tbuckley/cabot-search huggingface dataset:
Peritumoral administration of immunomodulatory antibodies as a triple combination suppresses skin tumor growth without systemic toxicity
Authors: Quentin G Wright, Debottam Sinha, James W Wells, Ian H Frazer, Jazmina L Gonzalez Cruz, Graham Robert Leggatt
Journal: Journal for ImmunoTherapy of Cancer (2024)

Skin cancers, particularly keratinocyte cancers, are the most commonly diagnosed tumors. Although surgery is often effective in early-stage disease, skin tumors are not always easily accessible, can reoccur and have the ability to metastasize. More recently, immunotherapies, including intravenously administered checkpoint inhibitors, have been shown to control some skin cancers, but with off-target toxicities when used in combination. Our study investigated whether peritumoral administration of an antibody combination targeting PD-1, 4-1BB (CD137) and VISTA might control skin tumors and lead to circulating antitumor immunity without off-target toxicity. The efficacy of combination immunotherapy administered peritumorally or intravenously was tested using transplantable tumor models injected into mouse ears (primary tumors) or subcutaneously in flank skin (secondary tumors). Changes to the tumor microenvironment were tracked using flow cytometry while tumor-specific, CD8 T cells were identified through enzyme-linked immunospot (ELISPOT) assays. Off-target toxicity of the combination immunotherapy was assessed via serum alanine aminotransferase ELISA and histological analysis of liver sections. The data showed that local administration of antibody therapy eliminated syngeneic murine tumors transplanted in the ear skin at a lower dose than required intravenously, and without measured hepatic toxicity. Tumor elimination was dependent on CD8 T cells and was associated with an increased percentage of CD8 T cells expressing granzyme B, KLRG1 and Eomes, and a decreased population of CD4 T cells including CD4+FoxP3+ cells in the treated tumor microenvironment. Importantly, untreated, distal tumors regressed following antibody treatment of a primary tumor, and immune memory prevented growth of subcutaneous flank tumors administered 50 days after regression of a primary tumor. Together, these data suggest that peritumoral immunotherapy for skin tumors offers advantages over conventional intravenous delivery, allowing antibody dose sparing, improved safety and inducing long-term systemic memory. Future clinical trials of immunotherapy for primary skin cancer should focus on peritumoral delivery of combinations of immune checkpoint antibodies.
No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: an observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC
Authors: Marjolein Metselaar-Albers, Irma Meijerman, Ferdi Engels, John Haanen, Jos Beijnen, Arief Lalmohamed
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were susceptible to confounding by indication. Our objective was therefore to assess whether the relationship between antibiotic use and ICI response is causative or merely associative. Methods A large, single-center observational cohort study was performed with individuals treated for either non-small cell lung carcinoma (NSCLC) or metastatic melanoma. An effect modification approach was used, aiming to estimate the association between antibiotic use and overall survival (OS) and compare these estimates between individuals receiving first-line ICI treatment versus those receiving first-line tyrosine kinase inhibitors (TKIs). Exposure of interest was antibiotic use within 30 days before the start of anticancer treatment. HRs for OS were estimated for antibiotics versus no antibiotics in each cohort using multivariable propensity adjusted analysis. The “true antibiotic effect” within the ICI versus TKI cohort was modeled using an interaction term. Results A total of 4534 patients were included, of which 1908 in the ICI cohort and 817 in the TKI cohort. Approximately 10% of patients in each cohort used antibiotics within 30 days before the start of anticancer treatment. Our results demonstrate a lack of synergistic interaction between current antibiotic use and ICI therapy in relation to OS: although antibiotic use was significantly associated with OS decline in the ICI cohort (HR=1.26 (95% CI 1.04 to 1.51)), a similar magnitude in OS decline was found within the TKI cohort (HR=1.24 (95% CI 0.95 to 1.62)). This was reflected by the synergy index (HR=0.96 (95% CI 0.70 to 1.31)), which implied no synergistic interaction between current antibiotic use and ICI. Conclusion This study strongly suggests that there is no causal detrimental association between antibiotic use and ICI therapy outcome when looking at OS in individuals with malignant melanoma or NSCLC. The frequently observed inverse association between antibiotics and ICI response in previous studies is most likely driven by confounding by indication, which was confirmed by the findings in our reference TKI cohort.
Sulforaphane activates CD8<sup>+</sup>T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’
Authors: Jinyan Liu, Huanan Chen, Caijuan Guo, Jieyao Li, Miaomiao Li, Ming Zhao, Ziyi Fu, Zhen Zhang, Feng Li, Xuan Zhao, Li Yang, Liping Wang, Quanjun Lv, Yi Zhang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Extensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME). Methods We monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8 + T cells in the blood samples from a phase I clinical trial (KY-2021–0350). Results In this study, we elucidated that SFN liberated CD8 + T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8 + T cells. Conclusions Collectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8 + T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.
Integrative analysis of spatial and single-cell transcriptome data from human pancreatic cancer reveals an intermediate cancer cell population associated with poor prognosis
Authors: Seongryong Kim, Galam Leem, Junjeong Choi, Yongjun Koh, Suho Lee, Sang-Hee Nam, Jin Su Kim, Chan Hee Park, Ho Kyoung Hwang, Kyoung Il Min, Jung Hyun Jo, Hee Seung Lee, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Si Young Song, Eui-Cheol Shin, Chang Moo Kang, Seungmin Bang, Jong-Eun Park
Journal: Genome Medicine (2024)

