tbuckley/cabot-search huggingface dataset:
Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors
Authors: Sheila N. Garland, Joshua Tulk, Josée Savard, Joshua A. Rash, Sondria Browne, Robin Urquhart, Melanie Seal, John Thoms, Kara Laing
Journal: Journal of Clinical Oncology (2024)

PURPOSE Comorbid insomnia and cancer-related cognitive impairment (CRCI) are experienced by up to 26% of individuals diagnosed with cancer. This study examined the efficacy and durability of cognitive behavioral therapy for insomnia (CBT-I) on perceived CRCI in cancer survivors. METHODS Atlantic Canadian cancer survivors with insomnia and CRCI were randomly assigned to receive seven weekly virtual CBT-I sessions (n = 63) or placed in a waitlist control group (n = 69) to receive treatment after the waiting period. Participants completed assessments at baseline, 1 month (mid-treatment), and 2 months (post-treatment). Age- and education-adjusted mixed-effects models using intention-to-treat principles assessed change at post-treatment. Data from both groups were then pooled to assess the durability of effects at 3 and 6 months. A mediation analysis examined whether change in insomnia symptoms mediated the effect of CBT-I on cognitive outcomes. RESULTS The mean age of the sample was 60 years, 77% were women, and breast cancer was the most common diagnosis (41%). The treatment group reported an 11.35-point reduction in insomnia severity, compared with a 2.67-point reduction in the waitlist control group ( P &lt; .001). The treatment group had a greater overall improvement than the waitlist control on perceived cognitive impairment ( P &lt; .001; d = 0.75), cognitive abilities ( P &lt; .001; d = 0.92), and impact on quality of life ( P &lt; .001; d = 1.01). These improvements were maintained at follow-up. Change in insomnia symptoms fully mediated the effect of CBT-I on subjective cognitive outcomes. CONCLUSION Treating insomnia with CBT-I produces clinically meaningful and durable improvements in CRCI. There is an urgent need increase access to evidence-based treatment for insomnia in cancer centers and the community.
Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL
Authors: Yaqi Zhao, Nicholas J. Short, Hagop M. Kantarjian, Ti-Cheng Chang, Pankaj S. Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H. Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S. Garris, Lewis F. Nasr, Richard W. Kriwacki, Kathryn G. Roberts, Marina Konopleva, Elias J. Jabbour, Charles G. Mullighan
Journal: Blood (2024)
Error in Discussion
Journal: JAMA Network Open (2024)

Investigation titled "Statin Use and the Risk of Venous Thromboembolism in Women Taking Hormone Therapy," 1 published December 15, 2023, the second paragraph of the Discussion reported results from the Heart and Estrogen/Progestin Replacement cohort re-analysis describing incidence of coronary death and nonfatal myocardial infarction rather than results describing the incidence of venous thromboembolism.This article has been corrected. 1
GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma
Authors: Roselia Ciccone, Concetta Quintarelli, Antonio Camera, Michele Pezzella, Simona Caruso, Simona Manni, Alessio Ottaviani, Marika Guercio, Francesca Del Bufalo, Maria Cecilia Quadraccia, Domenico Orlando, Stefano Di Cecca, Matilde Sinibaldi, Mariasole Aurigemma, Laura Iaffaldano, Andrea Sarcinelli, Maria Luisa D'Amore, Manuela Ceccarelli, Francesca Nazio, Veronica Marabitti, Ezio Giorda, Marco Pezzullo, Cristiano De Stefanis, Andrea Carai, Sabrina Rossi, Rita Alaggio, Giada Del Baldo, Marco Becilli, Angela Mastronuzzi, Biagio De Angelis, Franco Locatelli
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects. Experimental Design: GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9. Results: GD2 was expressed in 82.68% of MB tumors. The SHH and G3–G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood–brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells. Conclusions: Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients.
Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages
Authors: Yulan Deng, Liang Xia, Jian Zhang, Senyi Deng, Mengyao Wang, Shiyou Wei, Kaixiu Li, Hongjin Lai, Yunhao Yang, Yuquan Bai, Yongcheng Liu, Lanzhi Luo, Zhenyu Yang, Yaohui Chen, Ran Kang, Fanyi Gan, Qiang Pu, Jiandong Mei, Lin Ma, Feng Lin, Chenglin Guo, Hu Liao, Yunke Zhu, Zheng Liu, Chengwu Liu, Yang Hu, Yong Yuan, Zhengyu Zha, Gang Yuan, Gao Zhang, Luonan Chen, Qing Cheng, Shensi Shen, Lunxu Liu
Journal: Cell Reports Medicine (2024)

