tbuckley/cabot-search huggingface dataset:
Acquisition of suppressive function by conventional T cells limits antitumor immunity upon T <sub>reg</sub> depletion
Authors: Sarah K. Whiteside, Francis M. Grant, Giorgia Alvisi, James Clarke, Leqi Tang, Charlotte J. Imianowski, Baojie Zhang, Alexander C. Evans, Alexander J. Wesolowski, Alberto G. Conti, Jie Yang, Sarah N. Lauder, Mathew Clement, Ian R. Humphreys, James Dooley, Oliver Burton, Adrian Liston, Marco Alloisio, Emanuele Voulaz, Jean Langhorne, Klaus Okkenhaug, Enrico Lugli, Rahul Roychoudhuri
Journal: Science Immunology (2023)

Regulatory T (T
Early human lung immune cell development and its role in epithelial cell fate
Authors: Josephine L. Barnes, Masahiro Yoshida, Peng He, Kaylee B. Worlock, Rik G.H. Lindeboom, Chenqu Suo, J. Patrick Pett, Anna Wilbrey-Clark, Emma Dann, Lira Mamanova, Laura Richardson, Krzysztof Polanski, Adam Pennycuick, Jessica Allen-Hyttinen, Iván T. Herczeg, Romina Arzili, Robert E. Hynds, Vitor H. Teixeira, Muzlifah Haniffa, Kyungtae Lim, Dawei Sun, Emma L. Rawlins, Amanda J. Oliver, Paul A. Lyons, John C. Marioni, Christiana Ruhrberg, Zewen Kelvin Tuong, Menna R. Clatworthy, James L. Reading, Sam M. Janes, Sarah A. Teichmann, Kerstin B. Meyer, Marko Z. Nikolić
Journal: Science Immunology (2023)

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.
HLA DRB5∗01:01 is associated with pruritus in individuals with Fitzpatrick skin type IV-VI
Authors: Anusha Kambala, Ahmad Rajeh, Marina Z Joel, Emily Ma, Hannah Cornman, Jeni Zhang, Shawn G Kwatra
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Chronic pruritus (CP) is a common condition that significantly decreases quality of life and poses challenges for effective treatment.1 Racial disparities have been observed in various chronic pruritic dermatoses, with Black patients being more susceptible to conditions such as atopic dermatitis (AD), prurigo nodularis, and CP.2,3 However, the extent to which germline genetic variations, particularly HLA genotypes, influence the risk of pruritus across different Fitzpatrick skin types has not been well-established.
Impact of targeted agents on survival of chronic lymphocytic leukemia patients age &gt;65 relative to age‐ and sex‐matched population
Authors: Stefano Molica, Tait D. Shanafelt, David Allsup, Diana Giannarelli
Journal: American Journal of Hematology (2023)

Pooled analysis of six mature phase 3 trials (RESONATE2, ILLUMINATE, ALLIANCE041202, ELEVATE-TN, CLL14, and GLOW) evaluating Bruton's tyrosine kinase inhibitors (BTKis) and venetoclax-based treatments suggests that these agents have reduced but not completely eliminated the overall survival (OS) gap between elderly chronic lymphocytic leukemia (CLL) patients and the age and sex-matched general population (AGMGP).
Safety and efficacy of a new high‐dose regimen of panobinostat, gemcitabine, busulfan, and melphalan for 1st or 2nd salvage <scp>ASCT</scp> for refractory/relapsed or high‐risk myeloma: Matched‐pair comparisons with concurrent control cohorts
Authors: Yago Nieto, Zixi Yang, Benigno C. Valdez, Suprateek Kundu, Qaiser Bashir, Jeremy Ramdial, Samer Srour, Muzaffar Qazilbash
Journal: American Journal of Hematology (2023)

