tbuckley/cabot-search huggingface dataset:
Cyclic Fasting–Mimicking Diet Plus Bortezomib and Rituximab Is an Effective Treatment for Chronic Lymphocytic Leukemia
Authors: Franca Raucci, Claudio Vernieri, Maira Di Tano, Francesca Ligorio, Olga Blaževitš, Samuel Lazzeri, Anastasiya Shmahala, Giuseppe Fragale, Giulia Salvadori, Gabriele Varano, Stefano Casola, Roberta Buono, Euplio Visco, Filippo de Braud, Valter D. Longo
Journal: Cancer Research (2024)

Abstract Cyclic fasting–mimicking diet (FMD) is an experimental nutritional intervention with potent antitumor activity in preclinical models of solid malignancies. FMD cycles are also safe and active metabolically and immunologically in cancer patients. Here, we reported on the outcome of FMD cycles in two patients with chronic lymphocytic leukemia (CLL) and investigated the effects of fasting and FMD cycles in preclinical CLL models. Fasting-mimicking conditions in murine CLL models had mild cytotoxic effects, which resulted in apoptosis activation mediated in part by lowered insulin and IGF1 concentrations. In CLL cells, fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. Pharmacologic inhibition of this escape mechanism with the proteasome inhibitor bortezomib resulted in a strong enhancement of the proapoptotic effects of starvation conditions in vitro. In mouse CLL models, combining cyclic fasting/FMD with bortezomib and rituximab, an anti-CD20 antibody, delayed CLL progression and resulted in significant prolongation of mouse survival. Overall, the effect of proteasome inhibition in combination with FMD cycles in promoting CLL death supports the targeting of starvation escape pathways as an effective treatment strategy that should be tested in clinical trials. Significance: Chronic lymphocytic leukemia cells resist fasting-mimicking diet by inducing proteasome activation to escape starvation, which can be targeted using proteasome inhibition by bortezomib treatment to impede leukemia progression and prolong survival.
Nutrient Sensing in Macrophages Linked to Reorganized Tumor Vasculature
Authors: Hilda L. Chan, Xiang H.-F. Zhang
Journal: Cancer Research (2024)

Abstract Macrophages are plastic immune cells that have varying functions dependent on stimulation from their environment. In a recent issue of Immunity, Do and colleagues demonstrated that activating mechanistic target of rapamycin complex 1 signaling in tumor macrophages alters their metabolism, localization, and function. Specifically, these tumor macrophages promote vascular remodeling that develops a hypoxic environment toxic to cancer cells. This culminates in a tangible reduction in tumor burden in a murine model of breast cancer. Their findings reveal a unique strategy to promote vascular remodeling through macrophage polarization and thereby highlight the intimate connections between macrophage metabolism and function. Additionally, their model highlights parallels between tumor progression and wound healing contexts while emphasizing the amplified effect of small perturbations to a tumor ecosystem.
UK covid inquiry: Scotland’s infection control and care home policies face scrutiny
Authors: Jacqui Wise
Journal: BMJ (2024)

UK covid inquiry: Scotland's infection control and care home policies face scrutinyThis week, the inquiry turned its attention to the devolved nations, starting with Scotland.Jacqui Wise reports on some of the key takeaways Jacqui WiseInfection control was "like pulling down a portcullis to stop a swarm of bees" Jane Morrison, lead member for the campaign group Covid Bereaved Scotland, told the inquiry how her wife died five days after contracting covid in hospital.Morrison said 25% of the group, which represents grieving families in Scotland, lost someone because of nosocomial infection.She told the inquiry that one of the group's members was allowed to wander around Hairmyres hospital in East Kilbride after testing positive for covid."This makes a mockery of infection control, it's like pulling down a portcullis to stop a swarm of bees."Giving evidence on 17 January, Morrison said families had "pleaded" with hospital bosses not to release their loved ones to free up NHS beds.She also said there were concerns early in the pandemic about the ability of care homes to cope with discharged hospital patients. 11 Transcript of module 2a Public hearing on 17 January 2024.https://covid19.public-inquiry.uk/hearings/
Targeting IDH2R140Q and other neoantigens in acute myeloid leukemia
Authors: Wingchi K. Leung, Alejandro G. Torres Chavez, Matthew French-Kim, Paul Shafer, Maksim Mamonkin, LaQuisa C. Hill, Manik Kuvalekar, Yovana Velazquez, Ayumi Watanabe, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Ann M. Leen
Journal: Blood (2024)
When I use a word . . . Lexicographic anniversaries in 2024—anaemia
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