<h2>Summary</h2> Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8<sup>+</sup> T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8<sup>+</sup> T cells, driven by specific stromal cells such as <i>CTHCR1</i><sup>+</sup> fibroblasts. This study also highlights <i>EGFR</i>(L858R) neoantigens in GGO samples, suggesting potential CD8<sup>+</sup> T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.
Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma
Authors: Nguyet-Minh Hoang, Yunxia Liu, Paul D. Bates, Alexa R. Heaton, Angelica F. Lopez, Peng Liu, Fen Zhu, Ruoyu Chen, Apoorv Kondapelli, Xiyu Zhang, Paul E. Selberg, Vu N. Ngo, Melissa C. Skala, Christian M. Capitini, Lixin Rui
Journal: Cell Reports Medicine (2024)

The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib achieves a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and affects long-term survival of MCL patients. Here, we demonstrate that DNA methyltransferase 3A (DNMT3A) is involved in ibrutinib resistance. We find that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses reveal that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS). Targeting DNMT3A with low-dose decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-mediated metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.
Solid Organ Transplant Recipients Exhibit More <i>TET2</i>-Mutant Clonal Hematopoiesis of Indeterminate Potential Not Driven by Increased Transplantation Risk
Authors: Alexander J. Silver, Caitlyn Vlasschaert, Taralynn Mack, Brian Sharber, Yaomin Xu, Alexander G. Bick, C. Wright Pinson, Michael R. Savona
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutations across several types of solid organ transplants. Experimental Design: We use two national biobank cohorts comprised of &amp;gt;650,000 participants with linked genomic and longitudinal phenotypic data to describe the features of CHIP across 2,610 individuals who received kidney, liver, heart, or lung allografts. Results: We find individuals with an allograft before their biobank enrollment had an increased prevalence of TET2 mutations (OR, 1.90; P = 4.0e−4), but individuals who received transplants post-enrollment had a CHIP mutation spectrum similar to that of the general population, without enrichment of TET2. In addition, we do not observe an association between CHIP and risk of incident transplantation among the overall population (HR, 1.02; P = 0.91). And in an exploratory analysis, we do not find evidence for a strong association between CHIP and rates of transplant complications such as rejection or graft failure. Conclusions: These results demonstrate that recipients of solid organ transplants display a unique pattern of clonal hematopoiesis with enrichment of TET2 driver mutations, the causes of which remain unclear and are deserving of further study.
Time to Reimagine Equity in Knowledge Generation
Authors: Dike Ojji, Angela Aifah, Ucheoma C. Nwaozuru
Journal: JAMA Network Open (2024)

Equity in research collaboration and scientific authorship remains an important topic, 1 especially among researchers in higher-income countries (HICs) and low-and middle-income countries (LMICs). 2,3Elsewhere in JAMA Network Open, using a cross-sectional bibliometric assessment, Eldridge and colleagues 4 elucidate the representation of authors from LMICs on publications
Immunologic tumor microenvironment modulators for turning cold tumors hot
Authors: Gholam‐Reza Khosravi, Samaneh Mostafavi, Sanaz Bastan, Narges Ebrahimi, Roya Safari Gharibvand, Nahid Eskandari
Journal: Cancer Communications (2024)

Abstract Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death protein 1/programmed death‐ligand 1(PD‐1/PD‐L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune‐resistant tumors.
Outcomes After Initiation of Medications for Alcohol Use Disorder at Hospital Discharge
Authors: Eden Y. Bernstein, Travis P. Baggett, Shrunjal Trivedi, Shoshana J. Herzig, Timothy S. Anderson
Journal: JAMA Network Open (2024)