Abstract Improvement of autologous stem‐cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18–65 years with relapsed/refractory or high‐risk myeloma and adequate end‐organ function were eligible. Treatment included panobinostat (20 mg/day, days −9 to −2) and GemBuMel (days −8 to −2). Patients were enrolled in 1st (ASCT‐1) or 2nd ASCT (ASCT‐2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high‐risk cytogenetics, and response at ASCT. We enrolled 80 patients, 48 and 32 in the ASCT‐1 and ASCT‐2 cohorts, respectively; in these two cohorts, high‐risk cytogenetics were noted in 33 and 15 patients, respectively; unresponsive disease in 12 and 11 patients, respectively, after a median of 2 and 3 therapy lines, respectively. Transplant‐related mortality (TRM) occurred in two ASCT‐2 patients. One‐year PFS rates were 69% (ASCT‐1) and 72% (ASCT‐2); 1‐year OS rates were 79% (ASCT‐1) and 84% (ASCT‐2). Minimal residual disease negativity improved after ASCT‐1 (8.5%–23%, p &lt; .0001) and ASCT‐2 (34%–55%, p = .02), which correlated with improved outcomes. Trial patients and controls ( N = 371) had similar TRM and post‐ASCT maintenance. Trial patients had better PFS after either a 1st ( p = .02) or a 2nd ASCT ( p = .04) than matched‐paired control patients. In conclusion, panobinostat/GemBuMel is effective for relapsed/refractory or high‐risk myeloma patients, with better PFS than concurrent matched controls receiving melphalan or BuMel.
<i>Pharmacological Reviews’</i>75th Year Anniversary: Past and Future—Editorial
Authors: Lynette C. Daws
Journal: Pharmacological Reviews (2023)

I am excited and honored to be Editor in Chief of Pharmacological Reviews as it celebrates its 75th anniversary! Pharmacological Reviews enjoys a long and rich history of success, starting with its inception in 1949. The first editor was a pharmacology great, Louis S. Goodman, perhaps best known for
Breaking the performance ceiling for neoantigen immunogenicity prediction
Authors: Hugh O’Brien, Max Salm, Laura T. Morton, Maciej Szukszto, Felix O’Farrell, Charlotte Boulton, Pablo D. Becker, Yardena Samuels, Charles Swanton, Marc R. Mansour, Sine Reker Hadrup, Sergio A. Quezada
Journal: Nature Cancer (2023)
Better doctor-patient relationships start with the small things
Authors: Xuemin Yan, Jun Li
Journal: BMJ (2023)

Newton's third law of motion dictates that bodies exert forces upon each other. 1 The same can be true for doctor-patient interactions.Effective communication between doctors and patients, which accurately conveys intent and meaning and reduces misunderstandings, can improve patient prognosis. 2 3Communication is both verbal and non-verbal, with non-verbal communication, such as eye contact, voice modulation, and posture, constituting up to 80% of people's daily interpersonal interactions. 4 Even simple actions, like maintaining eye contact with a patient or sitting at their bedside, can improve the quality of communication between clinicians and patients.
“Nudging” clinicians to communicate more effectively with patients in hospital
Authors: Blair P Golden, Andrea Gilmore-Bykovskyi
Journal: BMJ (2023)

GAINS"Nudging" clinicians to communicate more effectively with patients in hospitalThe impact of sitting may not occur in isolation, but the approach seems promising Blair P Golden, 1 Andrea Gilmore-Bykovskyi 2Effective communication between patients and doctors is fundamental to the delivery of patient centered care, but it is both difficult to measure and challenging to attain in dynamic hospital environments.Specific behaviors on the part of doctors, including sitting at the hospital bedside, are associated with improved perception of doctors' communication by patients and have become an interventional target of interest. 1 -4 In the linked paper, Iyer and colleagues (doi:10.1136/bmj-2023-076309)add to a growing body of evidence showing that doctors' sitting behavior may be a potent, low cost tool to shape patients' perceptions of and experiences with communication, with potential implications for patients' outcomes.
Effect of chair placement on physicians’ behavior and patients’ satisfaction: randomized deception trial
Authors: Ruchita Iyer, Do Park, Jenny Kim, Courtney Newman, Avery Young, Andrew Sumarsono
Journal: BMJ (2023)

