Targeting adenocarcinoma and enzalutamide­resistant prostate cancer using the novel anti­androgen inhibitor ADA­308.

Prostate cancer (PCa) is the leading cause of cancer­related death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA­308 was evaluated through in vitro assessments of AR activity and cell proliferation, alongside in vivo studies. ADA­308 has emerged as a promising candidate, demonstrating potent inhibition of AR­sensitive adenocarcinoma as well as ENZ­resistant PCa cell lines. The results of the study revealed that ADA­308 effectively blocked AR activity, including its nuclear localization, and inhibited cell proliferation in vitro. Furthermore, ADA­308 demonstrated notable efficacy in vivo, with a robust antitumor response in ENZ­resistant models. These findings establish the role of ADA­308 as a potent AR inhibitor that overcomes resistance to AR­targeted therapies and highlights its potential as a novel therapeutic approach in advanced PCa management.

Jejunal Gastrointestinal Stromal Tumor Presenting as Hemorrhagic Shock.

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract. Intermittent GI bleeding is the most common manifestation. Massive GI bleeding leading to syncopal episodes and hemorrhagic shock is a rare presentation of these tumors. Herein, we describe a case of a jejunal GIST presenting as massive bleeding.

Effectiveness of mobile health intervention for non alcoholic fatty liver disease- A meta analysis of randomized controlled trials.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Lifestyle modification is the mainstay of management, however, most patients find it difficult to significantly modify their lifestyle. Mobile health is an innovative healthcare system that has an established role in treating chronic diseases like asthma, cancer and cardiovascular disease. Hence, we conducted an updated meta analysis to evaluate the efficacy of mobile health intervention (mHI) for NAFLD. METHODS: Literature search of five electronic databases was performed from the inception of the paper till 15th May, 2024. Studies were included if they met the inclusion criteria; Randomized controlled trials evaluating use of mHI along with standard care in comparison to standard care only for patients with NAFLD over 18 years. Primary outcomes of interest included changes in weight, body mass index (BMI), and liver markers from baseline to post intervention. Risk of bias was evaluated using the Cochrane bias assessment tool while the Mantel-Haenszel Random-effects model on Review manager was used to pool outcomes. RESULTS: Outcomes were pooled from 7 RCTs comprising a total of 621 participants. There was a significant decrease in weight (P < 0.0001), aspartate aminotransferase (AST) (P = 0.002) and alkaline aminotransferase (ALT) (P = 0.0009) from baseline to follow-up in the intervention group as compared to the control group. However, the reduction in BMI was found to be non-significant (P = 0.64). CONCLUSION: Our meta analysis reports that mHI plays an important role in significantly reducing weight and liver markers in patients with NAFLD. Considering that the improvement of these factors plays a key role in the management of the disease, mHI could be the key towards paving better outcomes for patients with NAFLD.

Cell-Permeable Fluorescent Sensors Enable Rapid Live Cell Visualization of Plasma Membrane and Nuclear PIP3 Pools.

Phosphoinositides, phospholipids that are key cell-signal mediators, are present at very low levels in cellular membranes and within nuclei. Phosphatidylinositol-(3,4,5)-trisphosphate (PIP3), a phosphoinositide barely present in resting cell membranes, is produced when cells receive either growth, proliferation, or movement signals. Aberrant PIP3 levels are associated with the formation of cancers. PIP3 pools are also present in the nucleus, specifically in the nucleolus. However, questions related to the organization and function of this lipid in such membraneless intranuclear structures remain unanswered. Therefore, chemical sensors for tracking cellular PIP3 are invaluable not only for timing signal initiation in membranes but also for identifying the organization and function of membraneless nuclear PIP3 pools. Because PIP3 is present in the inner leaflet of cell membranes and in the nucleus, cell-permeable, rapid-response fluorescent sensors would be ideal. We have designed two peptide-based, water-soluble, cell-permeable, ratiometric PIP3 sensors named as MFR-K17H and DAN-NG-H12G. MFR-K17H rapidly entered into the cell cytoplasm, distinctly reporting rapid (<1 min) time scales of growth factor-stimulated PIP3 generation and depletion within cell membranes in living cells. Importantly, MFR-K17H lighted up inherently high levels of PIP3 in triple-negative breast cancer cell membranes, implying future applications in the detection of enhanced PIP3 levels in cancerous cells. On the other hand, DAN-NG-H12G targeted intranuclear PIP3 pools, revealing that within membraneless structures, PIP3 resided in a hydrophobic environment. Together, both probes form a unique orthogonally targeted combination of cell-permeable, ratiometric probes that, unlike previous cell-impermeable protein-based sensors, are easy to apply and provide an unprecedented handle into PIP3-mediated cellular processes.

