Demographics, Histopathology, and Treatment Outcomes of Squamous Cell Carcinoma of the Prostate.

BACKGROUND: Squamous cell carcinoma of the prostate (SCCP) is a neoplasm that comprises fewer than 1% of all primary prostate cancer diagnoses. Given its rarity, there is a paucity of data regarding the treatment of this disease. The limited literature points to the potential of local therapy in conjunction with chemotherapy to improve patient mortality. METHODS: Using the National Cancer Initiative's Surveillance, Epidemiology, and End Results (SEER) database, a retrospective review of patients diagnosed with primary SCCP between 2000 and 2018 was performed. Patient demographics, tumor characteristics, and patient outcomes based on treatment modality were analyzed. Univariate and survival analyses were conducted with p < 0.05 indicating statistical significance. RESULTS: A total of 66 patients were identified. Five-year overall survival (5y OS) was 24%; mean and median survival were 2.2 years (1.8, 2.7) and 1.2 years (0.3, 2.1), respectively. Patients with Grade I or Grade II disease had an increased 5y OS of 55% (27%, 83%). In comparison, 5y OS was 13% (-2%, 29%) for patients with Grade III and Grade IV disease (p = 0.017). Analysis of 5y OS based on disease histology revealed patients with papillary SCC had a 5y OS of 50% [9.2%, 91%], compared to 21% [9%, 34%] for patients with SCC, not otherwise specified and 0% for those with lymphoepithelial carcinoma (p = 0.048). Analysis of 5y OS stratified by treatment modality revealed no statistically significant change with any treatment (surgery, radiotherapy, and chemotherapy). No difference in 5y OS was seen between those treated with radical prostatectomy versus external beam radiation therapy. CONCLUSIONS: The literature on SCCP remains sparse; the rarity of this disease limits analysis. While the investigation undertaken in this paper does not find any change in 5y OS regardless of treatment modality, the variation in 5y OS based on histologic classification of SCCP points to a potential route for the future treatment of this disease.

Automated design of multi-target ligands by generative deep learning.

Generative deep learning models enable data-driven de novo design of molecules with tailored features. Chemical language models (CLM) trained on string representations of molecules such as SMILES have been successfully employed to design new chemical entities with experimentally confirmed activity on intended targets. Here, we probe the application of CLM to generate multi-target ligands for designed polypharmacology. We capitalize on the ability of CLM to learn from small fine-tuning sets of molecules and successfully bias the model towards designing drug-like molecules with similarity to known ligands of target pairs of interest. Designs obtained from CLM after pooled fine-tuning are predicted active on both proteins of interest and comprise pharmacophore elements of ligands for both targets in one molecule. Synthesis and testing of twelve computationally favored CLM designs for six target pairs reveals modulation of at least one intended protein by all selected designs with up to double-digit nanomolar potency and confirms seven compounds as designed dual ligands. These results corroborate CLM for multi-target de novo design as source of innovation in drug discovery.

Tuning RXR Modulators for PGC1α Recruitment.

The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. The ability of RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue to tissue- or gene-selective RXR activation. Here, we identified strong induction of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) binding to RXR by a synthetic agonist but not by the endogenous ligand 9-cis retinoic acid. Structure-guided diversification of this lead resulted in a set of three structurally related RXR agonists with different ability to promote PGC1α recruitment in cell-free and cellular context. These results demonstrate that selective modulation of coregulator recruitment to RXR can be achieved with molecular glues and potentially open new therapeutic opportunities by targeting the ligand-induced RXR-PGC1α interaction.

Big data and experimental biology: the complementary roles of hypothesis-led and blue skies research.

JEB has broadened its scope to include non-hypothesis-led research. In this Perspective, based on our lab's lived experience, I argue that this is excellent news, because truly novel insights can occur from 'blue skies' idea-led experiments. Hypothesis-led and hypothesis-free experimentation are not philosophically antagonistic; rather, the latter can provide a short-cut to an unbiased view of organism function, and is intrinsically hypothesis generating. Insights derived from hypothesis-free research are commonly obtained by the generation and analysis of big datasets - for example, by genetic screens - or from omics-led approaches (notably transcriptomics). Furthermore, meta-analyses of existing datasets can also provide a lower-cost means to formulating new hypotheses, specifically if researchers take advantage of the FAIR principles (findability, accessibility, interoperability and reusability) to access relevant, publicly available datasets. The broadened scope will thus bring new, original work and novel insights to our journal, by expanding the range of fundamental questions that can be asked.

