Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma

Neuroendocrine prostate cancer (NEPC) can arise de novo, but much more commonly occurs as a consequence of a selective pressure from androgen deprivation therapy or androgen receptor antagonists used for prostate cancer (PCa) treatment. The process is known as neuroendocrine transdifferentiation. There is little molecular characterization of NEPCs and consequently there is no standard treatment for this kind of tumors, characterized by highly metastases rates and poor survival. For this purpose, we profiled 54 PCa samples with more than 10-years follow-up for gene and miRNA expression. We divided samples into two groups (NE-like vs. AdenoPCa), according to their clinical and molecular features. NE-like tumors were characterized by a neuroendocrine fingerprint made of known neuroendocrine markers and novel molecules, including long non-coding RNAs and components of the estrogen receptor signaling. A gene expression signature able to predict NEPC was built and tested on independently published datasets. This study identified molecular features (protein-coding, long non-coding, and microRNAs), at the time of surgery, that may anticipate the NE transformation process of prostate adenocarcinoma. Our results may contribute to improving the diagnosis and treatment of this subgroup of tumors for which traditional therapy regimens do not show beneficial effects.
In Silico Models Accurately Predict In Vivo Response for IL6 Blockade in Head and Neck Cancer

A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs. Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies. Significance: A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.
Clinical, radiological, and pathological findings of primary nasal osteosarcoma in a Libyan cat

Background: Although bone tumors are common pathologies in companion animals, limited reports describe nasal osteosarcoma (OSA) in cats. Case description: A case of nasal OSA in a local Libyan cat was admitted to the Veterinary Teaching Hospital at the Faculty of Veterinary Medicine, University of Tripoli–Libya, with nasal swelling and discharges and facial deformity. The radiological findings revealed nasal osteolysis with the absence of evidence of lung metastasis. In addition, fungal growth was not identified in microbiological culture. Furthermore, the pathological examination has grossly revealed a destructed nasal bone due to the presence of a tumor mass, with a mucohemorrhagic nasal discharge and absence of metastasis. OSA was confirmed histopathologically. Conclusion: This report presents the clinical, radiological, and pathological findings of a primary nasal OSA in a Libyan cat with no tumor metastasis to other body organs.
Towards an ontology of cognitive processes and their neural substrates: A structural equation modeling approach

A key challenge in the field of cognitive neuroscience is to identify discriminable cognitive functions, and then map these functions to brain activity. In the current study, we set out to explore the relationships between performance arising from different cognitive tasks thought to tap different domains of cognition, and then to test whether these distinct latent cognitive abilities also are subserved by corresponding “latent” brain substrates. To this end, we tested a large sample of adults under the age of 40 on twelve cognitive tasks as they underwent fMRI scanning. Exploratory factor analysis revealed 4-factor model, dissociating tasks into processes corresponding to episodic memory retrieval, reasoning, speed of processing and vocabulary. An analysis of the topographic covariance patterns of the BOLD-response acquired during each task similarity also converged on four neural networks that corresponded to the 4 latent factors. These results suggest that distinct ontologies of cognition are subserved by corresponding distinct neural networks.
I Am a Compassionate Conservation Welfare Scientist: Considering the Theoretical and Practical Differences Between Compassionate Conservation and Conservation Welfare

Simple Summary The well-being of individual wild animals is threatened in many ways, including by activities aiming to conserve species, ecosystems and biodiversity, i.e., conservation activities. Scientists working in two related disciplines, Compassionate Conservation and Conservation Welfare, are attentive to the well-being of individual wild animals. The purpose of this essay is to highlight the commonalities between these disciplines and to consider key differences, in order to stimulate discussion among interested parties and use our collective expertise and energy to best effect. An emerging scenario, the use of genetic technologies for control of introduced animals, is used to explore the ways each discipline might respond to novel conservation-related threats to wild animal well-being. Abstract Compassionate Conservation and Conservation Welfare are two disciplines whose practitioners advocate consideration of individual wild animals within conservation practice and policy. However, they are not, as is sometimes suggested, the same. Compassionate Conservation and Conservation Welfare are based on different underpinning ethics, which sometimes leads to conflicting views about the kinds of conservation activities and decisions that are acceptable. Key differences between the disciplines appear to relate to their views about which wild animals can experience harms, the kinds of harms they can experience and how we can know about and confidently evidence those harms. Conservation Welfare scientists seek to engage with conservation scientists with the aim of facilitating ongoing incremental improvements in all aspects of conservation, i.e., minimizing harms to animals. In contrast, it is currently unclear how the tenets of Compassionate Conservation can be used to guide decision-making in complex or novel situations. Thus, Conservation Welfare may offer modern conservationists a more palatable approach to integrating evidence-based consideration of individual sentient animals into conservation practice and policy.
Predictive Relevance of Circulating miR-622 in Patients with Newly Diagnosed and Recurrent High-Grade Serous Ovarian Carcinoma.

