tbuckley/cabot-search huggingface dataset:
Opioid access barriers for cancer pain relief in Vietnam: A qualitative study.
Authors: Trang Nguyen, Tung Pham, Linh Bui, Eric Lewis Krakauer, Caroline Phelan
Journal: Journal of Clinical Oncology (2024)

154 Background: Although the World Health Organization designates opioids as an essential medication and recommends them as the cornerstone for managing moderate to severe cancer pain, their accessibility is severely restricted, particularly in low and middle-income countries. Despite Vietnam's early endeavors in the advancement of palliative care, including a revised opioid prescription policy in 2008, opioid use for cancer pain remains suboptimal, with oral morphine available only in a few major hospitals. To inform comprehensive strategies for improving opioid access, this study aims to explore the views of healthcare providers, regulators, cancer patients, and caregivers in Vietnam on the barriers to safely accessing opioids for cancer pain management. Methods: We conducted a qualitative, descriptive study and recruited five healthcare providers, six cancer patients and caregivers, and six regulators (i.e., policymakers in the Ministry of Health, heads or deputy heads of pharmacy, oncology, or palliative care departments) across Vietnam via purposeful sampling technique. Data were collected using semi-structured interviews, and the audio recordings were transcribed verbatim and subjected to inductive content analysis using a Framework Method. Results: Five categories of barriers were identified: 1) Patient-related barriers (fear of addiction and other side effects, morphine's association with impending death, negative administration experiences, religious beliefs); 2) Professional-related barriers (knowledge and experience deficit, fear of addiction and other side effects, concerns about opioid diversion and associated liabilities, lack of guidance, education, and training); 3) Medicine-related barriers (limited oral morphine availability, limited domestic pharmaceutical manufacturers and suppliers, supply interruptions, poor variety of opioid types and formulations, difficulties accessing parenteral opioids); 4) Services delivery barriers (scarce palliative and home care services); 5) Regulatory barriers (lack of information on opioid distribution channels, difficulties obtaining confirmation letters for patients' opioid usage needs, overly strict regulation enforcement). Conclusions: Barriers to opioid access for cancer pain control in Vietnam are multifactorial and mutually reinforcing, necessitating interdisciplinary solutions to overcome them. This approach should involve enhancing education about the appropriate use and management of opioids, along with current opioid policies for patients, communities, healthcare providers, and regulators; enacting and implementing policies mandating oral morphine availability at local health facilities; expanding palliative care services; utilizing telemedicine; and establishing an electronic opioid prescription monitoring system.
Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells
Authors: Ian A. Mellis, Madeline E. Melzer, Nicholas Bodkin, Yogesh Goyal
Journal: Genome biology (2024)

Cells and tissues have a remarkable ability to adapt to genetic perturbations via a variety of molecular mechanisms. Nonsense-induced transcriptional compensation, a form of transcriptional adaptation, has recently emerged as one such mechanism, in which nonsense mutations in a gene trigger upregulation of related genes, possibly conferring robustness at cellular and organismal levels. However, beyond a handful of developmental contexts and curated sets of genes, no comprehensive genome-wide investigation of this behavior has been undertaken for mammalian cell types and conditions. How the regulatory-level effects of inherently stochastic compensatory gene networks contribute to phenotypic penetrance in single cells remains unclear. We analyze existing bulk and single-cell transcriptomic datasets to uncover the prevalence of transcriptional adaptation in mammalian systems across diverse contexts and cell types. We perform regulon gene expression analyses of transcription factor target sets in both bulk and pooled single-cell genetic perturbation datasets. Our results reveal greater robustness in expression of regulons of transcription factors exhibiting transcriptional adaptation compared to those of transcription factors that do not. Stochastic mathematical modeling of minimal compensatory gene networks qualitatively recapitulates several aspects of transcriptional adaptation, including paralog upregulation and robustness to mutation. Combined with machine learning analysis of network features of interest, our framework offers potential explanations for which regulatory steps are most important for transcriptional adaptation. Our integrative approach identifies several putative hits—genes demonstrating possible transcriptional adaptation—to follow-up on experimentally and provides a formal quantitative framework to test and refine models of transcriptional adaptation.
Progression-free survival as a surrogate endpoint in myeloma clinical trials: an evolving paradigm
Authors: Charlotte Pawlyn, Fredrik H. Schjesvold, David A. Cairns, L. J. Wei, Faith Davies, Omar Nadeem, Haifaa Abdulhaq, Maria-Victoria Mateos, Jacob Laubach, Katja Weisel, Heinz Ludwig, S. Vincent Rajkumar, Pieter Sonneveld, Graham Jackson, Gareth Morgan, Paul G. Richardson
Journal: Blood Cancer Journal (2024)

Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed.
Gene panel predicts neoadjuvant chemoimmunotherapy response and benefit from immunotherapy in HER2-negative breast cancer
Authors: Xunxi Lu, Zongchao Gou, Hong Chen, Li Li, Fei Chen, Chunjuan Bao, Hong Bu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background It is encountering the dilemma of lacking precise biomarkers to predict the response to neoadjuvant chemoimmunotherapy (NACI) and determine whether patients should use immune checkpoint inhibitors (ICIs) in early breast cancer (BC). We aimed to develop a gene signature to predict NACI response for BC patients and identify individuals suitable for adding ICIs. Patients and methods Two I-SPY2 cohorts and one West China Hospital cohort of patients treated with NACI were included. Machine learning algorithms were used to identify key genes. Principal component analysis was used to calculate the ImPredict (IP) score. The interaction effects between biomarkers and treatment regimens were examined based on the logistic regression analysis. The relationship between the IP score and immune microenvironment was investigated through immunohistochemistry (IHC) and multiplex IHC. Results The area under the curves of the IP score were 0.935, 0.865, and 0.841 in the discovery cohort, validation cohort 1, and in-house cohort. Marker-treatment interaction tests indicated that the benefits from immunotherapy significantly varied between patients with high and low IP scores (p for interaction &lt;0.001), and patients with high IP scores were more suitable for immunotherapy addition. Conclusions Our IP model shows favorable performance in predicting NACI response and is an effective tool for identifying BC patients who will benefit from ICIs. It may help clinicians optimize treatment strategies and guide clinical decision-making.
Five-year follow-up of neoadjuvant PD-1 inhibitor (sintilimab) in non-small cell lung cancer
Authors: Bolun Zhou, Fan Zhang, Wei Guo, Shuhang Wang, Ning Li, Bin Qiu, Liang Zhao, Jian Li, Kang Shao, Qi Xue, Fang Lv, Shugeng Gao
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Neoadjuvant anti-programmed cell death protein-1 (PD-1) therapy exhibits potential in treating resectable non-small cell lung cancer (NSCLC). Previously, we have reported the 3-year clinical outcomes of this trial, implying the effectiveness and feasibility of neoadjuvant sintilimab monotherapy. However, the long-term prognosis of patients receiving neoadjuvant mono-immunotherapy has yet to be elucidated. Methods For patients with stage IA-IIIB NSCLC, two doses of sintilimab (200 mg) were administered intravenously in the neoadjuvant setting. The 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) were assessed in these updated results. The predictive role of specific biomarkers in neoadjuvant immunotherapy was also explored. Results With a median follow-up of 61.0 months, 5-year DFS and OS rates of patients who underwent R0 resection were 65.7% and 80.4%, respectively. The 5-year DFS and OS rates of patients with positive programmed death-ligand 1 (PD-L1) expression were 71.9% and 90.9%, respectively. The presence of PD-L1 positivity (tumor proportion score ≥1%) showed a tendency toward the promising prognosis (OS, HR, 0.143; 95% CI: 0.027 to 0.743), especially for those who did not achieve pathological complete response (pCR). In addition, tumor mutation burden was positively correlated with a favorable prognosis. A total of 10 recurrences and 5 subsequent deaths were identified within the 5-year follow-up, with lung metastasis being the predominant. Conclusions These updated analyses were the first to unveil the 5-year survival benefits of neoadjuvant sintilimab monotherapy, implying the potential value of PD-1 inhibitors in neoadjuvant therapy.
Gene content, phage cycle regulation model and prophage inactivation disclosed by prophage genomics in the <i>Helicobacter pylori</i> Genome Project
Authors: Filipa F. Vale, Richard J. Roberts, Ichizo Kobayashi, M. Constanza Camargo, Charles S. Rabkin
Journal: Gut Microbes (2024)

