tbuckley/cabot-search huggingface dataset:
Acceptance and Commitment Therapy, Combined with Bedtime Restriction, versus Cognitive Behavioral Therapy for Insomnia: A Randomized Controlled Pilot Trial
Authors: Elisabeth Hertenstein, Ersilia Trinca, Carlotta L Schneider, Kristoffer D Fehér, Anna F Johann, Christoph Nissen
Journal: Psychotherapy and Psychosomatics (2024)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Cognitive behavioral therapy for insomnia (CBT-I) is the current first-line treatment for insomnia. However, rates of nonresponse and nonremission are high and effects on quality of life are only small to moderate, indicating a need for novel treatment developments. We propose that Acceptance and Commitment Therapy (ACT) addresses core pathophysiological pathways of insomnia. ACT therefore has the potential to improve treatment efficacy when combined with bedtime restriction, the most effective component of CBT-I. The aim of this study was to compare the efficacy of ACT for insomnia combined with bedtime restriction (ACT-I) and CBT-I in improving insomnia severity and sleep-related quality of life. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Sixty-three patients with insomnia disorder (mean age 52 years, 65% female, 35% male) were randomly assigned to receive either ACT-I or CBT-I in a group format. The primary outcomes were insomnia severity (Insomnia Severity Index) and sleep-related quality of life (Glasgow Sleep Impact Index). Outcomes were assessed before randomization (T0), directly after treatment (T1), and at 6-month follow-up (T2). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The results indicated significant, large pre-to-post improvements in both groups, for both primary and secondary outcomes. Improvements were maintained at the 6-month follow-up. However, there was no significant group by time interactions in linear mixed models, indicating an absence of differential efficacy. On a subjective treatment satisfaction scale, patients in the ACT-I group indicated significantly greater satisfaction with their improvement of several aspects of health including their energy level and work productivity. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The results suggest that ACT-I is feasible and effective, but not more effective than CBT-I for the improvement of insomnia severity and sleep-related quality of life. Future studies are needed to assess whether ACT-I is noninferior to CBT-I and to shed light on mechanisms of change in both treatments.
When Less Is More — The Importance of Patient Selection
Authors: Pedro T Ramirez
Journal: New England Journal of Medicine (2024)

The field of gynecologic oncology is rapidly evolving with the increasing availability of new therapeutics, including targeted therapies. In parallel, the field of surgery is shifting from the use of radical procedures to more-conservative approaches with fewer risks of complications. For patients with early-stage cervical cancer, the current recommendation according to National Comprehensive Cancer Network (NCCN) guidelines is open radical hysterectomy with bilateral pelvic lymphadenectomy (with or without sentinel lymph-node mapping) when fertility preservation is not desired.1 However, prospective data have shown that radical hysterectomy is associated with high rates of perioperative complications (e.g., urinary and bowel dysfunction).2 Numerous retrospective . . .
Cognition and Memory after Covid-19 in a Large Community Sample
Authors: Adam Hampshire, Adriana Azor, Christina Atchison, William Trender, Peter J Hellyer, Valentina Giunchiglia, Masud Husain, Graham S Cooke, Emily Cooper, Adam Lound, Christl A Donnelly, Marc Chadeau-Hyam, Helen Ward, Paul Elliott
Journal: New England Journal of Medicine (2024)

BackgroundCognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear.MethodsWe invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting ≥12 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating ("brain fog").ResultsOf the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no–Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (−0.23 SD [95% confidence interval {CI}, −0.33 to −0.13] and −0.24 SD [95% CI, −0.36 to −0.12], respectively); larger deficits as compared with the no–Covid-19 group were seen in participants with unresolved persistent symptoms (−0.42 SD; 95% CI, −0.53 to −0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., −0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, −0.20 to −0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, −0.35 SD; 95% CI, −0.49 to −0.20). Results of the analyses were similar to those of propensity-score–matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no–Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (−0.33 to −0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported.ConclusionsParticipants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.)
Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma
Authors: Romain Riscal, Sarah M. Gardner, Nathan J. Coffey, Madeleine Carens, Clementina Mesaros, Jimmy P. Xu, Yizheng Xue, Leah Davis, Sara Demczyszyn, Austin Vogt, Adam Olia, Jennifer M. Finan, Jason Godfrey, David C. Schultz, Ian A. Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, M. Celeste Simon
Journal: Cancer Research (2024)

Abstract Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. Significance: The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death.
Case 7-2024: A 67-Year-Old Woman with Alternating Sixth Cranial Nerve Palsy
Authors: Janeth M Yinh, Jeremy N Ford, April M Jorge, Reza Zonozi
Journal: New England Journal of Medicine (2024)