The word "anaemia" is listed in the <i>Oxford English Dictionary</i> as having made its first appearance in print in 1824, 200 years ago. However, earlier instances can be found. Currently, the year 1800 seems to be the likeliest date of its print birthday.
Hypoxia-Directed Treatment of Human Papillomavirus–Related Oropharyngeal Carcinoma
Authors: Nancy Y. Lee, Eric J. Sherman, HeiKo Schöder, Rick Wray, Jay O. Boyle, Bhuvanesh Singh, Milan Grkovski, Ramesh Paudyal, Louise Cunningham, Zhigang Zhang, Vaios Hatzoglou, Nora Katabi, Bill H. Diplas, James Han, Brandon S. Imber, Khoi Pham, Yao Yu, Kaveh Zakeri, Sean M. McBride, Jung J. Kang, C. Jillian Tsai, Linda C. Chen, Daphna Y. Gelblum, Jatin P. Shah, Ian Ganly, Marc A. Cohen, Jennifer R. Cracchiolo, Luc G.T. Morris, Lara A. Dunn, Loren S. Michel, James V. Fetten, Anuja Kripani, David G. Pfister, Alan L. Ho, Amita Shukla-Dave, John L. Humm, Simon N. Powell, Bob T. Li, Jorge S. Reis-Filho, Luis A. Diaz, Richard J. Wong, Nadeem Riaz
Journal: Journal of Clinical Oncology (2024)

PURPOSE Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)–related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463 ). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18 F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.
Locoregional Breast Cancer Recurrence in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 MINDACT Trial: Analysis of Risk Factors Including the 70-Gene Signature
Authors: Sena Alaeikhanehshir, Taiwo Ajayi, Frederieke H. Duijnhoven, Coralie Poncet, Ridwan O. Olaniran, Esther H. Lips, Laura J. van 't Veer, Suzette Delaloge, Isabel T. Rubio, Alastair M. Thompson, Fatima Cardoso, Martine Piccart, Emiel J.T. Rutgers
Journal: Journal of Clinical Oncology (2024)

PURPOSE A number of studies are currently investigating de-escalation of radiation therapy in patients with a low risk of in-breast relapses on the basis of clinicopathologic factors and molecular tests. We evaluated whether 70-gene risk score is associated with risk of locoregional recurrence (LRR) and estimated 8-year cumulative incidences for LRR in patients with early-stage breast cancer treated with breast conservation. METHODS In this exploratory substudy of European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 MINDACT trial, we evaluated women with a known clinical and genomic 70-gene risk score test result and who had breast-conserving surgery (BCS). The primary end point was LRR at 8 years, estimated by cumulative incidences. Distant metastasis and death were considered competing risks. RESULTS Among 6,693 enrolled patients, 5,470 (81.7%) underwent BCS, of whom 98% received radiotherapy. At 8-year follow-up, 189 patients experienced a LRR, resulting in an 8-year cumulative incidence of 3.2% (95% CI, 2.7 to 3.7). In patients with a low-risk 70-gene signature, the 8-year LRR incidence was 2.7% (95% CI, 2.1 to 3.3). In univariable analysis, adjusted for chemotherapy, five of 12 variables were associated with LRR, including the 70-gene signature. In multivariable modeling, adjuvant endocrine therapy and to a lesser extent tumor size and grade remained significantly associated with LRR. CONCLUSION This exploratory analysis of the MINDACT trial estimated an 8-year low LRR rate of 3.2% after BCS. The 70-gene signature was not independently predictive of LRR perhaps because of the low number of events observed and currently cannot be used in clinical decision making regarding LRR. The overall low number of events does provide an opportunity to design trials toward de-escalation of local therapy.
AKT1 interacts with DHX9 to Mitigate R Loop–Induced Replication Stress in Ovarian Cancer
Authors: Tzu-Ting Huang, Chih-Yuan Chiang, Jayakumar R. Nair, Kelli M. Wilson, Ken Cheng, Jung-Min Lee
Journal: Cancer Research (2024)

Abstract PARP inhibitor (PARPi)–resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop–mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop–mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. Significance: Inhibition of the AKT and ATR pathways cooperatively induces R loop–associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793
Ketocyanine‐Based Fluorescent Probe Revealing the Polarity Heterogeneity of Lipid Droplets and Enabling Accurate Diagnosis of Hepatocellular Carcinoma
Authors: Deming He, Minmin Yan, Qiuling Sun, Mingwei Zhang, Yu Xia, Yuanqiang Sun, Zhaohui Li
Journal: Advanced Healthcare Materials (2024)