Barriers to Completing Preoperative Hair Removal for Penile Inversion Vaginoplasty.

Penile inversion vaginoplasty (PIV) is a gender-affirming surgical procedure where the skin of the penis and scrotum is reconstructed into the neovaginal lining. To prevent hair-bearing skin from becoming incorporated into the neovaginal canal, transgender patients are encouraged to undergo hair removal of their external genitalia. The goal of this preoperative hair removal is to minimize the risk of potential hair-related complications after vaginoplasty. To better support patients seeking preoperative hair removal and identify current treatment barriers, we surveyed patients about their progress and satisfaction with hair removal. A cross-sectional survey was constructed to assess patient experiences with hair removal in advance of PIV. Sixty-seven patients met the inclusion criteria, of which 46 participated (68.7%). Both laser hair removal (LHR) and electrolysis were used. Although all patients had completed some preoperative hair removal at the time of survey (average of 14 sessions), the cohort completed only two-thirds of their total expected hair clearance. Multiple peri-procedural pain management therapies were employed, but overall satisfaction with pain management was low (57.4 ± 5.0 out of 100). LHR was associated with significantly lower procedural pain compared to electrolysis (p < .001). The average global satisfaction with the hair removal process was 57.9 ± 5.7 and incidents of mistreatment were associated with a statistically significant reduction in overall satisfaction (p = .02). Most patients felt that hair removal was important prior to surgery. Overall, LHR and electrolysis were both utilized as effective preoperative hair removal modalities; however, LHR has better pain tolerability than electrolysis.

Burkholderia-associated polymyositis.

A diagnosis of polymyositis can readily be made when there is a typical history of proximal muscle weakness together with clinical findings, and there is corroboratory evidence in the form of elevated creatine kinase lactate dehydrogenase, aldolase, and serum glutamic-oxaloacetic transaminase (aspartate aminotransferase). A muscle biopsy usually helps in making the confirmatory diagnosis. A female in her 50s presented with non-healing multiple deep necrotic ulcers with muscle weakness. The initial possibility of vasculitis ulcers remained. Later, this proved to be a case of polymyositis with mildly elevated creatine kinase (which is usually not the case), atypical skin manifestations (usually there is no skin involvement), and negative extended myositis specific antibody panel with the growth of Burkholderia cepacia (perhaps the triggering factor). Hence, polymyositis can present with a myriad of atypical findings. Thus, thorough clinical examination and an integrated approach are necessary for early identification and treatment of the disease.

Interfacial nanoarchitectonics of nickel phosphide supported on activated carbon for transfer hydrogenation of nitroarenes under mild conditions.

Metal phosphides are promising catalysts for hydrogenation reactions due to their unique ability to generate active hydrogen species which are essential for desired reactions. In this work, the hydrogenation potential of nickel phosphide (Ni2P) is explored for the transfer hydrogenation of aromatic nitro compounds using hydrazine hydrate as hydrogen source. The Ni2P was supported on activated carbon (AC) to facilitate highly exposed active reaction sites. The as-synthesized Ni2P-AC catalyst showed excellent catalytic potential for the hydrogenation of nitro compounds to corresponding amines with 100% conversion efficiency and resulted in excellent yields. The reaction conditions were optimized by varying different reaction parameters, such as time, temperature, solvents, catalyst amount and hydrogen sources. The developed reaction protocol is highly selective for nitro compounds having reduction susceptible functional groups like -Cl, -Br, -CHO, etc. The structure-activity relationship of the Ni2P-AC was also examined which suggested that both acidic and basic sites present in Ni2P-AC catalyst plays crucial role in hydrogenation reaction. Besides, an in-depth insight into the reaction mechanism illustrates that the reaction proceeds via N-phenyl hydroxylamine as the reaction intermediate. In addition, decent recyclability and stability of Ni2P-AC catalyst demonstrates its highly versatile nature for potential large-scale applications. The use of highly efficient Ni2P-AC catalyst for hydrogenation reactions can lead the way towards sustainable and effective industrial organic catalysis.