BACKGROUND Identifying patients with high-grade serous ovarian cancer (HGSOC) who will respond to treatment remains a clinical challenge. We focused on miR-622, a miRNA involved in the homologous recombination repair (HRR) pathway, and we assessed its predictive value in serum prior to first-line chemotherapy and at relapse. METHODS Serum miR-622 expression was assessed in serum prior to first-line platinum-based chemotherapy in a prospective multicenter study (miRNA Serum Analysis, miRSA, NCT01391351) and a retrospective cohort (Biological Resource Center, BRC), and was also studied at relapse. Progression-free survival (PFS) and overall survival (OS) were used as primary and secondary endpoints prior to first-line chemotherapy and OS as a primary endpoint at relapse. RESULTS The group with high serum miR-622 expression was associated with a significantly lower PFS (15.4 versus 24.4 months; adjusted HR 2.11, 95% CI 1.2 3.8, P = 0.015) and OS (29.7 versus 40.6 months; adjusted HR 7.68, 95% CI 2.2-26.2, P = 0.0011) in the miRSA cohort. In the BRC cohort, a high expression of miR-622 was also associated with a significantly lower OS (22.8 versus 35.9 months; adjusted HR 1.98, 95% CI 1.1-3.6, P = 0.026). At relapse, high serum miR-622 was associated with a significantly lower OS (7.9 versus 20.6 months; adjusted HR 3.15, 95% CI 1.4-7.2, P = 0.0062). Serum miR-622 expression is a predictive independent biomarker of response to platinum-based chemotherapy for newly diagnosed and recurrent HGSOC. CONCLUSIONS These results may open new perspectives for HGSOC patient stratification and monitoring of resistance to platinum-based and poly(ADP-ribose)-polymerase-inhibitor-maintenance therapies, facilitating better and personalized treatment decisions.
The Effect of Solvent Vapor Annealing on Drug-Loaded Electrospun Polymer Fibers

Electrospinning has emerged as a powerful strategy to develop controlled release drug delivery systems but the effects of post-fabrication solvent vapor annealing on drug-loaded electrospun fibers have not been explored to date. In this work, electrospun poly(ε-caprolactone) (PCL) fibers loaded with the hydrophobic small-molecule spironolactone (SPL) were explored. Immediately after fabrication, the fibers are smooth and cylindrical. However, during storage the PCL crystallinity in the fibers is observed to increase, demonstrating a lack of stability. When freshly-prepared fibers are annealed with acetone vapor, the amorphous PCL chains recrystallize, resulting in the fiber surfaces becoming wrinkled and yielding shish-kebab like structures. This effect does not arise after the fibers have been aged. SPL is found to be amorphously dispersed in the PCL matrix both immediately after electrospinning and after annealing. In vitro dissolution studies revealed that while the fresh fibers show a rapid burst of SPL release, after annealing more extended release profiles are observed. Both the rate and extent of release can be varied through changing the annealing time. Further, the annealed formulations are shown to be stable upon storage.
Energy System Assessment in Survivors of Breast Cancer.

BACKGROUND Survivors of breast cancer commonly report functional limitations, including cancer-related fatigue (CRF) and decreased aerobic capacity. One key gap is addressing the 3 energy systems (aerobic, anaerobic lactic, and alactic), requiring assessment to establish a baseline exercise intensity and duration. OBJECTIVE This study examined the feasibility of energy system-based assessment, also providing descriptive values for assessment performance in this population. DESIGN This was a cross-sectional study. METHODS Seventy-two posttreatment survivors of breast cancer were recruited. Following a baseline musculoskeletal assessment, women attempted 3 energy system assessments: submaximal aerobic (multistage treadmill), anaerobic alactic (30-second sit-to-stand [30-STS]), and anaerobic lactic (adapted burpees). Heart rate (HR) and rating of perceived exertion (RPE) were recorded. Secondary outcomes included body composition, CRF, and upper- and lower-limb functionality. RESULTS Seventy of 72 participants performed the 30-STS and 30 completed the adapted burpees task. HR and RPE specific to each task were correlated, reflecting increased intensity. Women reported low-moderate levels of CRF scores (3% [2.1]) and moderate-high functionality levels (upper-limb: 65.8% [23.3]; lower-limb: 63.7% [34.7]). LIMITATIONS All survivors of breast cancer had relatively low levels of CRF and moderate functioning. Additionally, on average, participants were classified as "overweight" based on BMI. CONCLUSION This study is the first to our knowledge to demonstrate feasibility of energy system assessment in survivors of breast cancer. Using a combination of HR and RPE, as well as baseline assessment of each energy system, clinicians may improve ability to prescribe personalized exercise and give patients greater ability to self-monitor intensity and progress.
Synergistic Interactions of Indole-2-Carboxamides and β-Lactam Antibiotics against Mycobacterium abscessus