Prophages can have major clinical implications through their ability to change pathogenic bacterial traits. There is limited understanding of the prophage role in ecological, evolutionary, adaptive processes and pathogenicity of Helicobacter pylori, a widespread bacterium causally associated with gastric cancer. Inferring the exact prophage genomic location and completeness requires complete genomes. The international Helicobacter pylori Genome Project (HpGP) dataset comprises 1011 H. pylori complete clinical genomes enriched with epigenetic data. We thoroughly evaluated the H. pylori prophage genomic content in the HpGP dataset. We investigated population evolutionary dynamics through phylogenetic and pangenome analyses. Additionally, we identified genome rearrangements and assessed the impact of prophage presence on bacterial gene disruption and methylome. We found that 29.5% (298) of the HpGP genomes contain prophages, of which only 32.2% (96) were complete, minimizing the burden of prophage carriage. The prevalence of H. pylori prophage sequences was variable by geography and ancestry, but not by disease status of the human host. Prophage insertion occasionally results in gene disruption that can change the global bacterial epigenome. Gene function prediction allowed the development of the first model for lysogenic-lytic cycle regulation in H. pylori. We have disclosed new prophage inactivation mechanisms that appear to occur by genome rearrangement, merger with other mobile elements, and pseudogene accumulation. Our analysis provides a comprehensive framework for H. pylori prophage biological and genomics, offering insights into lysogeny regulation and bacterial adaptation to prophages.
Symbiotic biofilms formed by <i>Clostridioides difficile</i> and <i>bacteroides thetaiotaomicron</i> in the presence of vancomycin
Authors: Jingpeng Yang, Wen Rui, Saiwei Zhong, Xiaoqian Li, Wenzheng Liu, Lingtong Meng, Yanan Li, He Huang
Journal: Gut Microbes (2024)

Vancomycin (VAN) treatment in
Correction: Effect of the 1-h bundle on mortality in patients with suspected sepsis in the emergency department: a stepped wedge cluster randomized clinical trial
Authors: Yonathan Freund, Marta Cancella de Abreu, Soufiane Lebal, Alexandra Rousseau, Thomas Lafon, Youri Yordanov, Richard Macrez, Fabien Coisy, Pierrick Le Borgne, Florent Femy, Delphine Douillet, Neus Robert Boter, Xavier Eyer, Jean-Baptiste Bouillon-Minois, Carl Ogereau, Donia Bouzid, Hélène Goulet, Mélanie Roussel, Geoffroy Rousseau, Jeremy Guénézan, Celine Occelli, Tahar Chouihed, Gina Osorio Quispe, Marine Clea Renard, Judith Gorlicki, Ben Bloom, Tabassome Simon, Camille Gerlier
Journal: Intensive Care Medicine (2024)
DNA methylation in mammalian development and disease
Authors: Zachary D. Smith, Sara Hetzel, Alexander Meissner
Journal: Nature Reviews Genetics (2024)

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype. In this Review, Smith et al. describe DNA methylation landscapes that emerge over mammalian development and within key disease states, as well as how different methyltransferases interface with histone modifications and other proteins to create and maintain them.
<i>Porphyromonas gingivalis</i> fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion
Authors: Angélica Díaz-Basabe, Georgia Lattanzi, Federica Perillo, Chiara Amoroso, Alberto Baeri, Andrea Farini, Yvan Torrente, Giuseppe Penna, Maria Rescigno, Michele Ghidini, Elisa Cassinotti, Ludovica Baldari, Luigi Boni, Maurizio Vecchi, Flavio Caprioli, Federica Facciotti, Francesco Strati
Journal: Gut Microbes (2024)

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). The pathobiont Fusobacterium nucleatum influences the anti-tumor functions of CRC-infiltrating iNKT cells. However, the impact of other bacteria associated with CRC, like Porphyromonas gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumor microenvironment. Mechanistically, in vivo and in vitro experiments showed that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery through increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing the upregulation of CHI3L1 in iNKT cells, thus impairing their cytotoxic functions and promoting host tumor immune evasion.
Biometrics of complete human pregnancy recorded by wearable devices
Authors: Lauryn Keeler Bruce, Dalila González, Subhasis Dasgupta, Benjamin L. Smarr
Journal: npj Digital Medicine (2024)