A Recent Advance on Phytochemicals, Nutraceutical and Pharmacological Activities of Buckwheat.

Buckwheat, a member of the Fagopyrum genus in the Polygonaceae family, is an ancient pseudocereal with noteworthy nutraceutical properties that have been relatively less explored. This crop holds great promise for the future due to its gluten-free protein, wellbalanced amino acid profile, and the presence of bioactive flavonoids that promote good health. With its gluten-free nature and a combination of beneficial nutritional components, buckwheat shows significant potential for a variety of health benefits. The objective of the present review aims to explore various nutritional and pharmacological properties of buckwheat. With the help of various search engines Pubmed, Google and Semantic Scholar, research and review papers. Data were analyzed and summarized in a comprehensive review. A fascinating spectrum of nutritional and pharmacological activities of common buckwheat and Tartary buckwheat were explored such as antidiabetic, anti-inflammatory, neurological disorders, antiobesity, anticancer, cardiovascular agents and many more. This review provides a concise overview of the current understanding of the chemical composition of both common buckwheat and Tartary buckwheat and the captivating spectrum of pharmacological activity and also underscoring their immense potential for future advancements.

Beneath the Layers: Deciphering the Molecular Pathways, Therapeutic Avenues, and Neurological Connections of Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are a heterogeneous group of malignancies that have long posed challenges in terms of diagnosis, treatment, and management. This narrative review provides a comprehensive exploration into the multifaceted realm of STS, spanning from its historical origins to the latest advancements in research and clinical care. We delve into the molecular intricacies of STS, highlighting the genetic and epigenetic aberrations that drive these tumors. The review emphasizes the neurological implications of STS, a relatively underexplored area, shedding light on the interplay between tumor biology and neural processes. The evolving therapeutic landscape is discussed, with a focus on the promise of targeted therapies, immunotherapy, and precision medicine. A significant portion is dedicated to the patient-centric approach, underscoring the importance of holistic care that addresses both the physical and psychological needs of STS patients. Furthermore, we highlight the gaps in current research and clinical practices, offering insights into potential avenues for future exploration. This review serves as a valuable resource for clinicians, researchers, and the broader scientific community, encapsulating the current state of STS knowledge and pointing toward future directions in this dynamic field.

Schistosoma japonicum Associated Colorectal Cancer and Its Management.

BACKGROUND: An association between Schistosoma japonicum and colorectal cancer in humans has been known since a long time; however, this association remains understudied and lacks comprehensive experimentation support. OBJECTIVE: Various epidemiological and pathological studies have established the role of chronic inflammation as a major factor behind the induction of colorectal cancer. The aim of this review is to present the current knowledge on the association of Schistosoma japonicum with colorectal cancer. RESULT: Mechanisms which lead to induction and progression of colorectal cancer are highlighted along with diagnosis and treatment for the same. Further, various methodologies, including mass drug administration, use of new drugs and vaccines, role of apoptosis, and histone-modifying enzymes, have been described which can either prevent the schistosomal infection itself or can check it from reaching an advanced stage. CONCLUSIONS: Epidemiological, clinical, pathological and surgical studies suggest that Schistosoma japonicum is responsible for induction of colorectal cancer. However, thorough clinical studies are required to support and globally accept this notion. Further, methodologies highlighted in this work can be employed in order to take care of schistosomal infection or address the cancer induction and progression.