Abstract Background Recent studies using single-cell transcriptomic analysis have reported several distinct clusters of neoplastic epithelial cells and cancer-associated fibroblasts in the pancreatic cancer tumor microenvironment. However, their molecular characteristics and biological significance have not been clearly elucidated due to intra- and inter-tumoral heterogeneity. Methods We performed single-cell RNA sequencing using enriched non-immune cell populations from 17 pancreatic tumor tissues (16 pancreatic cancer and one high-grade dysplasia) and generated paired spatial transcriptomic data from seven patient samples. Results We identified five distinct functional subclusters of pancreatic cancer cells and six distinct cancer-associated fibroblast subclusters. We deeply profiled their characteristics, and we found that these subclusters successfully deconvoluted most of the features suggested in bulk transcriptome analysis of pancreatic cancer. Among those subclusters, we identified a novel cancer cell subcluster, Ep_VGLL1, showing intermediate characteristics between the extremities of basal-like and classical dichotomy, despite its prognostic value. Molecular features of Ep_VGLL1 suggest its transitional properties between basal-like and classical subtypes, which is supported by spatial transcriptomic data. Conclusions This integrative analysis not only provides a comprehensive landscape of pancreatic cancer and fibroblast population, but also suggests a novel insight to the dynamic states of pancreatic cancer cells and unveils potential therapeutic targets. Graphical Abstract
Outcomes in Clinical Subgroups of Patients With Alcohol-Related Hospitalizations
Authors: Erik L. Friesen, Andrea Mataruga, Nathan Nickel, Paul Kurdyak, James M. Bolton
Journal: JAMA Network Open (2024)

Importance Alcohol-related hospitalizations are common and associated with significant cost to the health care system. We have a limited understanding of the characteristics of individuals who experience alcohol-related hospitalizations, which limits our capacity to prioritize those at the highest risk of postdischarge harm. Objective To identify and characterize the clinical subgroups of individuals who are hospitalized for alcohol-related harms. Design, Setting, and Participants This cohort study used latent class analysis (LCA) to identify clinical subgroups of individuals experiencing alcohol-related hospitalizations in 2 provinces in Canada. All individuals between ages 10 and 105 years who were hospitalized for an alcohol-related harm between January 2017 and December 2018 (ie, the index hospitalization) were eligible. Data were analyzed between June 2023 and August 2023. Exposures The exposure of interest was the clinical subgroup that an individual belonged to. These subgroups were identified using an LCA based on (1) the characteristics of the index hospitalization and (2) the history of alcohol-related health service use. Main Outcomes and Measures In-hospital mortality, alcohol-related hospital readmission, and all-cause mortality in the year following discharge from the index hospitalization. The association between subgroup membership and the risk of in-hospital and postdischarge outcomes was evaluated using multivariable regression. Results A total of 34 043 individuals were included in analysis, 4753 from Manitoba (median [IQR] age, 49 [40-58] years; 1786 female [37.6%]) and 29 290 from Ontario (median [IQR] age, 57 [45-67] years; 8527 female [29.1%]). Seven subgroups were identified following a gradient from low-frequency service use for acute intoxication to high-frequency service use for severe alcohol use disorder and liver disease. In Ontario, there were 4431 individuals in the liver disease subgroup representing 15.5% of the cohort who were at the highest risk of 1-year mortality (1382 [31.2%]) relative to the acute intoxication subgroup (42 [4.0%]) (adjusted hazard ratio [aHR], 3.83; 95% CI, 2.80-5.24). There was also a small subgroup (10.6%) of individuals with high-frequency alcohol-related health service use who had a much higher hazard of readmission following the index hospitalization (1-year readmission: 703 of 1526 [46.1%] vs 104 of 1058 [9.8%] in the acute intoxication subgroup; aHR, 5.09; 95% CI, 4.11-6.31). Conclusions and Relevance In this population-based cohort study of individuals experiencing alcohol-related hospitalizations, we identified several small, clinically distinct subgroups that were at a disproportionately high risk of readmission and mortality. These groups could merit prioritization in strategies aimed at reducing the risk of adverse outcomes following alcohol-related hospitalizations.
Undiagnosed Cirrhosis and Hepatic Encephalopathy in a National Cohort of Veterans With Dementia
Authors: Jasmohan S. Bajaj, Scott G. Silvey, Shari Rogal, Jacqueline G. O’Leary, Heather Patton, Timothy R. Morgan, Gowthami Kanagalingam, Angela Gentili, Michael Godschalk, Nilang Patel
Journal: JAMA Network Open (2024)