Importance US Food and Drug Administration–approved medications for alcohol use disorder (MAUD) are significantly underused. Hospitalizations may provide an unmet opportunity to initiate MAUD, but few studies have examined clinical outcomes of patients who initiate these medications at hospital discharge. Objective To investigate the association between discharge MAUD initiation and 30-day posthospitalization outcomes. Design, Setting, and Participants This cohort study was conducted among patients with Medicare Part D who had alcohol-related hospitalizations in 2016. Data were analyzed from October 2022 to December 2023. Exposures Discharge MAUD initiation was defined as oral naltrexone, acamprosate, or disulfiram pharmacy fills within 2 days of discharge. Main outcomes The primary outcome was a composite of all-cause mortality or return to hospital (emergency department visits and hospital readmissions) within 30 days of discharge. Secondary outcomes included these components separately, return to hospital for alcohol-related diagnoses, and primary care or mental health follow-up within 30 days of discharge. Propensity score 3:1 matching and modified Poisson regressions were used to compare outcomes between patients who received and did not receive discharge MAUD. Results There were 6794 unique individuals representing 9834 alcohol-related hospitalizations (median [IQR] age, 54 [46-62] years; 3205 hospitalizations among females [32.6%]; 1754 hospitalizations among Black [17.8%], 712 hospitalizations among Hispanic [7.2%], and 7060 hospitalizations among White [71.8%] patients). Of these, 192 hospitalizations (2.0%) involved discharge MAUD initiation. After propensity matching, discharge MAUD initiation was associated with a 42% decreased incidence of the primary outcome (incident rate ratio, 0.58 [95% CI, 0.45 to 0.76]; absolute risk difference, −0.18 [95% CI, −0.26 to −0.11]). These findings were consistent among secondary outcomes (eg, incident rate ratio for all-cause return to hospital, 0.56 [95% CI, 0.43 to 0.73]) except for mortality, which was rare in both groups (incident rate ratio, 3.00 [95% CI, 0.42 to 21.22]). Discharge MAUD initiation was associated with a 51% decreased incidence of alcohol-related return to hospital (incident rate ratio, 0.49 [95% CI, 0.34 to 0.71]; absolute risk difference, −0.15 [95% CI, −0.22 to −0.09]). Conclusion and relevance In this cohort study, discharge initiation of MAUD after alcohol-related hospitalization was associated with a large absolute reduction in return to hospital within 30 days. These findings support efforts to increase uptake of MAUD initiation at hospital discharge.
Sobering Perspectives on the Treatment of Alcohol Use Disorder
Authors: Wid Yaseen, Jonathan Mong, Jonathan Zipursky
Journal: JAMA Network Open (2024)

Eden Y. Bernstein, MD; Travis P. Baggett, MD, MPH; Shrunjal Trivedi, MPH; Shoshana J. Herzig, MD, MPH; Timothy S. Anderson, MD, MAS
Retraction Note: Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression
Authors: Atsunori Kamiya, Yohsuke Hayama, Shigeki Kato, Akihiko Shimomura, Takushi Shimomura, Katsumasa Irie, Ryosuke Kaneko, Yuchio Yanagawa, Kazuto Kobayashi, Takahiro Ochiya
Journal: Nature Neuroscience (2024)
The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity
Authors: Jack Lockett, Warrick J Inder, Vicki L Clifton
Journal: Endocrine Reviews (2024)

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.
Matrix mechanics regulates muscle regeneration by modulating kinesin-1 activity
Authors: Wan-Yu Chiang, Helen Wenshin Yu, Ming-Chung Wu, Yi-Man Huang, Yin-Quan Chen, Jong-Wei Lin, Yen-Wenn Liu, Li-Ru You, Arthur Chiou, Jean-Cheng Kuo
Journal: Biomaterials (2024)