Urethroplasty Outcomes for Pars Fixa Urethral Strictures Following Gender-affirming Phalloplasty and Metoidioplasty: A Retrospective Study.

OBJECTIVE: To evaluate outcomes of three urethroplasty techniques for pars fixa (PF) urethral strictures and provide a treatment algorithm based on stricture characteristics. The PF is an essential anatomic region of the neourethra created in gender-affirming phalloplasty and metoidioplasty. Urethral strictures in this region present a reparative challenge given its unique anatomy and vascularization. METHODS: A total of 41 urethroplasties performed on 41 patients between March 2018 and June 2021 were reviewed at two surgical centers. A Heineke-Mikulicz (HM) repair was done for strictures under 20 mm when the proximal and distal urethral segments were mobile and supported a tension-free closure. Substitution urethroplasty with ventral onlay buccal mucosal graft was utilized for strictures under 40 mm not suitable for HM repair. Complex or long (≥40 mm) strictures were treated by two-stage Johansen urethroplasty. Success of each surgical approach was defined by a minimum of 12-month follow-up without the need for a repeat intervention. RESULTS: Mean follow-up was 30.2 months (range: 12.4-52.0 months). Mean stricture length was 16.9 mm (range: 2-55 mm). Most strictures (46%) were located at the distal PF. HM urethroplasty had a success rate of 44% (n = 16). Substitution urethroplasty had a success rate of 92% (n = 13). Two-stage Johansen urethroplasty had a success rate of 75% (n = 12). CONCLUSION: The success rates of PF urethral stricture repair ranged from 44% to 92% depending on the surgical approach, and the best reparative procedure depends on stricture length, severity, and local tissue mobility.

Novel vs. modified platelet-rich plasma therapy for hair loss treatment: a systematic review and meta-analysis.

Platelet-rich plasma (PRP) therapy, is a stand-alone therapy or is used in combination with other treatments for the treatment of androgenic alopecia. The purpose of this meta-analysis was to compare the improvement in hair density seen, when PRP was used alone and when used as an adjunct. Methods: Conforming to systematic review and meta-analysis recommendations, we performed a meta-analysis of relevant articles in multiple databases, from inception till May 2022. Randomized clinical trials were included that evaluated the use of PRP alone or used PRP as an adjuvant with previously used therapies. Hair density data at the start of treatment and follow-up after 3 and 6 months was used for analysis. Results: A review of 255 articles included nine studies, for a cumulative data set of 230 individuals. In comparison to the placebo, stand-alone PRP therapy resulted in a significant increase in hair density (MD=25.39, P<0.00001.) PRP combination therapy also showed marked improvement in hair density compared to placebo (MD=34.38, P=0.002.) When comparing stand-alone PRP to combination therapy, MD=36.16, and MD=34.63 was observed for the two groups, respectively. Conclusions: The results of this meta-analysis reaffirm previous studies that suggest the role of PRP in improving hair density in AGA; however, the results cannot justify the use of PRP-combined therapy. Stand-alone PRP therapy should be considered in the management protocols for both men and women, whereas more studies and may be, different combination therapies are required before combined therapy can be included in the management guidelines for AGA.

Vaginal self-lubrication following peritoneal, penile inversion, and colonic gender-affirming vaginoplasty: a physiologic, anatomic, and histologic review.