New drugs or therapeutic combinations are urgently needed against Mycobacterium abscessus. Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against M. abscessus. We show here that these compounds act synergistically with imipenem and cefoxitin in vitro and increase the bactericidal activity of the β-lactams against M. abscessus. In addition, compound 12 also displays synergism with imipenem and cefoxitin within infected macrophages. ABSTRACT New drugs or therapeutic combinations are urgently needed against Mycobacterium abscessus. Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against M. abscessus. We show here that these compounds act synergistically with imipenem and cefoxitin in vitro and increase the bactericidal activity of the β-lactams against M. abscessus. In addition, compound 12 also displays synergism with imipenem and cefoxitin within infected macrophages. The clinical potential of these new drug combinations requires further evaluation.
Impact of Doxycycline as Malaria Prophylaxis on Risk of Influenza-Like Illness among International Travelers

Abstract. Travelers are often at risk for both influenza-like illness (ILI) and malaria. Doxycycline is active against pathogens causing ILI and is used for malaria prophylaxis. We evaluated the risk factors for ILI, and whether the choice of malaria prophylaxis was associated with ILI. TravMil is a prospective observational study enrolling subjects presenting to military travel clinics. Influenza-like illness was defined as subjective fever with either a sore throat or cough. Characteristics of trip and use of malaria prophylaxis were analyzed to determine association with development of ILI. Poisson regression models with robust error variance were used to estimate relative risk (RR) of ILI. A total of 3,227 trips were enrolled: 62.1% male, median age of 39 years (interquartile range [IQR] 27,59), median travel duration 19 days (IQR 12, 49); 32% traveled to Africa, 40% to Asia, and 27% to the Caribbean and Latin America. Military travel (46%) and vacation (40%) were most common reasons for travel. Among them, 20% took doxycycline, 50% other prophylaxis, and 30% took none; 8.7% developed ILI. Decreased RR of ILI was associated with doxycycline (RR 0.65 [0.43–0.99], P = 0.046) and military travel (RR 0.30 [0.21–0.43], P < 0.01). Increased risk of ILI was associated with female gender (RR 1.57 [1.24–1.98], P < 0.01), travel to Asia (RR 1.37 [1.08–1.75], P = 0.01), and cruises (RR 2.21 [1.73–2.83], P < 0.01). Use of doxycycline malaria prophylaxis is associated with a decreased risk of ILI. Possible reasons include anti-inflammatory or antimicrobial effects, or other unmeasured factors. With few strategies for decreasing ILI in travelers, these findings bear further investigation.
Development of a sheep model of atrioventricular block for the application of novel therapies

Introduction Sheep have been adopted as a pre-clinical large animal for scientific research as they are good models of cardiac anatomy and physiology, and allow for investigation of pathophysiological processes which occur in the large mammalian heart. There is, however, no defined model of atrioventricular block in sheep to allow for pre-clinical assessment of new cardiac treatment options. We therefore aimed to develop an adult sheep model of atrioventricular block with the focus on future novel applications. Methods and results We utilized six sheep to undergo two procedures each. The first procedure involved implantation of a single chamber pacemaker into the right ventricular apex, for baseline assessment over four weeks. The second procedure involved creating atrioventricular block by radiofrequency ablation of the His bundle, before holding for a further four weeks. Interrogation of pacemakers and electrocardiograms determined the persistence of atrioventricular block during the follow up period. Pacemakers were inserted, and atrioventricular block created in 6 animals using a conventional approach. One animal died following ablation of the His bundle, due to procedural complications. Four unablated sheep were assessed for baseline data over four weeks and showed 5.53 ± 1.28% pacing reliance. Five sheep were assessed over four weeks following His bundle ablation and showed continuous (98.89 ± 0.81%) ventricular pacing attributable to persistent atrioventricular block, with no major complications. Conclusion We have successfully developed, characterized and validated a large animal model of atrioventricular block that is stable and technically feasible in adult sheep. This model will allow for the advancement of novel therapies, including the development of cell and gene-based therapies.
Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