Hepatocellular carcinoma (HCC) has gradually become a pronoun for terrifying death owing to its high mortality rate. With the progression of HCC, lipid droplets (LDs) in HCC cells exhibit specific variations such as increased LDs number and decreased polarity, which can serve as the diagnostic target. However, developing an effective method to achieve HCC diagnosis and reveal LDs polarity heterogeneity is still a crucial challenge. Herein, the first high-performance LDs-targeting probe (1) is reported based on ketocyanine strategy with ultrasensitive polarity-responding ability and near-infrared emission. Probe 1 shows excellent sensitivity to polarity parameter Δf (0.027-0.290) with 808-fold fluorescence enhancement and the emission wavelength red-shifts 91 nm. In HCC cells, probe 1 shows a 2.5- to 5.9-fold fluorescence enhancement compared with normal and other cancer cells which exceeds clinical threshold of 2.0, indicating probe 1 can distinguish HCC cells. The LDs polarity heterogeneity is revealed and it displays a sequence, HCC cells < other cancer cells < normal cells, which may provide useful insight to engineer LDs-targeting probes for HCC cell discrimination. Finally, probe 1 realizes accurate HCC diagnosis on the cellular, organ, and in vivo levels, providing a satisfying tool for clinical HCC diagnosis and surgical navigation.
Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology
Authors: Shaji K. Kumar, Natalie S. Callander, Kehinde Adekola, Larry D. Anderson, Muhamed Baljevic, Rachid Baz, Erica Campagnaro, Jorge J. Castillo, Caitlin Costello, Christopher D’Angelo, Benjamin Derman, Srinivas Devarakonda, Noura Elsedawy, Alfred Garfall, Kelly Godby, Jens Hillengass, Leona Holmberg, Myo Htut, Carol Ann Huff, Malin Hultcrantz, Yubin Kang, Sarah Larson, Hans Lee, Michaela Liedtke, Thomas Martin, James Omel, Timothy Robinson, Aaron Rosenberg, Douglas Sborov, Mark A. Schroeder, Daniel Sherbenou, Attaya Suvannasankha, Jason Valent, Asya Nina Varshavsky-Yanovsky, Jenna Snedeker, Rashmi Kumar
Journal: Journal of the National Comprehensive Cancer Network (2024)

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.
NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024
Authors: Chrysalyne D. Schmults, Rachel Blitzblau, Sumaira Z. Aasi, Murad Alam, Arya Amini, Kristin Bibee, Diana Bolotin, Jeremy Bordeaux, Pei-Ling Chen, Carlo M. Contreras, Dominick DiMaio, Jessica M. Donigan, Jeffrey M. Farma, Karthik Ghosh, Kelly Harms, Alan L. Ho, John Nicholas Lukens, Susan Manber, Lawrence Mark, Theresa Medina, Kishwer S. Nehal, Paul Nghiem, Kelly Olino, Soo Park, Tejesh Patel, Igor Puzanov, Jason Rich, Aleksandar Sekulic, Ashok R. Shaha, Divya Srivastava, Valencia Thomas, Courtney Tomblinson, Puja Venkat, Yaohui Gloria Xu, Siegrid Yu, Mehran Yusuf, Beth McCullough, Sara Espinosa
Journal: Journal of the National Comprehensive Cancer Network (2024)

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled “Clinical N0 Disease, Locally Advanced MCC.” This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term “nonsurgical” by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.
A Methodological Framework for Meta-analysis and Clinical Interpretation of Subgroup Data: The Case of Major Adverse Cardiovascular Events With GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 2 Diabetes
Authors: Thomas Karagiannis, Apostolos Tsapas, Eleni Bekiari, Konstantinos A. Toulis, Michael A. Nauck
Journal: Diabetes Care (2024)

We present a methodological framework for conducting and interpreting subgroup meta-analyses. Methodological steps comprised evaluation of clinical heterogeneity regarding the definition of subpopulations, credibility assessment of subgroup meta-analysis, and translation of relative into absolute treatment effects. We used subgroup data from type 2 diabetes cardiovascular outcomes trials (CVOTs) with glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors for patients with established cardiovascular disease and those at high cardiovascular risk without manifest cardiovascular disease. First, we evaluated the variability in definitions of the subpopulations across CVOTs using major adverse cardiovascular events (MACE) incidence in the placebo arm as a proxy for baseline cardiovascular risk. As baseline risk did not differ considerably across CVOTs, we conducted subgroup meta-analyses of hazard ratios (HRs) for MACE and assessed the credibility of a potential effect modification. Results suggested using the same overall relative effect for each of the two subpopulations (HR 0.85, 95% CI 0.80–0.90, for GLP-1 receptor agonists and HR 0.91, 95% CI 0.85–0.97, for SGLT2 inhibitors). Finally, we calculated 5-year absolute treatment effects (number of fewer patients with event per 1,000 patients). Treatment with GLP-1 receptor agonists resulted in 30 fewer patients with event in the subpopulation with established cardiovascular disease and 14 fewer patients with event in patients without manifest cardiovascular disease. For SGLT2 inhibitors, the respective absolute effects were 18 and 8 fewer patients with event per 1,000 patients. This framework can be applied to subgroup meta-analyses regardless of outcomes or modification variables.
Response to Comment on Curovic et al. Optimization of Albuminuria-Lowering Treatment in Diabetes by Crossover Rotation to Four Different Drug Classes: A Randomized Crossover Trial. Diabetes Care 2023;46:593–601
Authors: Viktor Rotbain Curovic, Frederik Persson, Niels Jongs, Hiddo J.L. Heerspink
Journal: Diabetes Care (2024)
Comment on Chen et al. Ultra-Processed Food Consumption and Risk of Type 2 Diabetes: Three Large Prospective U.S. Cohort Studies. Diabetes Care 2023;46:1335–1344
Authors: Fabio S. Gomes, Leandro F.M. Rezende, Michael Schlüssel, Mark Lawrence, Priscila Machado, Melissa M. Lane
Journal: Diabetes Care (2024)
Performance of Artificial Intelligence in Detecting Diabetic Macular Edema From Fundus Photography and Optical Coherence Tomography Images: A Systematic Review and Meta-analysis
Authors: Ching Lam, Yiu Lun Wong, Ziqi Tang, Xiaoyan Hu, Truong X. Nguyen, Dawei Yang, Shuyi Zhang, Jennifer Ding, Simon K.H. Szeto, An Ran Ran, Carol Y. Cheung
Journal: Diabetes Care (2024)