INTRODUCTION: Vaginal self-lubrication is central to the sexual satisfaction and healthy genitourinary function of patients who have undergone gender-affirming vaginoplasty (GAV). Secretory capacities of different neovaginal lining tissues have been variably described in the literature, with little evidence-based consensus on their success in providing a functionally self-lubricating neovagina. We review the existing neovaginal lubrication data and the anatomy, histology, and physiology of penile and scrotal skin, colon, and peritoneum to better characterize their capacity to be functionally self-lubricating when used as neovaginal lining. OBJECTIVES: The study sought to review and compare the merits of penile and scrotal skin grafts, spatulated urethra, colon, and peritoneal flaps to produce functional lubrication analogous to that of the natal vagina in the setting of GAV. METHODS: We conducted a systematic review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Medline, EMBASE, ClinicalTrials.gov, and the Cochrane Library databases were searched for peer-reviewed studies published prior to December 12, 2022, that (1) included data specific to transfeminine individuals; (2) were full-text randomized controlled studies, case reports, case series, retrospective cohort studies, prospective cohort studies, qualitative studies, and cross-sectional studies; and (3) included specific discussion of vaginal lubrication or fluid secretion following GAV utilizing penile skin, colonic tissue, or peritoneum. RESULTS: We identified 580 studies, of which 28 met our inclusion criteria. Data on neovaginal lubrication were limited to qualitative clinician observations, patient-reported outcomes, and satisfaction measures. No studies quantifying neovaginal secretions were identified for any GAV graft or flap technique. Anatomically, penile and scrotal skin have no self-lubricating potential, though penile inversion vaginoplasty may produce some sexually responsive secretory fluid when urethral tissue is incorporated and lubricating genitourinary accessory glands are retained. Colonic and peritoneal tissues both have secretory capacity, but fluid production by these tissues is continuous, nonresponsive to sexual arousal, and likely inappropriate in volume, and so may not meet the needs or expectations of some patients. The impact of surgical tissue translocation on their innate secretory function has not been documented. CONCLUSIONS: None of penile/scrotal skin, colon, or peritoneum provides functional neovaginal lubrication comparable to that of the adult natal vagina. Each tissue has limitations, particularly with respect to inappropriate volume and/or chronicity of secretions. The existing evidence does not support recommending one GAV technique over others based on lubrication outcomes. Finally, difficulty distinguishing between physiologic and pathologic neovaginal fluid secretion may confound the assessment of neovaginal self-lubrication, as many pathologies of the neovagina present with symptomatic discharge.

Brevicillin, a novel lanthipeptide from the genus Brevibacillus with antimicrobial, antifungal, and antiviral activity.

AIM: This study was aimed to determine antimicrobial and antiviral activity of a novel lanthipeptide from a Brevibacillus sp. for disinfectant application. METHODS AND RESULTS: The antimicrobial peptide (AMP) was produced by a bacterial strain AF8 identified as a member of the genus Brevibacillus representing a novel species. Whole genome sequence analysis using BAGEL identified a putative complete biosynthetic gene cluster involved in lanthipeptide synthesis. The deduced amino acid sequence of lanthipeptide named as brevicillin, showed >30% similarity with epidermin. Mass determined by MALDI-MS and Q-TOF suggested posttranslational modifications like dehydration of all Ser and Thr amino acids to yield Dha and Dhb, respectively. Amino acid composition determined upon acid hydrolysis is in agreement with core peptide sequence deduced from the putative biosynthetic gene bvrAF8. Biochemical evidence along with stability features ascertained posttranslational modifications during formation of the core peptide. The peptide showed strong activity with 99% killing of pathogens at 12 µg ml-1 within 1 minute. Interestingly, it also showed potent anti-SARS-CoV-2 activity by inhibiting ∼99% virus growth at 10 µg ml-1 in cell culture-based assay. Brevicillin did not show dermal allergic reactions in BALB/c mice. CONCLUSION: This study provides detailed description of a novel lanthipeptide and demonstrates its effective antibacterial, antifungal and anti-SARS-CoV-2 activity.

Design and Molecular Docking Studies of N-Mannich Base Derivatives of Primaquine Bearing Isatin on the Targets involved in the Pathophysiology of Cerebral Malaria.