Abstract Objective To evaluate the effect of chair placement on length of time physicians sit during a bedside consultation and patients’ satisfaction. Design Single center, double blind, randomized controlled deception trial. Setting County hospital in Texas, USA. Participants 51 hospitalist physicians providing direct care services, and 125 observed encounters of patients who could answer four orientation questions correctly before study entry, April 2022 to February 2023. Intervention Each patient encounter was randomized to either chair placement (≤3 feet (0.9 m) of patient’s bedside and facing the bed) or usual chair location (control). Main outcome measures The primary outcome was the binary decision of the physician to sit or not sit at any point during a patient encounter. Secondary outcomes included patient satisfaction, as assessed with the Tool to Assess Inpatient Satisfaction with Care from Hospitalists (TAISCH) and the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys, time in the room, and both physicians’ and patients’ perception of time in the room. Results 125 patient encounters were randomized (60 to chair placement and 65 to control). 38 of the 60 physicians in the chair placement group sat during the patient encounter compared with five of the 65 physicians in the control group (odds ratio 20.7, 95% confidence interval 7.2 to 59.4; P&lt;0.001). The absolute risk difference between the intervention and control groups was 0.55 (95% confidence interval 0.42 to 0.69). Overall, 1.8 chairs needed to be placed for a physician to sit. Intervention was associated with 3.9% greater TAISCH scores (effect estimate 3.9, 95% confidence interval 0.9 to 7.0; P=0.01) and 5.1 greater odds of complete scores on HCAHPS (95% confidence interval 1.06 to 24.9, P=0.04). Chair placement was not associated with time spent in the room (10.6 minutes v control 10.6 minutes) nor perception of time in the room for physicians (9.4 minutes v 9.8 minutes) or patients (13.1 minutes v 13.5 minutes). Conclusion Chair placement is a simple, no cost, low tech intervention that increases a physician’s likelihood of sitting during a bedside consultation and resulted in higher patients’ scores for both satisfaction and communication. Trial registration ClinicalTrials.gov NCT05250778 .
Sumoylation of methionine adenosyltransferase alpha 1 promotes mitochondrial dysfunction in alcohol-associated liver disease
Authors: Andrea Floris, Swati Chandla, Youngyi Lim, Lucia Barbier-Torres, Karina Seth, Arash Khangholi, Tony W.H. Li, Aaron Robison, Ben J. Murray, Sion Lee, Michitaka Matsuda, Ramachandran Murali, Maria Lauda Tomasi, Shelly C. Lu
Journal: Hepatology (2023)

Background and Aims: Methionine adenosyltransferase alpha1 (MATα1) is responsible for the biosynthesis of S-adenosylmethionine in normal liver. Alcohol consumption enhances MATα1 interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which blocks MATα1 mitochondrial targeting, resulting in lower mitochondrial MATα1 content and mitochondrial dysfunction in alcohol-associated liver disease (ALD) in part through upregulation of cytochrome P450 2E1. Conversely, alcohol intake enhances SUMOylation, which enhances cytochrome P450 2E1 expression. MATα1 has potential SUMOylation sites, but whether MATα1 is regulated by SUMOylation in ALD is unknown. Here, we investigated if MATα1 is regulated by SUMOylation and, if so, how it impacts mitochondrial function in ALD. Approach and Results: Proteomics profiling revealed hyper-SUMOylation of MATα1, and prediction software identified lysine 48 (K48) as the potential SUMOylation site in mice (K47 in humans). Experiments with primary hepatocytes, mouse, and human livers revealed that SUMOylation of MAT1α by SUMO2 depleted mitochondrial MATα1. Furthermore, mutation of MATα1 K48 prevented ethanol-induced mitochondrial membrane depolarization, MATα1 depletion, and triglyceride accumulation. Additionally, CRISPR/CRISPR associated protein 9 gene editing of MATα1 at K48 hindered ethanol-induced MATα1-PIN1 interaction, degradation, and phosphorylation of MATα1 in vitro. In vivo, CRISPR/CRISPR associated protein 9 MATα1 K48 gene-edited mice were protected from ethanol-induced fat accumulation, liver injury, MATα1-PIN1 interaction, mitochondrial MATα1 depletion, mitochondrial dysfunction, and low S-adenosylmethionine levels. Conclusions: Taken together, our findings demonstrate an essential role for SUMOylation of MATα1 K48 for interaction with PIN1 in ALD. Preventing MATα1 K48 SUMOylation may represent a potential treatment strategy for ALD.
Lights, fiber, action! A primer on in vivo fiber photometry
Authors: Eleanor H. Simpson, Thomas Akam, Tommaso Patriarchi, Marta Blanco-Pozo, Lauren M. Burgeno, Ali Mohebi, Stephanie J. Cragg, Mark E. Walton
Journal: Neuron (2023)

