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Abstract Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor genes PTEN and TP53 are frequently mutated in prostate cancer and are predictive of early metastatic dissemination and unfavorable patient outcomes. The progression of solid tumors to metastasis is often associated with increased cell plasticity, but the complex events underlying TP53-loss-induced disease aggressiveness remain incompletely understood. Using genetically engineered mice, we show that Trp53 deficiency in Pten-null prostatic epithelial cells (PECs) does not impact early cell proliferation and neoplasia formation, nor growth arrest and senescence entry at a later time. However, Trp53-deficiency enhances invasive adenocarcinoma development and promotes metastatic cell dissemination. Importantly, our single-cell transcriptomic and chromatin accessibility analyses combined with histological examinations uncovered an epithelial cell population characterized by an induction of Jak/Stat3 signaling and displaying mesenchymal features. Moreover, we show that the transcriptomic signature of this cell population is prominent in tumors of patients with high-risk prostate cancer or metastatic disease. In addition, our in vivo and organoid-based experiments provide evidence that PEC plasticity occurs through bi-directional communication with cancer-associated fibroblasts (CAFs). Thus, our study demonstrates that p53 loss induces a protumorigenic crosstalk between PECs and CAFs, and identifies new vulnerabilities that might be targeted to limit cancer progression.

Abstract Given the ongoing environmental degradation from local to global scales, it is fundamental to develop more efficient means of gathering data on species and ecosystems. Local ecological knowledge, in which local communities can consistently provide information on the status of animal species over time, has been shown to be effective. Several studies demonstrate that data gathered using local ecological knowledge (LEK)‐based methods are comparable with data obtained from conventional methods (such as line transects and camera traps). Here, we employ a consensus analysis to validate and evaluate the accuracy of interview data on LEK. Additionally, we investigate the influence of social and bioecological variables on enhancing data quality. We interviewed 323 persons in 19 villages in the Western and Central Amazon to determine the level of consensus on the abundance of hunted and non‐hunted forest species. These villages varied in size, socio‐economic characteristics and in the experience with wildlife of their dwellers. Interviewees estimated the relative abundance of 101 species with a broad spectrum of bioecological characteristics using a four‐point Likert scale. High consensus was found for species population abundance in all sampled villages and for 79.6% of interviewees. The village consensus of all species abundance pooled was negatively correlated with village population size. The consensus level was high regardless of the interviewees' hunting experience. Species that are more frequently hunted or are more apparent had greater consensus values; only two species presented a low consensus level, which are rare and solitary species. We show in our study in the Amazon that information gathered by local peoples, Indigenous as well as non‐Indigenous, can be useful in understanding the status of animal species found within their environment. The high level of cultural consensus we describe likely arises from knowledge sharing and the strong connection between the persons interviewed and the forest. We suggest that consensus analysis can be used to validate LEK‐generated data instead of comparing these types of data with information obtained by conventional methods. Read the free Plain Language Summary for this article on the Journal blog.

The COVID-19 pandemic caused disruptions in colorectal cancer (CRC) care by interrupting CRC screening across Canada, posing problems for program participants, patients, and physicians and no clear understanding of how provincial healthcare systems would adapt in the face of another pandemic or shock to the system. A nationwide online survey targeted to members of the National Colorectal Cancer Screening Network (NCCSN) using the SurveyMonkey platform was conducted to gain insight into the impact of the pandemic on CRC screening from March 2020 to March 2022 across all thirteen Canadian jurisdictions. The survey included 25 multiple-choice and free-text questions. Both quantitative and qualitative methods were used to analyze the data using Microsoft Excel and NVivo software. Twenty-one provincial and territorial representatives participated in the survey conducted between 13 May 2022 and 27 October 2022. All jurisdictions (100%) reported decreased screenings, including fecal immunochemical testing (FIT) or Fecal Occult Blood testing (FOBT) procedures, and subsequent diagnostic colonoscopies. The average wait time for colonoscopies due to a positive FIT/FOBT was 76 days. To mitigate the backlog and initiate an effective intervention plan, representatives highlighted some key points, including the importance of prioritizing high-risk patients. Survey results concluded that the COVID-19 pandemic impacted CRC screening across Canada. This landscape assessment can help inform intervention measures and policy-related solutions to create greater resilience for CRC screening in provincial and territorial healthcare systems.