BACKGROUND: Malaria is considered one of the life-threatening mosquito-borne infectious diseases responsible for approximately more than 4,00,000 deaths every year all over the world. Plasmodium falciparum and Plasmodium vivax are widespread species, but infections caused by the former are of great concern. OBJECTIVE: Among the various forms of infections associated with Plasmodium falciparum, cerebral malaria (CM) is the most severe neurological complication, accounting for almost 13% of all malariarelated mortality. The development of effective therapeutics is urgently needed to overcome the fatality of this dreadful disease. METHODS: The present work attempted to design and virtually screen a chemical library of 75 molecules (N-Mannich base derivatives of primaquine bearing isatin moiety as heterocyclic) by molecular docking studies against anti-malarial target proteins-Cystein Protease Falcipain-2; Dipeptidyl Aminopeptidase- 1; Dipeptidyl Aminopeptidase-3 and Glycogen synthase Kinase-3ß receptors, for evaluating their anti-malarial potential. Among all studied anti-malarial target receptors, the designed molecules showed an overall higher affinity for Dipeptidyl Aminopeptidase-3. Furthermore, the molecules were analyzed for binding affinity and drug-like properties using Lipinski rules, and 30 best hits were shortlisted and analyzed for the pharmacokinetic profile. RESULTS: Two of these hits were found to be more toxic than primaquine, hence were omitted in further analysis. Later, these 28 hits were docked against two target proteins, (a) Plasmodium falciparum erythrocyte membrane protein-1 and (b) Intracellular adhesion molecule-1, to determine their efficiency against cerebral malaria, and the results were recorded. Analysis of docking results led to the identification of the 8 studied molecules as lead molecules which were selected for chemical synthesis, in vivo studies, and further preclinical evaluation. CONCLUSION: The molecule DSR 11 was predicted as the most appropriate lead molecule for anti-CM activity in the present investigation apart from the other seven molecules (DSR4, DSR26, DSR38, DSR40, DSR49, DSR56, and DSR70).

Serum estradiol levels decrease after oophorectomy in transmasculine individuals on testosterone therapy.

Transmasculine individuals, considering whether to undergo total hysterectomy with bilateral salpingectomy, have the option to have a concomitant oophorectomy. While studies have evaluated hormone changes following testosterone therapy initiation, most of those patients have not undergone oophorectomy. Data are currently limited to support health outcomes regarding the decision to retain or remove the ovaries. We performed a retrospective chart review of transmasculine patients maintained on high-dose testosterone therapy at a single endocrine clinic in Vancouver, British Columbia, Canada. Twelve transmasculine individuals who underwent bilateral oophorectomy and had presurgical and postsurgical serum data were included. We identified 12 transmasculine subjects as controls, who were on testosterone therapy and did not undergo oophorectomy, but additionally matched to the first group by age, testosterone dosing regimen, and body mass index. There was a statistically significant decrease in the estradiol levels of case subjects postoophorectomy, when compared to presurgical estradiol levels (P = 0.02). There was no significant difference between baseline estradiol levels between control and case subjects; however, the difference in estradiol levels at follow-up measurements was significant (P = 0.03). Total testosterone levels did not differ between control and case subjects at baseline and follow-up (both P > 0.05). Our results demonstrate that oophorectomy further attenuates estradiol levels below what is achieved by high-dose exogenous testosterone alone. Correlated clinical outcomes, such as impacts on bone health, were not available. The clinical implications of oophorectomy versus ovarian retention on endocrinological and overall health outcomes are currently limited.

Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor.