BACKGROUND & AIMS We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily, or 24 mg once daily, and evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P<.1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo; endoscopic remission was achieved by 10% (P<.1 vs placebo), 8%, 8% (P<.1 vs placebo), 22% (P<.01 vs placebo), and 14% (P<.05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections versus placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol, compared with patients in the placebo group. CONCLUSIONS In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients, compared with placebo. Upadacitinib's benefit-risk profile supports further development for treatment of CD. Clinicaltrials.gov ID no: NCT02365649.
miR159 Represses a Constitutive Pathogen Defense Response in Tobacco1[OPEN]

Repression of miR159 in tobacco triggers a constitutive defense response that confers immunity to Phytophthora parasitica. MicroR159 (miR159) regulation of GAMYB expression is highly conserved in terrestrial plants; however, its functional role remains poorly understood. In Arabidopsis (Arabidopsis thaliana), although GAMYB-like genes are constitutively transcribed during vegetative growth, their effects are suppressed by strong and constitutive silencing by miR159. GAMYB expression occurs only if miR159 function is inhibited, which results in detrimental pleiotropic defects, questioning the purpose of the miR159-GAMYB pathway. Here, miR159 function was inhibited in tobacco (Nicotiana tabacum) and rice (Oryza sativa) using miRNA MIM159 technology. Similar to observations in Arabidopsis, inhibition of miR159 in tobacco and rice resulted in pleiotropic defects including stunted growth, implying functional conservation of the miR159-GAMYB pathway among angiosperms. In MIM159 tobacco, transcriptome profiling revealed that genes associated with defense and programmed cell death were strongly activated, including a suite of 22 PATHOGENESIS-RELATED PROTEIN (PR) genes that were 100- to 1,000-fold upregulated. Constitutive expression of a miR159-resistant GAMYB transgene in tobacco resulted in phenotypes similar to that of MIM159 tobacco and activated PR gene expression, verifying the dependence of the above-mentioned changes on GAMYB expression. Consistent with the broad defense response, MIM159 tobacco appeared immune to Phytophthora infection. These findings suggest that the tobacco miR159-GAMYB pathway functions in the biotic defense response, which becomes activated upon miR159 inhibition. However, PR gene expression was not upregulated in Arabidopsis or rice when miR159 was inhibited, suggesting that miR159-GAMYB pathway functional differences exist between species, or factors in addition to miR159 inhibition are required in Arabidopsis and rice to activate this broad defense response.
Erythrocyte Ascorbate Is a Potential Indicator of Steady-State Plasma Ascorbate Concentrations in Healthy Non-Fasting Individuals

Plasma vitamin C concentrations fluctuate in response to recent dietary intake; therefore levels are typically determined in the fasting state. Erythrocyte ascorbate concentrations have been shown to be similar to plasma levels, but little is known about the kinetics of ascorbate accumulation in these cells. In this study, we investigated ascorbate uptake into erythrocytes after dietary supplementation with vitamin C and compared it to changes in plasma ascorbate concentrations. Seven individuals with baseline fasting plasma vitamin C concentrations ≥ 50 µmol/L were depleted of vitamin C-containing foods and drinks for one week, and then supplemented with 250 mg vitamin C/day in addition to resuming their normal diet. Fasting or steady-state plasma ascorbate concentrations declined to almost half of their baseline concentration over the week of vitamin C depletion, and then returned to saturation within two days of beginning supplementation. Erythrocyte ascorbate concentrations exhibited a very similar profile to plasma levels, with values ~76% of plasma, and a strong linear correlation (r = 0.89, p < 0.0001). Using a pharmacokinetic study design in six individuals with baseline fasting plasma vitamin C concentrations ≥50 µmol/L, we also showed that, unlike plasma, which peaked between 2 and 4 h following ingestion of 200 mg of vitamin C, erythrocyte ascorbate concentrations did not change in the six hours after supplementation. The data from these two intervention studies indicate that erythrocyte ascorbate concentration provides a stable measure of steady-state plasma ascorbate status and could be used to monitor ascorbate status in healthy non-fasting individuals.