BACKGROUND Diabetic macular edema (DME) is the leading cause of vision loss in people with diabetes. Application of artificial intelligence (AI) in interpreting fundus photography (FP) and optical coherence tomography (OCT) images allows prompt detection and intervention. PURPOSE To evaluate the performance of AI in detecting DME from FP or OCT images and identify potential factors affecting model performances. DATA SOURCES We searched seven electronic libraries up to 12 February 2023. STUDY SELECTION We included studies using AI to detect DME from FP or OCT images. DATA EXTRACTION We extracted study characteristics and performance parameters. DATA SYNTHESIS Fifty-three studies were included in the meta-analysis. FP-based algorithms of 25 studies yielded pooled area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of 0.964, 92.6%, and 91.1%, respectively. OCT-based algorithms of 28 studies yielded pooled AUROC, sensitivity, and specificity of 0.985, 95.9%, and 97.9%, respectively. Potential factors improving model performance included deep learning techniques, larger size, and more diversity in training data sets. Models demonstrated better performance when validated internally than externally, and those trained with multiple data sets showed better results upon external validation. LIMITATIONS Analyses were limited by unstandardized algorithm outcomes and insufficient data in patient demographics, OCT volumetric scans, and external validation. CONCLUSIONS This meta-analysis demonstrates satisfactory performance of AI in detecting DME from FP or OCT images. External validation is warranted for future studies to evaluate model generalizability. Further investigations may estimate optimal sample size, effect of class balance, patient demographics, and additional benefits of OCT volumetric scans.
Optimal Dose and Type of Physical Activity to Improve Glycemic Control in People Diagnosed With Type 2 Diabetes: A Systematic Review and Meta-analysis
Authors: Daniel Gallardo-Gómez, Eduardo Salazar-Martínez, Rosa M. Alfonso-Rosa, Javier Ramos-Munell, Jesús del Pozo-Cruz, Borja del Pozo Cruz, Francisco Álvarez-Barbosa
Journal: Diabetes Care (2024)

BACKGROUND The optimal dose or type of physical activity to control glycosylated hemoglobin (HbA1c) in people with diabetes remains unknown. Current guidelines do not include consideration of baseline HbA1c for activity prescription. PURPOSE To examine the dose-response relationship between physical activity and HbA1c (%) in individuals with type 2 diabetes. DATA SOURCES A systematic search was performed in Embase, MEDLINE, Scopus, CINAHL, SPORTDiscus, and Web of Science. STUDY SELECTION We included trials that involved participants diagnosed with type 2 diabetes that included any type of physical activity as intervention. DATA EXTRACTION Pre- and postintervention HbA1c data, population and interventions characteristics, and descriptive statistics were collected to calculate change scores for each study arm. DATA SYNTHESIS We used Bayesian random-effects meta-analyses to summarize high-quality evidence from 126 studies (6,718 participants). The optimal physical activity dose was 1,100 MET min/week, resulting in HbA1c reductions, ranging from −1.02% to −0.66% in severe uncontrolled diabetes, from −0.64% to −0.49% in uncontrolled diabetes, from −0.47% to −0.40% in controlled diabetes, and from −0.38% to −0.24% in prediabetes. LIMITATIONS The time required to achieve these HbA1c reductions could not be estimated due to the heterogeneity between interventions’ duration and protocols and the interpersonal variability of this outcome. CONCLUSIONS The result of this meta-analysis provide key information about the optimal weekly dose of physical activity for people with diabetes with consideration of baseline HbA1c level, and the effectiveness of different types of active interventions. These results enable clinicians to prescribe tailored physical activity programs for this population.