An immunological hallmark of visceral leishmaniasis (VL), caused by Leishmania donovani, is profound immunosuppression. However, the molecular basis for this immune dysfunction has remained ill defined. Since dendritic cells (DCs) normally initiate antileishmanial immune responses, we investigated whether DCs are dysregulated during L. donovani infection and assessed its role in immunosuppression. Accordingly, we determined the regulatory effect of L. donovani on DCs. Notably, it is still unclear whether L. donovani activates or suppresses DCs. In addition, the molecular mechanism and the relevant receptor (or receptors) mediating the immunoregulatory effect of L. donovani on DCs are largely undefined. Here, we report that L. donovani inhibited DC activation/maturation by transmitting inhibitory signals through the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby suppressed antileishmanial immune responses. L. donovani in fact triggered TIM-3 phosphorylation in DCs, which in turn recruited and activated a nonreceptor tyrosine kinase, Btk. Btk then inhibited DC activation/maturation by suppressing the NF-κB pathway in an interleukin-10 (IL-10)-dependent manner. Treatment with TIM-3-specific blocking antibody or suppressed expression of TIM-3 or downstream effector Btk made DCs resistant to the inhibitory effects of L. donovani. Adoptive transfer experiments further demonstrated that TIM-3-mediated L. donovani-induced inhibition of DCs plays a crucial role in the suppression of the antileishmanial immune response in vivo. These findings identify TIM-3 as a new regulator of the antileishmanial immune response and demonstrate a unique mechanism for host immunosuppression associated with L. donovani infection. IMPORTANCE Visceral leishmaniasis (VL), a poverty-related disease caused by Leishmania donovani, is ranked by the World Health Organization as the second largest killer parasitic disease in the world. The protective immune response against VL is primarily regulated by dendritic cells (DCs), which upon activation/maturation initiate an antileishmanial immune response. However, it remains obscure whether L. donovani promotes or inhibits DC activation. In addition, the receptor through which L. donovani exerts immunoregulatory effect on DCs is ill defined. Here, we for the first time report that L. donovani inhibits DC activation and maturation via the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby attenuates the capacity of DCs to trigger antileishmanial immune responses in vivo. In fact, we demonstrate here that suppression of TIM-3 expression in DCs augments antileishmanial immunity. Our study uncovers a unique mechanism by which L. donovani subverts host immune responses and suggests TIM-3 as a potential new target for immunotherapy against VL.

Health Outcomes Associated With Having an Oophorectomy Versus Retaining One's Ovaries for Transmasculine and Gender Diverse Individuals Treated With Testosterone Therapy: A Systematic Review.

INTRODUCTION: The transmasculine and gender diverse (TMGD) spectrum includes transgender men and non-binary individuals whose sex was assigned female at birth. Many TMGD patients pursue treatment with exogenous testosterone to acquire masculine characteristics. Some may choose to undergo gynecological gender-affirming surgery for total hysterectomy with bilateral salpingectomy and/or bilateral oophorectomy (TH/BSO). The decision to retain or remove the ovaries in the setting of chronic testosterone therapy has implications on reproductive health, oncologic risk, endocrine management, cardiovascular health, bone density and neurocognitive status. However, there is limited evidence on the long-term outcomes from this intervention. OBJECTIVE: Here we review health-related outcomes of oophorectomy in TMGD population treated with chronic testosterone therapy in order to guide clinicians and patients in the decision to retain or remove their ovaries. METHOD: We conducted a systematic literature review following PRISMA guidelines. MEDLINE, EMBASE, ClinicalTrials.gov, and Cochrane Library databases were searched for peer-reviewed studies published prior to October 26, 2021 that: (i) included transgender men/TMGD individuals in the study populations; (ii) were full-text randomized controlled studies, case reports, case series, retrospective cohort studies, prospective cohort studies, qualitative studies, and cross-sectional studies; and (iii) specifically discussed ovaries, hysterectomy, oophorectomy, ovariectomy, or gonadectomy. RESULTS: We identified 469 studies, of which 39 met our inclusion criteria for this review. Three studies discussed fertility outcomes, 11 assessed histopathological changes to the ovaries, 6 discussed ovarian oncological outcomes, 8 addressed endocrine considerations, 3 discussed cardiovascular health outcomes, and 8 discussed bone density. No studies were found that examined surgical outcomes or neurocognitive changes. CONCLUSION: There is little information to guide TMGD individuals who are considering TH/BSO versus TH/BS with ovarian retention. Our review suggests that there is limited evidence to suggest that fertility preservation is successful after TH/BS with ovarian retention. Current evidence does not support regular reduction in testosterone dosing following oophorectomy. Estradiol levels are likely higher in individuals that choose ovarian retention, but this has not been clearly demonstrated. Although bone mineral density decreases following oophorectomy, data demonstrating an increased fracture risk are lacking. No studies have described the specific impact on neurocognitive function, or changes in operative complications. Further research evaluating long-term health outcomes of oophorectomy for TMGD individuals treated with chronic testosterone therapy is warranted to provide comprehensive, evidence-based healthcare to this patient population. Sahil Kumar, Smita Mukherjee, Cormac O'Dwyer, et al. Health Outcomes Associated With Having an Oophorectomy Versus Retaining One's Ovaries for Transmasculine and Gender Diverse Individuals Treated With Testosterone Therapy: A Systematic Review. Sex Med Rev 2022;10:636-647.