Abstract In the United States, normal-risk pregnancies are monitored with the recommended average of 14 prenatal visits. Check-ins every few weeks are the standard of care. This low time resolution and reliance on subjective feedback instead of direct physiological measurement, could be augmented by remote monitoring. To date, continuous physiological measurements have not been characterized across all of pregnancy, so there is little basis of comparison to support the development of the specific monitoring capabilities. Wearables have been shown to enable the detection and prediction of acute illness, often faster than subjective symptom reporting. Wearables have also been used for years to monitor chronic conditions, such as continuous glucose monitors. Here we perform a retrospective analysis on multimodal wearable device data (Oura Ring) generated across pregnancy within 120 individuals. These data reveal clear trajectories of pregnancy from cycling to conception through postpartum recovery. We assessed individuals in whom pregnancy did not progress past the first trimester, and found associated deviations, corroborating that continuous monitoring adds new information that could support decision-making even in the early stages of pregnancy. By contrast, we did not find significant deviations between full-term pregnancies of people younger than 35 and of people with “advanced maternal age”, suggesting that analysis of continuous data within individuals can augment risk assessment beyond standard population comparisons. Our findings demonstrate that low-cost, high-resolution monitoring at all stages of pregnancy in real-world settings is feasible and that many studies into specific demographics, risks, etc., could be carried out using this newer technology.
Controlled Transdermal Delivery of Dexamethasone for Pain Management via Photochemically 3D‐Printed Bioresorbable Microneedle Arrays
Authors: Alexander J. Bahnick, Courtney S. Dziewior, Yize Li, Amy Chou, Maddison Segal, Emily K. Augustine, Ru‐Rong Ji, Matthew L. Becker
Journal: Advanced Healthcare Materials (2024)

Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.
Rational Design of Human Hair Keratin−Driven Proteins for Hair Growth Promotion
Authors: Haojie Zhang, Rui Qing, Wenfeng Li, Yuhan Yuan, Yinping Pan, Ni Tang, Qiulan Huang, Bochu Wang, Shilei Hao
Journal: Advanced Healthcare Materials (2024)

Keratins, the most abundant proteins in human hair, are excellent hair nutrients for growth. However, the complex components of keratin extract hinder their mechanism investigation, and the pure recombinant keratin with poor solubility limited its hair growth promotion efficiency. Here, the water-soluble recombinant keratins (RKs) of K31 and K81 are rationally designed through QTY Code methodology, which are then used to fabricate the microneedles to study the effect of keratin on hair growth. Interestingly, it is discovered that more than 40% of the hair follicles (HFs) in the RK81
ENU-based dominant genetic screen identifies contractile and neuronal gene mutations in congenital heart disease
Authors: Xiaoxi Luo, Lifeng Liu, Haowei Rong, Xiangyang Liu, Ling Yang, Nan Li, Hongjun Shi
Journal: Genome Medicine (2024)

Congenital heart disease (CHD) is the most prevalent congenital anomaly, but its underlying causes are still not fully understood. It is believed that multiple rare genetic mutations may contribute to the development of CHD. In this study, we aimed to identify novel genetic risk factors for CHD using an ENU-based dominant genetic screen in mice. We analyzed fetuses with malformed hearts and compared them to control littermates by whole exome or whole genome sequencing (WES/WGS). The differences in mutation rates between observed and expected values were tested using the Poisson and Binomial distribution. Additionally, we compared WES data from human CHD probands obtained from the Pediatric Cardiac Genomics Consortium with control subjects from the 1000 Genomes Project using Fisher's exact test to evaluate the burden of rare inherited damaging mutations in patients. By screening 10,285 fetuses, we identified 1109 cases with various heart defects, with ventricular septal defects and bicuspid aortic valves being the most common types. WES/WGS analysis of 598 cases and 532 control littermates revealed a higher number of ENU-induced damaging mutations in cases compared to controls. GO term and KEGG pathway enrichment analysis showed that pathways related to cardiac contraction and neuronal development and functions were enriched in cases. Further analysis of 1457 human CHD probands and 2675 control subjects also revealed an enrichment of genes associated with muscle and nervous system development in patients. By combining the mice and human data, we identified a list of 101 candidate digenic genesets, from which each geneset was co-mutated in at least one mouse and two human probands with CHD but not in control mouse and control human subjects. Our findings suggest that gene mutations affecting early hemodynamic perturbations in the developing heart may play a significant role as a genetic risk factor for CHD. Further validation of the candidate gene set identified in this study could enhance our understanding of the complex genetics underlying CHD and potentially lead to the development of new diagnostic and therapeutic approaches.