tbuckley/cabot-search huggingface dataset:
Comparative analysis of immune infiltrates in head and neck cancers across anatomical sites
Authors: Tara Muijlwijk, Dennis N L M Nijenhuis, Sonja H Ganzevles, Arjen Brink, Changlin Ke, Joseph N Fass, Venkatesh Rajamanickam, C René Leemans, Yoshinobu Koguchi, Bernard A Fox, Jos B Poell, Ruud H Brakenhoff, Rieneke van de Ven
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The response rate to immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) receptor is 13%–18% for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Detailed understanding of the tumor immune microenvironment (TIME) is crucial in order to explain and improve this response rate. HNSCCs arise at various anatomical locations including the oral cavity, hypopharynx, larynx and oropharynx. Studies directly comparing immune infiltration between anatomical sites are scarce. Since the distinct locations could drive deviating microenvironments, we questioned whether the immune composition varies across these HNSCC sites. Methods Here, we characterized the TIME of 76 fresh tumor specimens using flow cytometry and performed single-cell RNA-sequencing on nine head and neck tumor samples. Results We found major differences in the composition of the TIME between patients. When comparing anatomical sites: tumors originating from the oral cavity had higher T cell infiltrates than tumors from other anatomical sites. The percentage of tumor-infiltrating T-lymphocytes positive for the immune checkpoint PD-1 varied considerably between patients, with the highest fraction of PD-1+ T cells found in larynx squamous cell carcinomas (SCCs). While we had hypothesized that the anatomical sites of tumor origin would drive sample clustering, our data showed that the type of TIME was more dominant and was particularly driven by the fraction of T cells positive for PD-1. Moreover, a high proportion of PD-1+ CD8+ T cells associated with an improved overall survival. Using single-cell RNA-sequencing, we observed that PD-1 expression was highest in the CD8-ENTPD1 tissue resident memory T cell/exhausted T cell and CD4-CXCL13 type 1 T helper cell clusters. Conclusions We found that oral cavity SCCs had the highest frequencies of T cells. We also observed considerable interpatient heterogeneity for PD-1 on T cells, with noticeably higher frequencies of PD-1+ CD4+ T helper cells in larynx SCCs. Within the entire cohort, a higher fraction of CD8+ T cells positive for PD-1 was linked to improved overall survival. Whether the fraction of PD-1+ T cells within the TIME enables immune checkpoint inhibitor response prediction for patients with head and neck cancer remains to be determined.
Immunology of Kidney Disease
Authors: Orestes Foresto-Neto, Luísa Menezes-Silva, Jefferson Antônio Leite, Magaiver Andrade-Silva, Niels Olsen Saraiva Câmara
Journal: Annual Review of Immunology (2024)

The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis.
<i>CCR5</i>and<i>CCL5</i>gene expression in colorectal cancer: comprehensive profiling and clinical value
Authors: Francesca Battaglin, Yasmine Baca, Joshua Millstein, Yan Yang, Joanne Xiu, Hiroyuki Arai, Jingyuan Wang, Fang-Shu Ou, Federico Innocenti, Shannon M Mumenthaler, Priya Jayachandran, Natsuko Kawanishi, Annika Lenz, Shivani Soni, Sandra Algaze, Wu Zhang, Taline Khoukaz, Evanthia Roussos Torres, Andreas Seeber, Jim P Abraham, Emil Lou, Philip A Philip, Benjamin A Weinberg, Anthony F Shields, Richard M Goldberg, John L Marshall, Alan P Venook, W Michael Korn, Heinz-Josef Lenz
Journal: Journal for ImmunoTherapy of Cancer (2024)

The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes. 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.
Opposite Mechanical Preference of Bone/Nerve Regeneration in 3D‐Printed Bioelastomeric Scaffolds/Conduits Consistently Correlated with YAP‐Mediated Stem Cell Osteo/Neuro‐Genesis
Authors: Xiaopeng Cheng, Bowen Xu, Bingxi Lei, Shanfeng Wang
Journal: Advanced Healthcare Materials (2024)