Fiber photometry is a key technique for characterizing brain-behavior relationships in vivo. Initially, it was primarily used to report calcium dynamics as a proxy for neural activity via genetically encoded indicators. This generated new insights into brain functions including movement, memory, and motivation at the level of defined circuits and cell types. Recently, the opportunity for discovery with fiber photometry has exploded with the development of an extensive range of fluorescent sensors for biomolecules including neuromodulators and peptides that were previously inaccessible in vivo. This critical advance, combined with the new availability of affordable "plug-and-play" recording systems, has made monitoring molecules with high spatiotemporal precision during behavior highly accessible. However, while opening exciting new avenues for research, the rapid expansion in fiber photometry applications has occurred without coordination or consensus on best practices. Here, we provide a comprehensive guide to help end-users execute, analyze, and suitably interpret fiber photometry studies.
Unravelling the Potential Mortality Benefits of Mass Drug Administration With Azithromycin in Niger
Authors: Zulfiqar A. Bhutta
Journal: JAMA Network Open (2023)

Dennis L. Chao, PhD; Ahmed M. Arzika, MS; Amza Abdou, MD; Ramatou Maliki, MS; Alio Karamba, MD; Nasser Galo, MD; Diallo Beidi, MS; Nasser Harouna, MD; Moustapha Abarchi, MS; Elisabeth Root, PhD; Anu Mishra, PhD; Elodie Lebas, RN; Benjamin F. Arnold, PhD; Catherine E. Oldenburg, PhD; Jeremy D. Keenan, MD; Thomas M. Lietman, MD; Kieran S. O’Brien, PhD, MPH
Management of chronic pain secondary to temporomandibular disorders: a systematic review and network meta-analysis of randomised trials
Authors: Liang Yao, Behnam Sadeghirad, Meixuan Li, Jing Li, Qi Wang, Holly N Crandon, Grace Martin, Rebecca Morgan, Ivan D Florez, Birk Stokke Hunskaar, Jeff Wells, Sara Moradi, Ying Zhu, Muhammad Muneeb Ahmed, Ya Gao, Liujiao Cao, Kehu Yang, Jinhui Tian, Jialing Li, Linda Zhong, Rachel J Couban, Gordon H Guyatt, Thomas Agoritsas, Jason W Busse
Journal: BMJ (2023)

We explored the comparative effectiveness of available therapies for chronic pain associated with temporomandibular disorders (TMD).
Age-Related Incidence and Peak Occurrence of Contralateral Breast Cancer
Authors: Hakyoung Kim, Tae In Yoon, Seonok Kim, Sae Byul Lee, Jisun Kim, Il Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Young Jin Lee, Sungchan Gwark, Hee Jeong Kim
Journal: JAMA Network Open (2023)

Importance Young patients with breast cancer have higher risk for developing contralateral breast cancer (CBC) and have epidemiologic characteristics different from those of older patients. Objective To examine the incidence and peak occurrence of CBC according to age at primary breast cancer (PBC) surgery. Design, Setting, and Participants This cohort study included patients who were diagnosed with and underwent surgery for unilateral nonmetastatic breast cancer at Asan Medical Center, Korea, between January 1, 1999, and December 31, 2013, with follow-up through December 31, 2018. Data were analyzed from December 1, 2021, through April 30, 2023. Patients were divided into 2 groups according to their age at surgery for PBC: younger (≤35 years) vs older (&amp;amp;gt;35 years). Main Outcomes and Measures The main outcomes were cumulative incidence and hazard rate of CBC in the entire study population and in subgroups divided by cancer subtype, categorized according to hormone receptor (HR) and ERBB2 status. Results A total of 16 251 female patients with stage 0 to III breast cancer were analyzed; all patients were Korean. The mean (SD) age was 48.61 (10.06) years; 1318 patients (8.11%) were in the younger group, and 14 933 (91.89%) were in the older group. Median follow-up was 107 months (IQR, 79-145 months). Compared with the older group, the younger group had significantly higher incidence of CBC (10-year cumulative incidence, 7.1% vs 2.9%; P &amp;amp;lt; .001) and higher risk (hazard ratio, 2.10; 95% CI, 1.62-2.74) of developing CBC. The hazard rate, which indicates risk for developing CBC at a certain time frame, differed according to the subtype of primary cancer. In patients with the HR+/ ERBB2 – subtype, the risk increased continuously in both age groups. In patients with the triple negative subtype, the risk increased until approximately 10 years and then decreased in both age groups. Meanwhile, in the HR−/ ERBB2 + subtype, risk peaked earlier, especially in the younger group (1.7 years since first surgery in the younger group and 4.8 years in the older group). Conclusions and Relevance In this cohort study, patients aged 35 years or younger with breast cancer had a higher risk of developing CBC than older patients. Moreover, young patients with the HR−/ ERBB2 + subtype tended to have a shorter interval for developing CBC. These findings might be useful in guiding treatment decisions, such as contralateral prophylactic mastectomy.
Facts and Hopes on Biomarkers for Successful Early Clinical Immunotherapy Trials: Innovative Patient Enrichment Strategies
Authors: Michael A. Cannarile, Vaios Karanikas, Bernhard Reis, Christoph Mancao, Eleni Lagkadinou, Dominik Rüttinger, Natascha Rieder, Franclim R. Ribeiro, Henry Kao, Sebastian Dziadek, Bruno Gomes
Journal: Clinical Cancer Research (2023)