A 67-year-old woman was evaluated because of headache and retro-orbital pain. MRI of the head showed edema and enhancement of the optic-nerve sheath, sparing the nerve. A diagnosis was made.
Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia
Authors: Peng Jin, Xiaoling Wang, Qiqi Jin, Yi Zhang, Jie Shen, Ge Jiang, Hongming Zhu, Ming Zhao, Dan Wang, Zeyi Li, Yan Zhou, Wenzhu Li, Wei Zhang, Yabin Liu, Siyang Wang, Wen Jin, Yuncan Cao, Guangying Sheng, Fangyi Dong, Shishuang Wu, Xiaoyang Li, Zhen Jin, Mengke He, Xiaxin Liu, Luonan Chen, Yunxiang Zhang, Kankan Wang, Junmin Li
Journal: Cancer Research (2024)

Abstract Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. Significance: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.
β-Catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma
Authors: Ye Wang, Chunxiao Cheng, Yanjun Lu, Zhaowu Lian, Qi Liu, Yanchao Xu, Yunzheng Li, Huan Li, Laizhu Zhang, Xiang Jiang, Binghua Li, Decai Yu
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is a typical tumor that undergoes metabolic reprogramming, differing from normal liver tissue in glucose, lipid, nucleic acid, and amino acid metabolism. Although ammonia is a toxic metabolic by-product, it has also been recently recognized as a signaling molecule to activate lipid metabolism, and it can be a nitrogen source for biosynthesis to support tumorigenesis. In this study, we revealed that β-catenin activation increases ammonia production in HCC mainly by stimulating glutaminolysis. β-Catenin/LEF1 activated the transcription of the glutamate dehydrogenase GLUD1, which then promoted ammonia utilization to enhance the production of glutamate, aspartate, and proline as evidenced by 15NH4Cl metabolic flux. β-Catenin/TCF4 induced the transcription of SLC4A11, an ammonia transporter, to excrete excess ammonia. SLC4A11 was upregulated in HCC tumor tissues, and high SLC4A11 expression was associated with poor prognosis and advanced disease stages. Loss of SLC4A11 induced HCC cell senescence in vitro by blocking ammonia excretion and reduced β-catenin–driven tumor growth in vivo. Furthermore, elevated levels of plasma ammonia promoted the progression of β-catenin mutant HCC, which was impeded by SLC4A11 deficiency. Downregulation of SLC4A11 led to ammonia accumulation in tumor interstitial fluid and decreased plasma ammonia levels in HCC with activated β-catenin. Altogether, this study indicates that β-catenin activation reprograms ammonia metabolism and that blocking ammonia excretion by targeting SLC4A11 could be a promising approach to induce senescence in β-catenin mutant HCC. Significance: Ammonia metabolism reprogramming mediated by aberrant activation of β-catenin induces resistance to senescence in HCC and can be targeted by inhibiting SLC4A11 as a potential therapy for β-catenin mutant liver cancer.
Reply to Jiang et al.
Authors: Laurelle van Tilburg, Arjun D. Koch
Journal: Endoscopy (2024)

Letter to: Unveiling the hidden threat: esophageal squamous cell neoplasm in patients with head and neck squamous cell carcinomaEndoscopy 2024; 56(02): 157-157DOI: 10.1055/a-2219-2993
Advancing the Practice of Gastrointestinal Endoscopy Through Research
Authors: Lorenzo Fuccio, Pradeep Bhandari
Journal: Endoscopy (2024)

The overarching mission of ESGE is to educate, innovate, disseminate, support, and promote quality in the practice of gastrointestinal endoscopy. One of the ways to achieve these objectives is to promote high quality endoscopy research. The ESGE Research Committee was founded in 2000 with the aim of promoting and endorsing high quality research in endoscopy, directly fund meritorious research projects, attract industry funding for themed research ideas, and actively teach and promote core principles of clinical investigation.
Placental inflammation, oxidative stress, and fetal outcomes in maternal obesity
Authors: Cindy X.W. Zhang, Alejandro A. Candia, Amanda N. Sferruzzi-Perri
Journal: Trends in Endocrinology and Metabolism (2024)

The obesity epidemic has led to a growing body of research investigating the consequences of maternal obesity on pregnancy and offspring health. The placenta, traditionally viewed as a passive intermediary between mother and fetus, is known to play a critical role in modulating the intrauterine environment and fetal development, and we now know that maternal obesity leads to increased inflammation, oxidative stress, and altered placental function. Here, we review recent research exploring the involvement of inflammation and oxidative stress as mechanisms impacting the placenta and fetus during obese pregnancy. Understanding them is crucial for informing strategies that can mitigate the adverse health effects of maternal obesity on offspring development and disease risk.
Gamma delta T cells in acute myeloid leukemia: biology and emerging therapeutic strategies
Authors: Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti
Journal: Journal for ImmunoTherapy of Cancer (2024)