To systematically unveil how substrate stiffness, a critical factor in directing cell fate through mechanotransduction, correlates with tissue regeneration, novel biodegradable and photo-curable poly(trimethylene carbonate) fumarates (PTMCFs) for fabricating elastomeric 2D substrates and 3D bone scaffolds/nerve conduits, are presented. These substrates and structures with adjustable stiffness serve as a unique platform to evaluate how this mechanical cue affects the fate of human umbilical cord mesenchymal stem cells (hMSCs) and hard/soft tissue regeneration in rat femur bone defect and sciatic nerve transection models; whilst, decoupling from topographical and chemical cues. In addition to a positive relationship between substrate stiffness (tensile modulus: 90-990 kPa) and hMSC adhesion, spreading, and proliferation mediated through Yes-associated protein (YAP), opposite mechanical preference is revealed in the osteogenesis and neurogenesis of hMSCs as they are significantly enhanced on the stiff and compliant substrates, respectively. In vivo tissue regeneration demonstrates the same trend: bone regeneration prefers the stiffer scaffolds; while, nerve regeneration prefers the more compliant conduits. Whole-transcriptome analysis further shows that upregulation of Rho GTPase activity and the downstream genes in the compliant group promote nerve repair, providing critical insight into the design strategies of biomaterials for stem cell regulation and hard/soft tissue regeneration through mechanotransduction.
RCAd-LTH-shPD-L1, a double-gene recombinant oncolytic adenovirus with enhanced antitumor immunity, increases lymphocyte infiltration and reshapes the tumor microenvironment
Authors: Yuan Meng, Haotian Liu, Haoran Zhu, Wanrong Zhang, Dong Sun, Xuefei Han, Ying Liu, Guangzuo Luo
Journal: Journal for ImmunoTherapy of Cancer (2024)

With the successful development of modern immunotherapy, immune checkpoint inhibitors (ICIs) are currently considered potential therapeutic options for patients with cancer. However, the therapeutic potential of ICIs in human cancer is mainly limited by their systemic toxicity and low response rate, which suggests the necessity of local drug delivery with an effective vector and reshaping the immunosuppressive tumor microenvironment (TME) to enhance ICI therapy. Here, we constructed a novel double-gene recombinant oncolytic adenovirus named RCAd-LTH-shPD-L1 based on the RCAd virus platform armed with a DNA fragment encoding an anti-VEGF antibody and shRNA to inhibit PD-L1 expression.
Treatment of Eating Disorders: Current Status, Challenges, and Future Directions
Authors: Carlos M. Grilo
Journal: Annual Review of Clinical Psychology (2024)

Specific psychological treatments have demonstrated efficacy and represent the first-line approaches recommended for anorexia nervosa, bulimia nervosa, and binge-eating disorder. Unfortunately, many patients, particularly those with anorexia nervosa, do not derive sufficient benefit from existing treatments, and better or alternative treatments for eating disorders are needed. Less progress has been made in developing pharmacologic options for eating disorders. No medications approved for anorexia nervosa exist, and only one each exists for bulimia nervosa and for binge-eating disorder; available data indicate that most patients fail to benefit from available medications. Longer and combined treatments have generally not enhanced outcomes. This review presents emerging findings from more complex and clinically relevant adaptive treatment designs, as they offer some clinical guidance and may serve as models for future enhanced treatment research.
The Alternative Model of Personality Disorders: Assessment, Convergent and Discriminant Validity, and a Look to the Future
Authors: Luis F. García, Fernando Gutiérrez, Oscar García, Anton Aluja
Journal: Annual Review of Clinical Psychology (2024)

The Alternative Model of Personality Disorders (AMPD) is a dimensional, empirically based diagnostic system developed to overcome the serious limitations of traditional categories. We review the mounting evidence on its convergent and discriminant validity, with an incursion into the less-studied ICD-11 system. In the literature, the AMPD's Pathological Trait Model (Criterion B) shows excellent convergence with normal personality traits, and it could be useful as an organizing framework for mental disorders. In contrast, Personality Functioning (Criterion A) cannot be distinguished from personality traits, lacks both discriminant and incremental validity, and has a shaky theoretical background. We offer some suggestions with a view to the future. These include removing Criterion A, using the real-life consequences of traits as indicators of severity, delving into the dynamic mechanisms underlying traits, and furthering the integration of currently disengaged psychological paradigms that can shape a sounder clinical science.
Abstract IA023: The role of RTF2 in replication and replication stress response
Authors: Agata Smogorzewska, Cayla Broton, Nicolas J. Blobel, Brooke Conti
Journal: Cancer Research (2024)