Importance Dementia and hepatic encephalopathy (HE) are challenging to distinguish clinically. Undiagnosed cirrhosis in a patient with dementia can lead to missed opportunities to treat HE. Objective To examine the prevalence and risk factors of undiagnosed cirrhosis and therefore possible HE in veterans with dementia. Design, Setting, and Participants A retrospective cohort study was conducted between 2009 and 2019 using data from the Veterans Health Administration (VHA) and 2 separate validation cohorts from the Richmond Veterans Affairs Medical Center. Data analysis was conducted from May 20 to October 15, 2023. Participants included 177 422 US veterans with a diagnosis of dementia at 2 or more clinic visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) score. Exposures Demographic and clinical characteristics. Main Outcomes and Measures An FIB-4 score (&amp;amp;gt;2.67 suggestive of advanced fibrosis and &amp;amp;gt;3.25 suggestive of cirrhosis), capped at age 65 years even for those above this cutoff who were included in the analysis. Results Among 177 422 veterans (97.1% men; 80.7% White; mean (SD) age, 78.35 [10.97] years) 5.3% (n = 9373) had an FIB-4 score greater than 3.25 and 10.3% (n = 18 390) had an FIB-4 score greater than 2.67. In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with older age (odds ratio [OR], 1.07; 95% CI, 1.06-1.09), male gender (OR, 1.43; 95% CI, 1.26-1.61), congestive heart failure (OR, 1.48; 95% CI, 1.43-1.54), viral hepatitis (OR, 1.79; 95% CI, 1.66-1.91), Alcohol Use Disorders Identification Test score (OR, 1.56; 95% CI, 1.44-1.68), and chronic kidney disease (OR, 1.11; 95% CI, 1.04-1.17), and inversely associated with White race (OR, 0.79; 95% CI, 0.73-0.85), diabetes (OR, 0.78; 95% CI, 0.73-0.84), hyperlipidemia (OR, 0.84; 95% CI, 0.79-0.89), stroke (OR, 0.85; 95% CI, 0.79-0.91), tobacco use disorder (OR, 0.78; 95% CI, 0.70-0.87), and rural residence (OR, 0.92; 95% CI, 0.87-0.97). Similar findings were associated with the FIB-4 greater than 2.67 threshold. These codes were associated with cirrhosis on local validation. A local validation cohort of patients with dementia showed a similar percentage of high FIB-4 scores (4.4%-11.2%). Conclusions and Relevance The findings of this cohort study suggest that clinicians encountering patients with dementia should be encouraged to screen for cirrhosis using the FIB-4 score to uncover reversible factors associated with cognitive impairment, such as HE, to enhance outcomes.
Live Birth After Oocyte Donation In Vitro Fertilization Cycles in Women With Endometriosis
Authors: Alessio Paffoni, Maíra Casalechi, Dominique De Ziegler, Ettore Cicinelli, Edgardo Somigliana, Paola Viganò, Amerigo Vitagliano
Journal: JAMA Network Open (2024)

Although multiple mechanisms have been proposed to explain the infertility related to endometriosis, there are no conclusive data on the association of endometriosis with endometrial receptivity. The oocyte donation model in assisted reproduction technology (ART) cycles can clarify this issue.
Leisure-Time Physical Activity and Falls With and Without Injuries Among Older Adult Women
Authors: Wing S. Kwok, Saman Khalatbari-Soltani, Xenia Dolja-Gore, Julie Byles, Anne Tiedemann, Marina B. Pinheiro, Juliana S. Oliveira, Catherine Sherrington
Journal: JAMA Network Open (2024)