Introduction Progress related to sexual, reproductive, maternal, newborn, child and adolescent health (SRMNCAH) has stalled. COVID-19, conflict and climate change threaten to reverse decades of progress and to ensure the health and well-being of vulnerable populations in humanitarian and fragile settings (HFS) going forward, there is a need for tailored guidance for women, children and adolescents (WCA). This review seeks to map and appraise current resources on SRMNCAH in HFS.Methods In line with the updated Joanna Briggs Institute guidance and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews framework, a manual literature review was conducted of global and regional guidance published between January 2008 and May 2023 from members of the Global Health Cluster, the Global Nutrition Cluster and the Inter-Agency Working Group on Reproductive Health in Crises. A content analysis was conducted. Scores were then calculated according to the Appraisal of Guidelines for Research and Evaluation II scoring tool and subsequently categorised as high quality or low quality.Results A total of 730 documents were identified. Of these, 141 met the selection criteria and were analysed. Available guidance for delivering SRMNCH services exists, which can inform policy and programming for the general population and WCA. Important gaps related to beneficiaries, health services and health system strengthening strategies were identified.Conclusion The review revealed there is evidence-based guidance available to support interventions targeting WCA in HFS, including: pregnant and lactating women, women of reproductive age, adolescents, newborns, small vulnerable newborns, stillbirths, refugees and internally displaced persons and WCA with disabilities. However, gaps related to beneficiaries, health services and health system strengthening strategies must be addressed in updated guidance that is created, disseminated and monitored in a standardised way that is mindful of the need to respond rapidly in HFS.

[This corrects the article DOI: 10.1371/journal.pone.0276297.].

Abstract Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten(i)pe−/− mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten(i)pe−/− mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.

ABSTRACT Terrestrial arthropod groups, including insects, spiders, and millipedes, represent an important food resource for primates. However, species consumed and patterns and rates of arthropod-related feeding for most frugivorous primates are still poorly known. We examined stomach contents of 178 Amazonian primate specimens of nine genera and three families obtained from community-based collections voluntarily donated by subsistence hunters. Based on our results, we assessed whether consumption patterns followed the expected negative relationship between arthropod ingestion and body size as postulated in the Jarman-Bell and Kay models. We identified 12 consumed arthropod taxa, including insects (beetles, grasshoppers, ants, flies, caterpillars, praying mantises, and others), spiders and millipedes. Medium and large-bodied primates consumed a greater diversity (measured by Simpson’s diversity index) and richness of arthropods, but differed in terms of composition of taxa consumed. Cacajao, Sapajus and Cebus consumed proportionally more Orthoptera and Coleoptera compared to the other primate genera analyzed. We did not find significant correlations between richness and diversity of arthropods consumed and primate body mass. There was a slight tendency for the decrease in the relative content of arthropods in the diet with increased body mass in medium and large primates, which does not provide full support for the Jarman-Bell and Kay models. The study of arthropod consumption by arboreal primates in the wild remains challenging. Our study suggests that arthropods supply essential nutrients for frugivorous primates, and provides an alternative method to analyse faunal consumption patterns in primates.

Abstract Cardiac myosin binding protein-C (cMyBP-C) is an important regulator of sarcomeric function. Reduced phosphorylation of cMyBP-C has been linked to compromised contractility in heart failure patients. Here, we used previously published cMyBP-C peptides 302A and 302S, surrogates of the regulatory phosphorylation site serine 302, as a tool to determine the effects of modulating the dephosphorylation state of cMyBP-C on cardiac contraction and relaxation in experimental heart failure (HF) models in vitro. Both peptides increased the contractility of papillary muscle fibers isolated from a mouse model expressing cMyBP-C phospho-ablation (cMyBP-CAAA) constitutively. Peptide 302A, in particular, could also improve the force redevelopment rate (k tr) in papillary muscle fibers from cMyBP-CAAA (nonphosphorylated alanines) mice. Consistent with the above findings, both peptides increased ATPase rates in myofibrils isolated from rats with myocardial infarction (MI), but not from sham rats. Furthermore, in the cMyBP-CAAA mouse model, both peptides improved ATPase hydrolysis rates. These changes were not observed in non-transgenic (NTG) mice or sham rats, indicating the specific effects of these peptides in regulating the dephosphorylation state of cMyBP-C under the pathological conditions of HF. Taken together, these studies demonstrate that modulation of cMyBP-C dephosphorylation state can be a therapeutic approach to improve myosin function, sarcomere contractility and relaxation after an adverse cardiac event. Therefore, targeting cMyBP-C could potentially improve overall cardiac performance as a complement to standard-care drugs in HF patients.