Abstract The replisome faithfully coordinates the essential process of genome duplication despite genomic sequences or lesions that slow or stall replication fork progression, collectively termed replication stress. Such lesions threaten the accurate transmission of the genome; as such, cells have evolved many mechanisms of replication fork protection and repair to ensure that the genome is fully replicated within the confines of S phase. Our group has previously characterized the essential protein Replication Termination Factor 2 (RTF2) as one such facilitator of replication control during both unperturbed and stalled conditions. During unperturbed replication, RTF2 localizes the Ribonuclease H2 heterotrimer (RNase H2) to replication forks, where RNase H2 facilitates the removal of ribonucleotides aberrantly incorporated into the genome to ensure replication fork speeds and promote the completion of genome duplication. When the replisome encounters fork-stalling lesions, however, RTF2-RNase H2 are removed from the replisome through the action of proteasome shuttle proteins DNA Damage Inducible 1 and 2 (DDI1/2) to promote replication restart dependent upon PRIM1, the primase subunit of DNA polymerase α. Further, we find that cells depleted of RTF2 accumulate mitotic markers, including phosphorylated FOXM1 and cyclin B1, during S phase and exhibit abnormal nuclear structures. Together, these findings suggest that RTF2-deficient cells bypass the S/G2 checkpoint, in which ATR functions to suppress CDK1 activity and mitotic progression while replication is ongoing and implicate RTF2 as a mediator of replication checkpoint control. Citation Format: Agata Smogorzewska, Cayla Broton, Nicolas J. Blobel, Brooke Conti. The role of RTF2 in replication and replication stress response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA023.
Evolution of cell therapy for renal cell carcinoma
Authors: Yufei Wang, Eloah Rabello Suarez, Gabriella Kastrunes, Najla Santos Pacheco de Campos, Rabia Abbas, Renata Schmieder Pivetta, Nithyassree Murugan, Ghanbar Mahmoodi Chalbatani, Vincent D’Andrea, Wayne A. Marasco
Journal: Molecular Cancer (2024)

Treatment for renal cell carcinoma (RCC) has improved dramatically over the last decade, shifting from high-dose cytokine therapy in combination with surgical resection of tumors to targeted therapy, immunotherapy, and combination therapies. However, curative treatment, particularly for advanced-stage disease, remains rare. Cell therapy as a "living drug" has achieved hematological malignancy cures with a high response rate, and significant research efforts have been made to facilitate its translation to solid tumors. Herein, we overview the cellular therapies for RCC focusing on allogeneic hematopoietic stem cell transplantation, T cell receptor gene-modified T cells, chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, lymphokine-activated killer (LAK) cells, γδ T cells, and dendritic cell vaccination. We have also included perspectives for using other recent approaches, such as CAR macrophages, dendritic cell-cytokine induced killer cells and regulatory CAR-T cells to shed light on preclinical development of cell therapy and advancing cell therapy into clinic to achieve cures for RCC.
Managing cirrhosis with limited resources: perspectives from sub-Saharan Africa
Authors: Mark W Sonderup, Patrick S Kamath, Yaw A Awuku, Hailemichael Desalegn, Neliswa Gogela, Leolin Katsidzira, Christian Tzeuton, Bilal Bobat, Chris Kassianides, C Wendy Spearman
Journal: The Lancet. Gastroenterology & hepatology (2024)
p53 suppresses lipid droplet–fueled tumorigenesis through phosphatidylcholine
Authors: Xiuduan Xu, Jianqin Wang, Li Xu, Peng Li, Peng Jiang
Journal: Journal of Clinical Investigation (2024)

Choline deficiency causes disorders including hepatic abnormalities and is associated with an increased risk of multiple types of cancer(1, 2). Here, by choline free diet-associated RNA-seq analyses, we found that the tumor suppressor p53 drives the Kennedy pathway via PCYT1B to control the growth of lipid droplets (LDs) and their fueling role in tumorigenesis. Mechanistically, through upregulation of PCYT1B, p53 channeled depleted choline stores to phosphatidylcholine (PC) biosynthesis during choline starvation, thus preventing LD coalescence. Cells lacking p53 failed to complete this response to choline depletion, leading to hepatic steatosis and tumorigenesis, and these effects could be reversed by enforcing PCYT1B expression or restoring PC abundance. Furthermore, loss of p53 or defects in the Kennedy pathway increased surface localization of hormone-sensitive lipase (HSL) on LDs to release specific fatty acids that fueled tumor cells in vivo and in vitro. Thus, p53 loss leads to dysregulation of choline metabolism and LD growth, and couples perturbed LD homeostasis to tumorigenesis.
Tick bites, <scp>IgE</scp> to galactose‐alpha‐1,3‐galactose and urticarial or anaphylactic reactions to mammalian meat: The alpha‐gal syndrome
Authors: Jeffrey M. Wilson, Loren Erickson, Michael Levin, Samuel M. Ailsworth, Scott P. Commins, Thomas A. E. Platts‐Mills
Journal: Allergy (2024)

Abstract The recent recognition of a syndrome of tick‐acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose‐alpha‐1,3‐galactose (alpha‐gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non‐primate mammals. Thus, fittingly, this allergic disorder is now called the alpha‐gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2–6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha‐gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick‐borne infections. IgE directed to alpha‐gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo‐ and ectoparasites, including ticks.
Anti-reflux mucosal ablation for refractory gastroesophageal reflux disease after Roux-en-Y gastric bypass
Authors: Fares Ayoub, Kalpesh K. Patel
Journal: Endoscopy (2024)