Sarcopenia, a prevalent muscle disease characterized by muscle mass and strength reduction, is associated with impaired skeletal muscle regeneration. However, the influence of the biomechanical properties of sarcopenic skeletal muscle on the efficiency of the myogenic program remains unclear. Herein, we established a mouse model of sarcopenia and observed a reduction in stiffness within the sarcopenic skeletal muscle in vivo. To investigate whether the biomechanical properties of skeletal muscle directly impact the myogenic program, we established an in vitro system to explore the intrinsic mechanism involving matrix stiffness control of myogenic differentiation. Our findings identify the microtubule motor protein, kinesin-1, as a mechano-transduction hub that senses and responds to matrix stiffness, crucial for myogenic differentiation and muscle regeneration. Specifically, kinesin-1 activity is positively regulated by stiff matrices, facilitating its role in transporting mitochondria and enhancing translocation of the glucose transporter GLUT4 to the cell surface for glucose uptake. Conversely, the softer matrices significantly suppress kinesin-1 activity, leading to the accumulation of mitochondria around nuclei and hindering glucose uptake by inhibiting GLUT4 membrane translocation, consequently impairing myogenic differentiation. The insights gained from the in-vitro system highlight the mechano-transduction significance of kinesin-1 motor proteins in myogenic differentiation. Furthermore, our study confirms that enhancing kinesin-1 activity in the sarcopenic mouse model restores satellite cell expansion, myogenic differentiation, and muscle regeneration. Taken together, our findings provide a potential target for improving muscle regeneration in sarcopenia.
FixNCut: single-cell genomics through reversible tissue fixation and dissociation
Authors: Laura Jiménez-Gracia, Domenica Marchese, Juan C. Nieto, Ginevra Caratù, Elisa Melón-Ardanaz, Victoria Gudiño, Sara Roth, Kellie Wise, Natalie K. Ryan, Kirk B. Jensen, Xavier Hernando-Momblona, Joana P. Bernardes, Florian Tran, Laura Katharina Sievers, Stefan Schreiber, Maarten van den Berge, Tessa Kole, Petra L. van der Velde, Martijn C. Nawijn, Philip Rosenstiel, Eduard Batlle, Lisa M. Butler, Ian A. Parish, Jasmine Plummer, Ivo Gut, Azucena Salas, Holger Heyn, Luciano G. Martelotto
Journal: Genome biology (2024)

Abstract The use of single-cell technologies for clinical applications requires disconnecting sampling from downstream processing steps. Early sample preservation can further increase robustness and reproducibility by avoiding artifacts introduced during specimen handling. We present FixNCut, a methodology for the reversible fixation of tissue followed by dissociation that overcomes current limitations. We applied FixNCut to human and mouse tissues to demonstrate the preservation of RNA integrity, sequencing library complexity, and cellular composition, while diminishing stress-related artifacts. Besides single-cell RNA sequencing, FixNCut is compatible with multiple single-cell and spatial technologies, making it a versatile tool for robust and flexible study designs.
Patients' values and preferences for health states in allergic rhinitis—An artificial intelligence supported systematic review
Authors: Jan Brozek, Ewa Borowiack, Ewelina Sadowska, Artur Nowak, Bernardo Sousa‐Pinto, Rafael José Vieira, Antonio Bognanni, Juan Jose Yepes Nuñez, Yuan Zhang, Torsten Zuberbier, Jean Bousquet, Holger J. Schünemann
Journal: Allergy (2024)

Abstract Background Allergic rhinitis (AR) impacts patients' physical and emotional well‐being. Assessing patients' values and preferences (V&amp;P) related to AR is an essential part of patient‐centered care and of the guideline development process. We aimed to systematically summarize the information about patients' V&amp;P on AR and its symptoms and impact on daily life. Methods We conducted systematic review in a MEDLINE, Embase, PsychInfo, and CINAHL databases. We included studies which quantitatively assessed patients' V&amp;P for specific outcomes in AR by assessing utilities, applying discrete choice approaches, or rating and ranking outcomes. We grouped outcomes as AR symptoms, functional status, and care‐related patient experience. Study selection and data extraction were supported by the Laser AI tool. We rated the certainty of evidence (CoE) using the GRADE approach. Results Thirty‐six studies (41 records) were included: nine utility studies, seven direct‐choice studies and 21 studies of rating or ranking outcomes. Utilities were lower with increased AR severity and with the concomitant presence of asthma, but not with whether AR was seasonal or perennial (CoE = low–high). Patients rated AR symptom‐related outcomes as more important than those related to care‐related patient experience and functional status (CoE = very low–moderate). Nasal symptoms (mainly nasal congestion) followed by breathing disorders, general and ocular symptoms were rated as the symptoms with the highest impact. Conclusions This systematic review provides a comprehensive overview of V&amp;P of patients with AR. Patients generally considered nasal symptoms as the most important. Future studies with standardized methods are needed to provide more information on V&amp;P in AR.