Intra-individual comparison of epicardial adipose tissue characteristics on coronary CT angiography between photon-counting detector and energy-integrating detector CT systems.

PURPOSE: To explore the potential differences in epicardial adipose tissue (EAT) volume and attenuation measurements between photon-counting detector (PCD) and energy-integrating detector (EID)-CT systems. METHODS: Fifty patients (mean age 69 ± 8 years, 41 male [82 %]) were prospectively enrolled for a research coronary CT angiography (CCTA) on a PCD-CT within 30 days after clinical EID-based CCTA. EID-CT acquisitions were reconstructed using a Bv40 kernel at 0.6 mm slice thickness. The PCD-CT acquisition was reconstructed at a down-sampled resolution (0.6 mm, Bv40; [PCD-DS]) and at ultra-high resolutions (PCD-UHR) with a 0.2 mm slice thickness and Bv40, Bv48, and Bv64 kernels. EAT segmentation was performed semi-automatically at about 1 cm intervals and interpolated to cover the whole epicardium within a threshold of -190 to -30 HU. A subgroup analysis was performed based on quartile groups created from EID-CT data and PCD-UHRBv48 data. Differences were measured using repeated-measures ANOVA and the Friedman test. Correlations were tested using Pearson's and Spearman's rho, and agreement using Bland-Altman plots. RESULTS: EAT volumes significantly differed between some reconstructions (e.g. EID-CT: 138 ml [IQR 100, 188]; PCD-DS: 147 ml [110, 206]; P<0.001). Overall, correlations between PCD-UHR and EID-CT EAT volumes were excellent, e.g. PCD-UHRBv48: r: 0.976 (95 % CI: 0.958, 0.987); P<0.001; with good agreement (mean bias: -9.5 ml; limits of agreement [LoA]: -40.6, 21.6). On the other hand, correlations regarding EAT attenuation was moderate, e.g. PCD-UHRBV48: r: 0.655 (95 % CI: 0.461, 0.790); P<0.001; mean bias: 6.5 HU; LoA: -2.0, 15.0. CONCLUSION: EAT attenuation and volume measurements demonstrated different absolute values between PCD-UHR, PCD-DS as well as EID-CT reconstructions, but showed similar tendencies on an intra-individual level. New protocols and threshold ranges need to be developed to allow comparison between PCD-CT and EID-CT data.

Fetal Cardiovascular Magnetic Resonance Feature Tracking Myocardial Strain Analysis in Congenital Heart Disease.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is an emerging imaging modality for assessing anatomy and function of the fetal heart in congenital heart disease (CHD). This study aimed to evaluate myocardial strain using fetal CMR feature tracking (FT) in different subtypes of CHD. METHODS: Fetal CMR FT analysis was retrospectively performed on four-chamber cine images acquired with Doppler US gating at 3 Tesla. Left ventricular (LV) global longitudinal strain (GLS), LV global radial strain (GRS), LV global longitudinal systolic strain rate (SR), and right ventricular (RV) GLS were quantified using a dedicated software optimized for fetal strain analysis. Analysis was performed in normal fetuses and different CHD subtypes (d-Transposition of the great arteries (dTGA), hypoplastic left heart syndrome (HLHS), coarctation of the aorta (CoA), tetralogy of Fallot (TOF), RV-dominant atrioventricular septal defect (AVSD), and critical pulmonary stenosis or atresia (PS/PA)). Analyses of variance (ANOVA) with Tukey post-hoc test was used for group comparisons. RESULTS: A total of 60 fetuses were analyzed (8/60 (13%) without CHD, 52/60 (87%) with CHD). Myocardial strain was successfully assessed in 113/120 ventricles (94%). Compared to controls, LV GLS was significantly reduced in fetuses with HLHS (-18.6±2.7% vs. -6.2±5.6%; p<0.001) and RV-dominant AVSD (-18.6±2.7% vs. -7.7±5.0%; p=0.003) and higher in fetuses with CoA (-18.6±2.7% vs. -25.0±4.3%; p=0.038). LV GRS was significantly reduced in fetuses with HLHS (25.7±7.5% vs. 11.4±9.7%; p=0.024). Compared to controls, RV GRS was significantly reduced in fetuses with PS/PA (-16.1±2.8% vs. -8.3±4.2%; p=0.007). Across all strain parameters, no significant differences were present between controls and fetuses diagnosed with dTGA and TOF. CONCLUSIONS: Fetal myocardial strain assessment with CMR FT in CHD is feasible. Distinct differences are present between various types of CHD, suggesting potential implications for clinical decision-making and prognostication in fetal CHD.

Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-ß) Agonist for the Treatment of MASH.

Agonists of thyroid hormone receptor ß (THR-ß) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent and selective compound ALG-055009 (14) as a potential best in class THR-ß agonist. The high metabolic stability and good permeability translated well in vivo to afford a long in vivo half-life pharmacokinetic profile with limited liability for DDI, and it overcomes certain drawbacks seen in recent clinical candidates.

Development of Tailless Homologue Receptor (TLX) Agonist Chemical Tools.

The human tailless homologue receptor (TLX) is a ligand-activated transcription factor acting as a master regulator of neural stem cell homeostasis. Despite its promising potential in neurodegenerative disease treatment, TLX ligands are rare but required to explore phenotypic effects of TLX modulation and for target validation. We have systematically studied and optimized a TLX agonist scaffold obtained by fragment fusion. Structural modification enabled the development of two TLX agonists endowed with nanomolar potency and binding affinity. Both exhibited favorable chemical tool characteristics including high selectivity and low toxicity. Most notably, the TLX agonists comprise different scaffolds and display high chemical diversity, enabling their use as a set for target identification and validation studies.

Navigation in Multiligament Knee Reconstruction: A Proof-of-Concept Study on a Femoral Sawbones Model.

Multiligament knee reconstruction surgery is technically challenging, requiring careful planning and execution. Accurate placement of bone tunnels is important for graft function and there is an inherent risk of tunnel collision, which can compromise graft integrity. In this proof-of-concept study, we present a technique using computer navigation to help optimize tunnel placement and to avoid collision during multiligament knee reconstruction. A computed tomography (CT)-based navigation system was used to plan and execute femoral tunnel placement on a Sawbones model, for a Schenck KD-IV multiligament knee reconstruction. After CT scanning of the Sawbones model, commercially available software was used to plan tunnel trajectories for reconstruction of the posterolateral corner, medial ligament complex, and both cruciate ligaments. Tunnel entry points and trajectories were based on bony landmarks as identified on CT. The model was successfully registered with an accuracy of <0.5 mm. Execution of tunnel drilling was carried out for 7 femoral tunnels, guided by computer navigation. A postprocedure CT scan was then performed and superimposed over the preoperative planning scan. This demonstrated excellent correlation between planned and executed tunnels with no evidence of tunnel collision. This study supports the idea of using computer navigation to plan and execute tunnels in multiligament knee reconstruction.

A High-Quality Photoswitchable Probe that Selectively and Potently Regulates the Transcription Factor RORγ.

Retinoic acid receptor-related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions. As an experimental therapeutic target in inflammation and immunity, there is great interest in spatially-localised RORγ inhibition; and its cyclic temporal role in circadian rhythms also makes it an intriguing target for time-resolved pharmacology. To create tools that can study RORγ biology with appropriate spatial and temporal resolution, we designed light-dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures. Optimizations gave photoswitchable RORγ inhibitors with a large degree of potency photocontrol, plus remarkable on-target potency, plus excellent selectivity over related off-target receptors. This still-rare, but urgently-needed combination of performance features, distinguishes them as high quality photopharmaceutical probes; and they can now serve as high precision tools to study the spatial and dynamic intricacies of RORγ action in signaling and in inflammatory disorders.

Nitrous Oxide Alters Functional Connectivity in Medial Limbic Structures in Treatment-Resistant Major Depression.