Falls and fall-related injuries are common among older adults. Older adults are recommended to undertake 150 to 300 minutes of physical activity per week for health benefits; however, the association between meeting the recommended level of physical activity and falls is unclear.
Short-Term Cardiovascular Complications in Dermatology Patients Receiving JAK-STAT Inhibitors
Authors: Patrick A. Ireland, Nicholas Jansson, Sascha K. R. Spencer, Jorja Braden, Deshan Sebaratnam
Journal: JAMA Dermatology (2024)

Evolving evidence suggests that patients receiving Janus kinase-signal transducer and activator of transcription inhibitors (JAK-STATi) may be at higher risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). Most existing literature has focused on indications that may confer a higher MACE and VTE risk than that among patients with isolated dermatological indications.
“They just knew, and that makes all the difference”: understanding positive healthcare experiences among trans people in Canada
Authors: Rachel Goldfarb, M. A. Katz, R. Travers, J. Poliwoda, M. Sadri-Gerrior, C. Valiant, A. Ananthavel Murugan, J. Tang, G. Henry, T. Coleman
Journal: International Journal of Transgender Health (2024)

Background Trans people face persistent systemic challenges and barriers in healthcare systems. Despite these obstacles, many trans people have had positive healthcare experiences, however little is known regarding their commonalities.
Trajectories of Postoperative Depressive Symptoms in Older Patients Undergoing Major Surgery
Authors: Irena Cenzer, Sharon K. Inouye, Patrick J. Raue, Christina Keny, Zara Cooper, Victoria L. Tang
Journal: JAMA Network Open (2024)

This cohort study examines the trajectories of postoperative depressive symptoms in older patients undergoing major surgery and the differences in patient characteristics between the trajectory groups.
Time to First Whole Blood Associated With Survival—First (Whole) Blood?
Authors: Jason L. Sperry, Matthew D. Neal
Journal: JAMA Surgery (2024)

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Timing to First Whole Blood Transfusion and Survival Following Severe Hemorrhage in Trauma Patients
Authors: Crisanto M. Torres, Kelly M. Kenzik, Noelle N. Saillant, Dane R. Scantling, Sabrina E. Sanchez, Tejal S. Brahmbhatt, Tracey A. Dechert, Joseph V. Sakran
Journal: JAMA Surgery (2024)

Civilian trauma centers have revived interest in whole-blood (WB) resuscitation for patients with life-threatening bleeding. However, there remains insufficient evidence that the timing of WB transfusion when given as an adjunct to a massive transfusion protocol (MTP) is associated with a difference in patient survival outcome.
Bariatric Surgery and Longitudinal Cancer Risk
Authors: Pei-Wen Lim, Chee-Chee H. Stucky, Nabil Wasif, David A. Etzioni, Kristi L. Harold, James A. Madura, Zhi Ven Fong
Journal: JAMA Surgery (2024)

Cancer is one of the leading causes of death in the United States, with the obesity epidemic contributing to its steady increase every year. Recent cohort studies find an association between bariatric surgery and reduced longitudinal cancer risk, but with heterogeneous findings.
Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol
Authors: Yiyi Zhang, Jacqueline S. Dron, Brandon K. Bellows, Amit V. Khera, Junxiu Liu, Pallavi P. Balte, Elizabeth C. Oelsner, Sami Samir Amr, Matthew S. Lebo, Anna Nagy, Gina M. Peloso, Pradeep Natarajan, Jerome I. Rotter, Cristen Willer, Eric Boerwinkle, Christie M. Ballantyne, Pamela L. Lutsey, Myriam Fornage, Donald M. Lloyd-Jones, Lifang Hou, Bruce M. Psaty, Joshua C. Bis, James S. Floyd, Ramachandran S. Vasan, Nancy L. Heard-Costa, April P. Carson, Michael E. Hall, Stephen S. Rich, Xiuqing Guo, Dhruv S. Kazi, Sarah D. de Ferranti, Andrew E. Moran
Journal: JAMA Cardiology (2024)

Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.
Estimated Spending on Beremagene Geperpavec for Dystrophic Epidermolysis Bullosa
Authors: Adam J. N. Raymakers, Aaron S. Kesselheim, Arash Mostaghimi, William B. Feldman
Journal: JAMA Dermatology (2024)

New gene therapies can offer substantial benefits to patients, particularly those with rare diseases who have few therapeutic options. In May 2023, the US Food and Drug Administration (FDA) approved the first topical gene therapy, beremagene geperpavec (B-VEC), for treating both autosomal recessive and autosomal dominant dystrophic epidermolysis bullosa (DEB). However, FDA approval was based on limited data in patients with autosomal dominant disease, even though they comprise approximately 50% of all DEB cases.