (2 mg), once daily only. Her blood counts subsequently stabilized, and she began to feel better and less fatigued. She did not require any blood transfusions for four months while on this therapy.The patient was started on hydroxyurea for the management of her symptoms; however, even with a subsequent increase in the dose of hydroxyurea that reached 1.5 g twice daily, her WBC count remained challenging to manage. Therefore, treatment with a hypomethylating agent with decitabine at 20 mg/mClostridium difficile infection. During this period of hospitalization, she required a blood transfusion and did not receive trametinib. Due to her debility and weakness, she was discharged to a nursing home. Shortly after that, she was admitted for injury secondary to falls, hypotension, and sepsis secondary to large decubitus ulcers. The patient had stopped taking trametinib since her previous hospitalization. Her WBC count was 108,000 TH/µL, and peripheral blasts had increased by 20%. The peripheral blood smear was significantly positive for transformation to acute leukemia with approximately 29% blasts. At this time, due to her considerable deconditioning and multiple medical comorbidities, the decision was made to not pursue cancer-directed treatment and to proceed with comfort care. Unfortunately, the patient died from septic shock secondary to an infected bed sore.Unfortunately, she was later hospitalized for approximately three weeks for sepsis secondary to pneumonia, encephalopathy, frequent falls, and a Clinical presentation and diagnostic criteriaThe most common presenting clinical scenario for aCML is related to the associated bone marrow (BM) depletion symptoms, including but not limited to anemia , thrombocytopenia , and BM-associated fibrosis  ,8. The iaCML is typically characterized by leukocytosis with a WBC count of more than 13 TH/µL, mainly neutrophilic with a left shift , less countable monocytosis (<10%), and basophilia (<2%) in the peripheral blood. Typically, aCML is associated with <20% blasts in the PS ,13. BM aMolecular pathogenesisThough the landscape of the molecular pathogenesis of MDS/MPN is yet to be clearly defined, the acute surge in NGS usage has led to a better understanding of MDS/MPN. There is no single mutation that can define a singular MDS/MPN disease, but certain mutations can be found at a higher percentage in certain types of MDS/MPN diseases, which can make diagnosis more feasible, especially if the morphological findings are vague. Moreover, certain mutations can guide tailored targeted therapy and serve as a prognostic factor. Genetic mutations in SETBP1, ASXL1, N/KRAS, SRSF2, and TET2 can be identified in more than 20% of aCML cases ,16,17.SETBP1 is considered a high-risk mutation of aCML. A retrospective study by Wang et al. investigated 134 patients diagnosed with either aCML or MDS/MPN-U disorders from seven large medical centers to evaluate which features may be characteristic for both groups. Interestingly, SETBP1 mutations were detected with a higher incidence in the subgroup of patients with highly elevated WBCs and with lower hemoglobin and platelet counts, a prognostic factor that is usually associated with poor prognosis . In addiTreatmentTo date, no defined algorithm or risk-stratified approach for aCML has been established. Because of the aggressive nature of aCML, the wait-and-watch approach typically cannot be applied in most cases. Hematopoietic stem cell transplantation (HSCT) has been reported in sporadic studies with inconsistent outcomes. In a retrospective study, Mittal et al. investigated a total of 20 patients  who underwent HSCT between 1991 and 2001 . Five paThere are no large control trials that have established the effectiveness of cytoreductive agents in treating aCML; however, based on their role in treating other myelogenous malignancies, they are usually recommended either as a bridge therapy until initiating the HSCT process or as palliative therapy for patients who are not eligible for HSCT . DiffereTargeted therapy has frequently been introduced in clinical practice of late. Though there is no defining genetic mutation for aCML yet, some targetable mutations can be used to tailor individual therapy plans. The main targetable mutations in aCML include NRAS, SETBP1, the rarely reported JAK2 VS17F, and CSF3R .Ruxolitinib has been successfully used in treating myelofibrosis and polycythemia vera patients harboring JAK2 VS17F mutations that are resistant to HU therapy ,37. BaseDasatinib, an SRC tyrosine kinase inhibitor, is another targeted therapy that targets CSF3R mutations, particularly CSF3R truncation mutations, based on in vitro trials . Though Trametinib, a MEK1/2 inhibitor, has shown promising results in in vitro trials when targeting mutated N/KRAS genes, leading to the downregulation of the MAPK pathway and prolonged survival rates in mice transplanted with mutated NRAS genes compared to untreated mice . In phasTo the best of our knowledge, this is the second published case report of a patient who received trametinib as a targeted therapy for aCML where a sustained response was achieved. Though our patient received trametinib for only four months, she was able to achieve stable blood counts throughout the entire therapy duration.Because of its low incidence and lack of standard care recommendations, the diagnosis and treatment of aCML are underdeveloped. To date, the only therapy that has shown some benefits in terms of survival benefits for aCML is HSCT, which is associated with a high rate of relapse due to late diagnosis and the aggressive nature of the disease. With new advancements in NGS, physicians are leaning more toward targeted therapy, which is currently under investigation, mainly in case series or small clinical trials.