While nitrous oxide (N2O) has demonstrated antidepressant properties in treatment-resistant major depression (TRD), little is known about neural mechanisms mediating these effects. Employing serial resting-state functional magnetic resonance imaging (rs-fMRI), we compared spatiotemporal effects of inhaled N2O on brain functional connectivity in TRD patients (n=14) and non-depressed healthy controls (n=16, CNTL). Participants received sequential, one-hour inhalations of either 50% N2O/oxygen or air/oxygen (placebo), with sessions separated by at least one month in random cross-over order. BOLD-contrast rs-fMRI scans were acquired at three time points: pre-inhalation, 2 hours post-inhalation, and 24 hours post-inhalation. For the rs-fMRI functional connectivity analyses, five a priori seeds in medial limbic structures targeted cortical networks implicated in major depression - the salience, anterior and posterior default mode, reward, and cingulo-opercular networks - and a nexus in the dorsal paracingulate region previously identified in MDD ("dorsal nexus"). Depression, dissociation, and psychosis assessments were made before and after inhalations. In TRD patients, functional connectivity was reduced in all seeded networks and the voxel-wise global analysis after N2O exposure. N2O progressively decreased connectivity in patients with TRD but increased connectivity in healthy controls. In TRD patients, each seeded network demonstrated post-inhalation functional connectivity reductions in the dorsal paracingulate gyrus ("dorsal nexus"). This study further elucidates neural mechanisms underlying the antidepressant properties of N2O, supporting the notion that N2O specifically alters mood-associated brain regions in the depressed brain state by reducing functional connectivity within these brain networks. The trial was registered at ClinicalTrials.gov (NCT02994433).

Factors Affecting Willingness to Report to Work During COVID-19 Pandemic among Health Care Workers in a Tertiary Government Hospital.

Background: Healthcare workers' (HCWs) willingness to report to work despite personal risk is a requisite for an effective pandemic response. At present, there are no local studies that have examined the factors affecting willingness to report to work during the COVID-19 pandemic. Objective: To determine the factors associated with willingness to report to work during COVID-19 pandemic among healthcare workers in a tertiary government hospital. Methods: This was a cross sectional study among the nursing staff (nursing attendants, nurses), doctors (residents, fellows), medical technologists, radiologic technologists, and respiratory technicians in a tertiary government hospital, who were employed from January 2021 to January 2022. Data was collected through an online questionnaire and was analyzed using SPSS. Results: A total of 311 participants included in the study. The median age of the respondents was 34 (29-46) years old. More than a third of the workers were nurses (37%) followed by residents and fellows (34%), nursing attendants (19%), radiologic technologists, medical technologists, and respiratory technicians (10%). Over 4 out of 5 were assigned in a non-COVID area while 11% were assigned in the COVID area. The odds of willingness to report to work is 60% lower among males compared to females. On the other hand, the odds of willingness to report to work was 78% lower among nurses and 84% lower among residents and fellows compared to medical technologist, radiologic technologists, and respiratory therapists. The median rating of the staff on willingness to report to work was 80% (60-90), and 73% of respondents were willing to report to work during the entire COVID-19 pandemic. Conclusion: Factors that were associated with willingness to report to work were female gender and occupation (radiologic technologists, medical technologists, respiratory technicians).

The Effect of the COVID-19 Pandemic on the Family and Community Medicine Residency Training Program: The Philippine Experience.

Background: The COVID-19 pandemic had a profound impact on medical education, particularly in Family and Community Medicine training programs. This study aimed to assess the impact in the Philippines by comparing the number of cases and procedures before and during the pandemic, as well as the adaptations made by these programs. Objective: The objective of this study was to determine the effect of the COVID-19 pandemic on Family and Community Medicine training in the Philippines by comparing the average number of cases and procedures done before and during the pandemic and the changes implemented by the different accredited training programs. Methods: A cross-sectional study utilizing an explanatory sequential mixed methods approach was undertaken. The quantitative portion collected data on cases and procedures from the participating institutions' residents using the standardized checklist of the Philippine Academy of Family Physicians. The qualitative portion was done through a focused group discussion (FGD) following a prepared set of FGD questions. Analysis of variation (ANOVA) was used to compare the average cases seen and procedures across the four years and content analysis for the qualitative data. Results: There was a significant decrease in the average number of adult and pediatric cases during the pandemic years (2020-2021) compared to before (2018-2019). Various organ systems cases such as neurology, ophthalmology, dermatology, and gastrointestinal, showed significant differences (p-value <0.05) in the average number of pediatric cases. For adult cases, significant differences (p-value <0.05) were found for several organ system cases when comparing the years before (2018-2019) and during the pandemic (2020-2021), including neurology, ophthalmology, ENT, dermatology, cardiology, gastrointestinal, genitourinary, reproductive health, musculoskeletal, and endocrinology cases. The trainers adjusted training activities to support the hospital's COVID-19 response and that prompted an abrupt shift to online strategies for patient consultations, teaching sessions, and examinations. Conclusion: The COVID-19 pandemic led to a reduction in the variety of cases and procedures in Family and Community Medicine training, impacting the fulfillment of specialty training requirements. However, it also drove innovation through the integration of technology, including online teaching methods. These experiences underscore the importance of resilience and adaptability in medical education and offer valuable lessons for future training programs, potentially leading to improvements in training and patient care through innovative methodologies.