Despite the clinical validation and unequivocal benefit to patients, the development of cancer immunotherapies is facing some key challenges and the attrition rate in early phases of development remains high. Identifying the appropriate patient population that would benefit most from the drug is on the critical path for successful clinical development. We believe that a systematic implementation of patient enrichment strategies early in the drug development process and trial design, is the basis for an innovative, more efficient, and leaner clinical development to achieve earlier a clear proof of concept or proof of failure. In this position article, we will describe and propose key considerations for the implementation of patient enrichment strategies as an opportunity to provide decision-enabling data earlier in the drug development process. We introduce an innovative multidimensional tool for immuno-oncology drug development that focuses on facilitating the identification and prioritization of enrichment-relevant biomarkers, based on the drug mechanism of action. To illustrate its utility, we discuss patient enrichment examples and use a case in the field of cancer immunotherapy, together with technical and regulatory considerations. Overall, we propose to implement fit for purpose enrichment strategies for all investigational drugs as early as possible in the development process. We believe that this will increase the success rate of immuno-oncology clinical trials, and eventually bring new and better medicines to patients faster.
Multiscale protein networks systematically identify aberrant protein interactions and oncogenic regulators in seven cancer types
Authors: Won-Min Song, Abdulkadir Elmas, Richard Farias, Peng Xu, Xianxiao Zhou, Benjamin Hopkins, Kuan-lin Huang, Bin Zhang
Journal: Journal of Hematology & Oncology (2023)

Abstract Global proteomic data generated by advanced mass spectrometry (MS) technologies can help bridge the gap between genome/transcriptome and functions and hold great potential in elucidating unbiased functional models of pro-tumorigenic pathways. To this end, we collected the high-throughput, whole-genome MS data and conducted integrative proteomic network analyses of 687 cases across 7 cancer types including breast carcinoma (115 tumor samples; 10,438 genes), clear cell renal carcinoma (100 tumor samples; 9,910 genes), colorectal cancer (91 tumor samples; 7,362 genes), hepatocellular carcinoma (101 tumor samples; 6,478 genes), lung adenocarcinoma (104 tumor samples; 10,967 genes), stomach adenocarcinoma (80 tumor samples; 9,268 genes), and uterine corpus endometrial carcinoma UCEC (96 tumor samples; 10,768 genes). Through the protein co-expression network analysis, we identified co-expressed protein modules enriched for differentially expressed proteins in tumor as disease-associated pathways. Comparison with the respective transcriptome network models revealed proteome-specific cancer subnetworks associated with heme metabolism, DNA repair, spliceosome, oxidative phosphorylation and several oncogenic signaling pathways. Cross-cancer comparison identified highly preserved protein modules showing robust pan-cancer interactions and identified endoplasmic reticulum-associated degradation (ERAD) and N-acetyltransferase activity as the central functional axes. We further utilized these network models to predict pan-cancer protein regulators of disease-associated pathways. The top predicted pan-cancer regulators including RSL1D1, DDX21 and SMC2, were experimentally validated in lung, colon, breast cancer and fetal kidney cells. In summary, this study has developed interpretable network models of cancer proteomes, showcasing their potential in unveiling novel oncogenic regulators, elucidating underlying mechanisms, and identifying new therapeutic targets.