Many neuroradiological and hemodynamic prognostic factors have been studied in newborns and infants with Vein of Galen aneurysmal malformation (VGAM), aiming to define the best therapeutic management. Severe presentation of VGAM, with high-output congestive heart failure, poor neurological status, and multiorgan failure, is known to be associated with adverse clinical outcomes and mortality. However, in the absence of established brain damage or signs of heart failure at birth, how can we try to predict both the short-term disease progression and outcome?To emphasize this key point in the management of VGAM, we share an illustrative case, see In our view, this case illustrates three essential points to contemplate in newborns presenting with VGAM. Firstly, cerebral damage from arteriovenous shunts may rapidly evolve in the early stages. Secondly, despite extensive brain damage, a newborn's clinical exam may be normal since the correlation between neuroimaging and clinical status is often unreliable at this age. Therefore, MRI is an essential tool for evaluating the disease progression. Thirdly, it is vital to identify the appropriate time window for treatment, balancing the risks and benefits of early embolization to prevent permanent brain damage.pseudo-feeders. Pseudo-feeders are abnormal, dilated branches of the M2 or M3 segments of the middle cerebral artery (MCA) in the Sylvian fissure that are not part of the choroidal system and that should not be considered as part of the VGAM itself. Indeed, these dilated arteries supply the normal brain and not the malformation. They have been previously described as a sign of severe vascular steal phenomena through the shunt, with venous loco-regional hypertension from both the shunt and right-side cardiac failure observed in postnatal (p = 0.003). Among the 17 patients with only pseudo-feeders visible on fetal MRIs and with no encephalomalacia, nine went on to develop encephalomalacia by the time of birth, over a mean time interval of 34 ± 18.6 days. Moreover, in prenatal presentation, when the fetal pseudo-feeders were unilateral, the encephalomalacia was always located on the same cerebral hemisphere and in the same vascular territory. In our illustrative postnatal case, while encephalomalacia was mainly located in the vascular territory of the pseudo-feeders, limited contralateral encephalomalacia was also visible. In fetuses with no pseudo-feeders visible on the MRIs, no brain damage was observed at birth. Finally, the presence of fetal pseudo-feeders on MRIs was associated with an elevated risk of severe heart failure at birth (p = 0.002) as well as severe pulmonary hypertension (p = 0.002).Are there findings that may help guide the difficult therapeutic pathway in babies with well-tolerated VGAM? We believe the answer is yes, by paying attention to ostnatal  and prenThis neuroradiological sign should therefore be treated as indicative of poor hemodynamics in fetuses and newborns. We do not believe that pseudo-feeders reflect vascular steal alone, but rather a combination of high-flow arteriovenous (AV) shunt, venous hypertension, and arterial steal, which, together, lead to progressive parenchymal damage and poor clinical outcomes. This pathophysiological setting is highly related to the systemic hemodynamic consequences of a low-resistance, high-flow cerebral lesion. The relevant venous return, causing dilation of the right heart chambers and pulmonary overflow, as well as the restrictive physiology of the left ventricle, with flow reversal in the aorta and right-to-left shunt through the foramen ovale and ductus arteriosus, account for the negative effects on cerebral blood flow and metabolism.In conclusion, pseudo-feeders identified on MRIs obtained at birth should alert physicians to the risk of poor cerebral hemodynamic status. In our illustrated case, MCA pseudo-feeders were clearly visible on the MRI performed at birth (indicated by arrows, Nowadays, historical neonatal scores that do not take into consideration cerebral MRI findings, especially the Bicetre neonatal evaluation score, are no longer appropriate in clinical practice. Early identification of relevant prognostic factors should help to improve the challenging management of fetuses and newborns with VGAM.


Frontiers Research Topic, we have put together an interesting series of articles on multiple aspects of how G protein-coupled receptors (GPCRs) and their associated G proteins signal in the nervous system. They range from describing novel drug targets, better understanding old ones to exploring how GPCRs organize into hetero-multimers as well as the analytic frameworks to capture all this meaningfully. Cellular signaling in the nervous system is complicated. While perhaps obvious, it is also true! This complexity is reflected in a need to better understand the particular contexts of cells in the brain regarding how signaling systems are arranged and how to approach them as drug targets.In this collection in Tse and Wong describe various computational approaches to capture dimerization interfaces of known heterodimers of the melatonin receptors, MT1/MT2, MT1/GPR50, MT2/GPR50, and MT2/5-HT2C using homology modeling and membrane protein docking analyses. Understanding dimer interfaces is a critical step to being able to target such heterodimers pharmacologically. Next, Lillo et al. add to our understanding of heterodimers between ghrelin and CB1 cannabinoid receptors in the striatum, demonstrating how they mutually regulate signaling driven by their respective ligands and that they are in fact upregulated developmentally in the offspring of mice exposed to a high fat diet. Much remains to be learned about the impact of GPCR homo- and heterodimerization.One of the complexities is that GPCRs assemble into both homo- and heterodimers [reviewed in Rozenfeld and Devi , BorrotoDegrandmaison et al. highlight the use of knock-in models to tag endogenous GPCRs for proteomic analysis. Such approaches combine all the power of modern proteomic techniques while limiting expression to endogenous levels and localizing in the correct cellular and subcellular compartments. In a distinct approach, some aspects of signaling important for neuropathic pain are described by Xie et al. It is clear that GPCRs impact Nf-kB signaling in the immune and nervous systems [reviewed in Fraser . TH was the holder of the Canadian Pacific Chair in Biotechnology.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.