A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.

Protein tertiary structure mimetics are valuable tools to target large protein-protein interaction interfaces. Here, we demonstrate a strategy for designing dimeric helix-hairpin motifs from a previously reported three-helix-bundle miniprotein that targets the receptor-binding domain (RBD) of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Through truncation of the third helix and optimization of the interhelical loop residues of the miniprotein, we developed a thermostable dimeric helix-hairpin. The dimeric four-helix bundle competes with the human angiotensin-converting enzyme 2 (ACE2) in binding to RBD with 2:2 stoichiometry. Cryogenic-electron microscopy revealed the formation of dimeric spike ectodomain trimer by the four-helix bundle, where all the three RBDs from either spike protein are attached head-to-head in an open conformation, revealing a novel mechanism for virus neutralization. The proteomimetic protects hamsters from high dose viral challenge with replicative SARS-CoV-2 viruses, demonstrating the promise of this class of peptides that inhibit protein-protein interaction through target dimerization.

The Sexual Goals of Metoidioplasty Patients and Their Attitudes Toward Using PDE5 Inhibitors and Intracavernosal Injections as Erectile Aids.

BACKGROUND: Following metoidioplasty, transmen (TM) experience sexual function challenges including erectile dysfunction, which is typically treated in cisgender men with phosphodiesterase-5 inhibitors (PDE5i) and intracavernosal injections (ICI). AIM: We aim to evaluate sexual function post-metoidioplasty and explore attitudes toward using PDE5i and ICI as potential erectile aids METHODS: All patients who had metoidioplasty completed at the Gender Surgery Program in Vancouver, British Columbia were contacted. Participants completed an electronically accessible self-constructed questionnaire consisting of 39 items on erectile function, orgasm, and penetrative intercourse which also captured Erection Hardness Scores (EHS). Data were analyzed via t-test and 1-way ANOVA. OUTCOMES: Our outcomes were the importance of erectile function, ability to orgasm, penetrative intercourse, and attitudes towards using PDE5i and ICI post-metoidioplasty. RESULTS: Fifteen out of 22 patients completed the survey (median age 32 years). Most had metoidioplasty within the past 2 years. The participants ranked the ability to orgasm and to achieve or maintain erections significantly higher than penetrative intercourse (P <.001, P =.005 respectively). Most participants reported facing challenges with penetrative intercourse (87%) and erectile function (80%). In contrast, a smaller proportion reported challenges with orgasm (33%). With regards to EHS, 83% of participants described their erections as either "larger but not hard," or "hard but not hard enough for penetration." A total of 47% of the participants had previously tried PDE5i, but none had used ICI. Although 87% were willing to use PDE5i, only 40% were willing to try ICI to improve their erections. Patients reported lack of knowledge and understanding among primary care physicians as barriers to accessing treatment for sexual dysfunction. CLINICAL TRANSLATION: The results of this study can facilitate decision making for TM undergoing genital gender-affirmation surgery and provide potential options for improving erectile function post surgery. STRENGTHS & LIMITATIONS: This study represents the first assessment of sexual function and use of erectile aids in post-metoidioplasty patients. The results of this study are limited by the small sample size and enrolment from a single surgical center. CONCLUSION: Metoidioplasty patients surveyed fail to achieve a fully rigid erection without treatment, typically retain the ability to orgasm, and are generally willing to try PDE5i. Khorrami A, Kumar S, Bertin E, et al. The Sexual Goals of Metoidioplasty Patients and Their Attitudes Toward Using PDE5 Inhibitors and Intracavernosal Injections as Erectile Aids. Sex Med 2022;10:100505.