Roux-en-Y gastric bypass (RYGB) is the gold standard bariatric surgical intervention in obese patients with pre-operative gastroesophageal reflux disease (GERD) [1]. Several hypotheses have been proposed to explain GERD recurrence postoperatively, including retained acid-secreting parietal cells in the pouch [2], dysmotility of the Roux limb, and herniation of the gastric pouch through the hiatus. We report the successful treatment of refractory GERD following RYGB using anti-reflux mucosal ablation (ARMA) ([Fig. 1]).
Patient-Reported Financial Burden of Treatment for Colon or Rectal Cancer
Authors: Sheetal Kircher, Fenghai Duan, Na An, Ilanan F. Gareen, JoRean D. Sicks, Gelareh Sadigh, Jennifer M. Suga, Heather Kehn, Paul T. Mehan, Rajesh Bajaj, David S. Hanson, Samir M. Dalia, Jared D. Acoba, Demet Gokalp Yasar, Elyse R. Park, Lynne I. Wagner, Ruth C. Carlos
Journal: JAMA Network Open (2024)

The longitudinal experience of patients is critical to the development of interventions to identify and reduce financial hardship. To evaluate financial hardship over 12 months in patients with newly diagnosed colorectal cancer (CRC) undergoing curative-intent therapy. This prospective, longitudinal cohort study was conducted between May 2018 and July 2020, with time points over 12 months. Participants included patients at National Cance Institute Community Oncology Research Program sites. Eligibility criteria included age at least 18 years, newly diagnosed stage I to III CRC, not started chemotherapy and/or radiation, treated with curative intent, and able to speak English. Data were analyzed from December 2022 through April 2023. The primary end point was financial hardship, measured using the Comprehensive Score for Financial Toxicity (COST), which assesses the psychological domain of financial hardship (range, 0-44; higher score indicates better financial well-being). Participants completed 30-minute surveys (online or paper) at baseline and 3, 6, and 12 months. A total of 450 participants (mean [SD] age, 61.0 [12.0] years; 240 [53.3%] male) completed the baseline survey; 33 participants (7.3%) were Black and 379 participants (84.2%) were White, and 14 participants (3.1%) identified as Hispanic or Latino and 424 participants (94.2%) identified as neither Hispanic nor Latino. There were 192 participants (42.7%) with an annual household income of $60 000 or greater. There was an improvement in financial hardship from diagnosis to 12 months of 0.3 (95% CI, 0.2 to 0.3) points per month (P < .001). Patients with better quality of life and greater self-efficacy had less financial toxicity. Each 1-unit increase in Functional Assessment of Cancer Therapy-General (rapid version) score was associated with an increase of 0.7 (95% CI, 0.5 to 0.9) points in COST score (P < .001); each 1-unit increase in self-efficacy associated with an increase of 0.6 (95% CI, 0.2 to 1.0) points in COST score (P = .006). Patients who lived in areas with lower neighborhood socioeconomic status had greater financial toxicity. Neighborhood deprivation index was associated with a decrease of 0.3 (95% CI, -0.5 to -0.1) points in COST score (P = .009). These findings suggest that interventions for financial toxicity in cancer care should focus on counseling to improve self-efficacy and mitigate financial worry and screening for these interventions should include patients at higher risk of financial burden.
TransCell: <i>In silico</i> Characterization of Genomic Landscape and Cellular Responses by Deep Transfer Learning
Authors: Shan-Ju Yeh, Shreya Paithankar, Ruoqiao Chen, Jing Xing, Mengying Sun, Ke Liu, Jiayu Zhou, Bin Chen
Journal: Genomics Proteomics & Bioinformatics (2024)

Gene expression profiling of new or modified cell lines becomes routine today; however, obtaining comprehensive molecular characterization and cellular responses for a variety of cell lines, including those derived from underrepresented groups, is not trivial when resources are minimal. Using gene expression to predict other measurements has been actively explored; however, systematic investigation of its predictive power in various measurements has not been well studied. Here, we evaluated commonly used machine learning methods and presented TransCell, a two-step deep transfer learning framework that utilized the knowledge derived from pan-cancer tumor samples to predict molecular features and responses. Among these models, TransCell had the best performance in predicting metabolite, gene effect score (or genetic dependency), and drug sensitivity, and had comparable performance in predicting mutation, copy number variation, and protein expression. Notably, TransCell improved the performance by over 50% in drug sensitivity prediction and achieved a correlation of 0.7 in gene effect score prediction. Furthermore, predicted drug sensitivities revealed potential repurposing candidates for new 100 pediatric cancer cell lines, and predicted gene effect scores reflected BRAF resistance in melanoma cell lines. Together, we investigated the predictive power of gene expression in six molecular measurement types and developed a web portal (http://apps.octad.org/transcell/) that enables the prediction of 352,000 genomic and cellular response features solely from gene expression profiles.