(1) Background: The COVID-19 pandemic illuminated vulnerabilities in the Canadian health care system and exposed gaps and challenges across the cancer care continuum. Canada is experiencing significant disruptions to cancer-related services, and the impact these disruptions (delays/deferrals/cancellations) have on the health care system and patients are yet to be determined. Given the potential adverse ramifications, how can Canada’s health care systems build resilience for future threats? (2) Methods: To answer this question, CCC facilitated a series of four thought-leadership roundtables, each representing the views of four different stakeholder groups: patients, physicians, health care system leaders, and researchers. (3) Results: Six themes of strength were identified to serve as a springboard for building resilience including, (1) advancing virtual care and digital health technologies to prevent future interruptions in cancer care delivery. (2) developing real-time data metrics, data sharing, and evidence-based decision-making. (3) enhancing public–private-non-profit partnerships to advance research and strengthen connections across the system. (4) advancing patient-centricity in cancer research to drive and encourage precision medicine approaches to care. (5) investing in training and hiring a robust supply of health care human resources. (6) implementing a national strategy and infrastructure to ensure inter-provincial collaborative data sharing (4). Conclusions: A resilient health care system that can respond to shocks and threats is not an emergency system; it is a robust everyday system that can respond to emergencies.

Globally, illegal sport hunting can threaten prey populations when unregulated. Due to its covert nature, illegal sport hunting poses challenges for data collection, hindering efforts to understand the full extent of its impacts. We gathered social media data to analyze patterns of illegal sport hunting and wildlife depletion across Brazil. We collected data for 2 years (2018–2020) across 5 Facebook groups containing posts depicting pictures of illegal sport hunting events of native fauna. We described and mapped these hunting events by detailing the number of hunters involved, the number of species, the mean body mass of individuals, and the number and biomass of individuals hunted per unit area, stratified by Brazilian biome. We also examined the effects of defaunation on hunting yield and composition via regression models, rank–abundance curves, and spatial interpolation. We detected 2046 illegal sport hunting posts portraying the hunting of 4658 animals (∼29 t of undressed meat) across all 27 states and 6 natural biomes of Brazil. Of 157 native species targeted by hunters, 19 are currently threatened with extinction. We estimated that 1414 hunters extracted 3251 kg/million km2. Some areas exhibited more pronounced wildlife depletion, in particular the Atlantic Forest and Caatinga biomes. In these areas, there was a shift from large mammals and reptiles to small birds as the main targeted taxa, and biomass extracted per hunting event and mean body mass across all taxonomic groups were lower than in other areas. Our results highlight that illegal sport hunting adds to the pressures of subsistence hunting and the wild meat trade on Brazil's wildlife populations. Enhanced surveillance efforts are needed to reduce illegal sport hunting levels and to develop well‐managed sustainable sport hunting programs. These can support wildlife conservation and offer incentives for local communities to oversee designated sport hunting areas. [ABSTRACT FROM AUTHOR]

Abstract Background Self-care interventions offer a solution to support the achievement of three goals of the World Health Organization (WHO): to improve universal health coverage, reach people in humanitarian situations, and improve health and well-being. In light of implementing WHO consolidated guidelines on self-care interventions to strengthen sexual and reproductive health (SRH) in the Eastern Mediterranean Region (EMR), especially during the COVID-19 pandemic, pharmacists from four different EMR countries discussed the current SRH situation, inequality gaps, barriers to SRH service access and the pharmacist’s crucial role as a first-line responder to patients before, during and after COVID-19. Case presentation Self-care interventions for SRH allow health care providers to serve a greater number of patients, improve progress toward universal health coverage, and reach people in humanitarian crises. In fact, these interventions can be significantly enhanced by utilizing community pharmacists as first-line health care providers. This review highlights the important role of community pharmacists in promoting self-care interventions and empowering individuals, families and communities. As a result, well-informed individuals will be authoritative in their health decisions. Exploring self-care interventions in the EMR was done through reviewing selected SRH services delivery through community pharmacists before and during the COVID-19 pandemic in Egypt, Jordan, Lebanon and Somalia. Before the COVID-19 pandemic, community pharmacists were found to be excluded from both governmental and nongovernmental SRH programmes. During the pandemic, community pharmacists managed to support patients with self-care interventions, whether voluntarily or through their pharmacy associations. This highlights the need for the health care decision-makers to involve and support community pharmacists in influencing policies and promoting self-care interventions. Conclusion Self-care interventions can increase individuals’ choice and autonomy over SRH. Supporting community pharmacists will definitely strengthen SRH in the EMR and may help make the health system more efficient and more targeted.

BackgroundThe QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (INaL) by the novel compound GS-458967 can suppress proarrhythmic markers.Methods and resultsNew experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion.ConclusionsOur computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.