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of relapse, enhanced graft-versus-leukemia effect, and decreased graft-versus-host disease in patients with AML who have higher reconstitution of γδ T cells following allogeneic hematopoietic stem cell transplantation. Clinical trials leveraging γδ T cell biology have used unmodified and modified allogeneic cells as well as bispecific engagers and monoclonal antibodies. In this review, we discuss γδ T cells' biology, roles in cancer and AML, and mechanisms of immune escape and antileukemia effect; we also discuss recent clinical advances related to γδ T cells in the field of AML therapeutics.
CAR-mediated targeting of NK cells overcomes tumor immune escape caused by ICAM-1 downregulation
Authors: Jiri Eitler, Wiebke Rackwitz, Natalie Wotschel, Venugopal Gudipati, Nivedha Murali Shankar, Anastasia Sidorenkova, Johannes B Huppa, Paola Ortiz-Montero, Corinna Opitz, Stephan R Künzel, Susanne Michen, Achim Temme, Liliana Rodrigues Loureiro, Anja Feldmann, Michael Bachmann, Laurent Boissel, Hans Klingemann, Winfried S Wels, Torsten Tonn
Journal: Journal for ImmunoTherapy of Cancer (2024)

The antitumor activity of natural killer (NK) cells can be enhanced by specific targeting with therapeutic antibodies that trigger antibody-dependent cell-mediated cytotoxicity (ADCC) or by genetic engineering to express chimeric antigen receptors (CARs). Despite antibody or CAR targeting, some tumors remain resistant towards NK cell attack. While the importance of ICAM-1/LFA-1 interaction for natural cytotoxicity of NK cells is known, its impact on ADCC induced by the ErbB2 (HER2)-specific antibody trastuzumab and ErbB2-CAR-mediated NK cell cytotoxicity against breast cancer cells has not been investigated. Here we used NK-92 cells expressing high-affinity Fc receptor FcγRIIIa in combination with trastuzumab or ErbB2-CAR engineered NK-92 cells (NK-92/5.28.z) as well as primary human NK cells combined with trastuzumab or modified with the ErbB2-CAR and tested cytotoxicity against cancer cells varying in ICAM-1 expression or alternatively blocked LFA-1 on NK cells. Furthermore, we specifically stimulated Fc receptor, CAR and/or LFA-1 to study their crosstalk at the immunological synapse and their contribution to degranulation and intracellular signaling in antibody-targeted or CAR-targeted NK cells. Blockade of LFA-1 or absence of ICAM-1 significantly reduced cell killing and cytokine release during trastuzumab-mediated ADCC against ErbB2-positive breast cancer cells, but not so in CAR-targeted NK cells. Pretreatment with 5-aza-2'-deoxycytidine induced ICAM-1 upregulation and reversed NK cell resistance in ADCC. Trastuzumab alone did not sufficiently activate NK cells and required additional LFA-1 co-stimulation, while activation of the ErbB2-CAR in CAR-NK cells induced efficient degranulation independent of LFA-1. Total internal reflection fluorescence single molecule imaging revealed that CAR-NK cells formed an irregular immunological synapse with tumor cells that excluded ICAM-1, while trastuzumab formed typical peripheral supramolecular activation cluster (pSMAC) structures. Mechanistically, the absence of ICAM-1 did not affect cell-cell adhesion during ADCC, but rather resulted in decreased signaling via Pyk2 and ERK1/2, which was intrinsically provided by CAR-mediated targeting. Furthermore, while stimulation of the inhibitory NK cell checkpoint molecule NKG2A markedly reduced FcγRIIIa/LFA-1-mediated degranulation, retargeting by CAR was only marginally affected. Downregulation of ICAM-1 on breast cancer cells is a critical escape mechanism from trastuzumab-triggered ADCC. In contrast, CAR-NK cells are able to overcome cancer cell resistance caused by ICAM-1 reduction, highlighting the potential of CAR-NK cells in cancer immunotherapy.
Targeting RAF dimers in RAS mutant tumors: From biology to clinic
Authors: Huanhuan Yin, Qiulin Tang, Hongwei Xia, Feng Bi
Journal: Acta Pharmaceutica Sinica B (2024)

RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
Using liver stiffness to predict and monitor the risk of decompensation and mortality in patients with alcohol-related liver disease
Authors: Katrine Holtz Thorhauge, Georg Semmler, Stine Johansen, Katrine Prier Lindvig, Maria Kjærgaard, Johanne Kragh Hansen, Nikolaj Torp, Camilla Dalby Hansen, Peter Andersen, Benedikt Silvester Hofer, Wenyi Gu, Mads Israelsen, Mattias Mandorfer, Thomas Reiberger, Jonel Trebicka, Maja Thiele, Aleksander Krag
Journal: Journal of Hepatology (2024)

Background & Aims Liver stiffness measurements (LSM) are recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD). Methods Observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: Baseline LSM ≥10 kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10 kPa or <20 kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10 kPa as a LSM increase ("No cACLD increasers"). Remaining patients were considered LSM stable. Results We followed 536 patients for 3,008 patient-years, median age 57 years (IQR 49–63), baseline LSM 8.1 kPa (IQR 4.9-21.7). 371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17–38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n=33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: Baseline LSM 0.85; Follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: Baseline LSM 0.74; Follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (SHR=4.39, P=0.004) and mortality (HR=3.22, P=0.01). Conclusion Liver stiffness by transient elastography predicts decompensation and all-cause mortality in patients with compensated alcohol-related liver disease both at diagnosis and when used for monitoring.