Shifts in Serum Bile Acid Profiles Associated With Barrett's Esophagus and Stages of Progression to Esophageal Adenocarcinoma.

INTRODUCTION: Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS: Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS: A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11-3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

Preimplantation genetic testing for aneuploidy is associated with reduced live birth rates in fresh but not frozen donor oocyte in vitro fertilization cycles: an analysis of 18,562 donor cycles reported to Society for Assisted Reproductive Technology Clinic Outcome Reporting System.

OBJECTIVE: To evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on first transfer live birth rate (LBR) and cumulative LBR (CLBR) in donor oocyte in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort study of the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database. SETTING: Fertility centers reporting to Society for Assisted Reproductive Technology. PATIENT(S): A total of 11,348 fresh and 7,214 frozen-thawed donor oocyte IVF cycles were analyzed. INTERVENTION(S): The first reported donor stimulation cycle per patient between January 1, 2014, and December 31, 2015, and all linked embryo transfer cycles between January 1, 2014, and December 31, 2016, were included in the study. MAIN OUTCOME MEASURE(S): Live birth rate was compared for patients using fresh and frozen-thawed donor oocytes, with or without PGT-A. Logistic regression models were adjusted for age, body mass index, gravidity, infertility etiology, and prior IVF cycles. RESULT(S): Among patients who had blastocysts available for transfer or PGT-A, the use of PGT-A was associated with a decreased first transfer LBR (46.9 vs. 53.2%) and CLBR (58.4 vs. 66.6%) in fresh oocyte donor cycles compared with no PGT-A. Live birth rate in frozen-thawed oocyte donor cycles with PGT-A were nominally higher than those without PGT-A (48.3% vs. 40.5%) but were not statistically significant in multivariable logistic regression models. Early pregnancy loss was not significantly different with and without PGT-A. Multiple gestation, preterm birth, and low birth weight infants were all reduced with the addition of PGT-A in fresh donor oocyte cycles, although these outcomes were not significantly different when comparing single embryo transfers in fresh oocyte cycles and also not significantly different among frozen-thawed donor oocyte cycles. CONCLUSION(S): Preimplantation genetic testing for aneuploidy in fresh oocyte donor cycles was associated with decreased LBR and CLBR, whereas effects on frozen-thawed oocyte donor cycles were clinically negligible. Obstetric benefits associated with PGT-A in fresh donor cycles appear linked to increased single embryo transfer.

Evaluation of SK-N-SH Cells as a Model for NMDA Receptor Induced Toxicity.

BACKGROUND/AIMS: Over the years, the number of patients with neurodegenerative diseases is constantly rising illustrating the need for new neuroprotective drugs. A promising treatment approach is the reduction of excitotoxicity induced by rising (S)-glutamate levels and subsequent NMDA receptor overactivation. To facilitate the search for new NMDA receptor inhibitors neuronal cell models are needed. In this study, we evaluated the suitability of human SK-N-SH cells to serve as a cell model for neurodegeneration induced by NMDA receptor overstimulation. METHODS: The cytoprotective effect of the unselective NMDA receptor blocker ketamine as well as the GluN2B-selective inhibitor WMS14-10 was evaluated utilizing different cell viability assays, such as endpoint (LDH, CCK-8, DAPI/FACS) and time dependent methods (bioimpedance). RESULTS: Non-differentiated as well as differentiated SK-N-SH cells express GluN1 and GluN2B subunits. Furthermore, 50 mM (S)-glutamate led to an instantaneous decrease in cell survival. Only application of unselective channel blocker ketamine could protect differentiated cells against this effect, while the selective inhibitor WMS14-10 did not significantly increase cell survival. CONCLUSION: SK-N-SH cells show an increased sensitivity to (S)-glutamate mediated cytotoxicity with higher differentiation level, that is only partially induced by NMDA receptor overstimulation. Furthermore, we showed that only unselective NMDA receptor inhibition can partially reverse (S)-glutamate-induced toxicity.