Aakash Ganju,1 Alessandra C Goulart,2 Amrit Ray,3 Anurita Majumdar,4 Barrett W Jeffers,3 Gloria Llamosa,5 Henry Cañizares,6 Ianne Jireh Ramos-Cañizares,6 Ibtihal Fadhil,7 Kannan Subramaniam,8 Lee-Ling Lim,9 Luna El Bizri,10 M Ramesh,11 Mathew Guilford,12 Raghib Ali,13 Ratna Duddi Devi,14,15 Rayaz A Malik,16 Shekhar Potkar,17 Yuan-Pang Wang18 1Executive Office, Saathealth, Mumbai, India; 2Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil; 3Research, Development and Medical, Upjohn – a Pfizer Division, New York, NY, USA; 4Research, Development and Medical, Emerging Markets, Upjohn – a Pfizer Division, Singapore; 5Mexican Neurology and Psychiatry Society, Mexico City, Mexico; 6Vicente Sotto Memorial Medical Center, Cebu City, Philippines; 7Eastern Mediterranean NCD Alliance, Kuwait City, Kuwait; 8Research, Development and Medical, Upjohn – a Pfizer Division, Sydney, Australia; 9Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 10School of Pharmacy, Lebanese University, Hadath, Lebanon; 11Lee Kuan Yew School of Public Policy, National University of Singapore, Singapore; 12Executive Office, Common Health, Kuala Lumpur, Malaysia; 13Public Health Research Center, New York University, Abu Dhabi, United Arab Emirates; 14Executive Office, DakshamA Health and Education, Gurgaon, India; 15Board of Directors, International Alliance of Patient Organizations, London, England; 16Weill Cornell Medicine, Doha, Qatar; 17Research, Development and Medical, Upjohn – a Pfizer Division, Dubai, United Arab Emirates; 18Instituto de Psiquiatria (LIM-23), Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilCorrespondence: Kannan SubramaniamResearch, Development and Medical, Upjohn – a Pfizer Division, Sydney, NSW 2000, AustraliaTel +61 413 569 077Email Kannan.Subramaniam@pfizer.comAbstract: Non-communicable diseases (NCDs) have been on the rise in low- and middle-income countries (LMICs) over the last few decades and represent a significant healthcare concern. Over 85% of “premature” deaths worldwide due to NCDs occur in the LMICs. NCDs are an economic burden on these countries, increasing their healthcare expenditure. However, targeting NCDs in LMICs is challenging due to evolving health systems and an emphasis on acute illness. The major issues include limitations with universal health coverage, regulations, funding, distribution and availability of the healthcare workforce, and availability of health data. Experts from across the health sector in LMICs formed a Think Tank to understand and examine the issues, and to offer potential opportunities that may address the rising burden of NCDs in these countries. This review presents the evidence and posits pragmatic solutions to combat NCDs.Keywords: low- and middle-income countries, multisectoral, non-communicable diseases, public–private partnership, universal health coverage

Patients with lower educational attainment are underrepresented in inflammatory bowel disease (IBD) research. To increase our understanding of the health care perspectives of patients with less than a university degree, semi-structured interviews were conducted among 23 outpatients at the McGill University Health Centre IBD Centre (Montreal, Canada). Thematic analysis was used to analyze the qualitative data. Perspectives focused on communication with health care professionals, access to care, symptoms and treatment, and outside support. Access to an IBD specialist was the most important aspect of care. Good care, kind and receptive staff, and a lengthy delay to diagnosis were frequently reported experiences. IBD specialists, nurses, and family and friends were most helpful in managing disease. Physical and emotional symptoms, reduced social engagement, and medications were difficult aspects of living with IBD. An ideal IBD clinic would provide access to traditional and non-traditional services and assist with obtaining support to help patients engage in social activities, increase affordability of care, and maintain employment. Study findings may be helpful in designing equitable models of health care delivery.

Many vertebrate species undergo population fluctuations that may be random or regularly cyclic in nature. Vertebrate population cycles in northern latitudes are driven by both endogenous and exogenous factors. Suggested causes of mysterious disappearances documented for populations of the Neotropical, herd-forming, white-lipped peccary (Tayassu pecari, henceforth “WLP”) include large-scale movements, overhunting, extreme floods, or disease outbreaks. By analyzing 43 disappearance events across the Neotropics and 88 years of commercial and subsistence harvest data for the Amazon, we show that WLP disappearances are widespread and occur regularly and at large spatiotemporal scales throughout the species’ range. We present evidence that the disappearances represent 7–12-year troughs in 20–30-year WLP population cycles occurring synchronously at regional and perhaps continent-wide spatial scales as large as 10,000–5 million km2. This may represent the first documented case of natural population cyclicity in a Neotropical mammal. Because WLP populations often increase dramatically prior to a disappearance, we posit that their population cycles result from over-compensatory, density-dependent mortality. Our data also suggest that the increase phase of a WLP cycle is partly dependent on recolonization from proximal, unfragmented and undisturbed forests. This highlights the importance of very large, continuous natural areas that enable source-sink population dynamics and ensure re-colonization and local population persistence in time and space.