tbuckley/cabot-search huggingface dataset:
Immunochemotherapy and Maintenance With Obinutuzumab or Rituximab in Patients With Previously Untreated Marginal Zone Lymphoma in the Randomized GALLIUM Trial
Authors: Michael Herold, Eva Hoster, Ann Janssens, Helen McCarthy, Alessandra Tedeschi, Chris Pocock, Andras Rosta, Marek Trněný, Tina G. Nielsen, Andrea Knapp, Wolfgang Hiddemann, Robert Marcus
Journal: HemaSphere (2022)

The aim of this study was to explore the efficacy and safety of obinutuzumab (G)- versus rituximab (R)-chemotherapy in a subgroup of patients with previously untreated marginal zone lymphoma (MZL) in the phase III GALLIUM trial (NCT01332968). Patients had stage III/IV (or stage II with bulky disease), splenic, nodal, or extranodal MZL requiring treatment. Patients were randomized 1:1 to receive G- or R-chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; cyclophosphamide, vincristine, and prednisone; or bendamustine, allocated at patient level). Patients with complete/partial response at the end of induction (EOI) received G/R maintenance. Investigator-assessed progression-free survival (PFS), other time-to-event endpoints, response, and safety were assessed. Overall, 195 patients with MZL were included in this analysis: G-chemotherapy (n = 99), R-chemotherapy (n = 96). Median observation time: 59.3 months. No meaningful difference was observed between arms for PFS (4-y PFS rates: G-chemotherapy, 72.6%; R-chemotherapy, 64.1%), other time-to-event endpoints, or EOI response rates (by computed tomography [CT; G-chemotherapy, 81.8%; R-chemotherapy, 81.3%] and positron emission tomography CT [G-chemotherapy, 79.2%; R-chemotherapy, 87.5%]). All patients experienced ≥1 adverse event (AE). G-chemotherapy was associated with a higher incidence of grade 3-5 (86.1% versus 77.4%), grade 5 (14.9% versus 9.7%), and serious (66.3% versus 51.6%) AEs versus R-chemotherapy. Both arms had a higher incidence of grade 3-5 and serious AEs than patients with follicular lymphoma (GALLIUM), with G-chemotherapy being less tolerable than R-chemotherapy. Based on the observed tolerability of G-chemotherapy versus R-chemotherapy, and the comparable efficacy of G-chemotherapy and R-chemotherapy in this analysis, G-chemotherapy cannot be recommended as first-line treatment for MZL.
Code of practice needed for samples donated by trial participants
Authors: Robert Coleman, Arlene Chan, Carlos Barrios, David Cameron, Luis Costa, Mitch Dowsett, David Harrison, Anthony Howell, Denis Lacombe, Mairead MacKenzie, Miguel Martin, Stuart McIntosh, Adrienne Morgan, Martine Piccart, Tanja Spanic
Journal: The Lancet Oncology (2022)
PET/CT With 68Ga-PSMA and 18F-FDG in Metastatic Adenoid Cystic Carcinoma
Authors: Serkan Isgoren, Turkay Hekimsoy, Erdem Koroglu, Hakan Demir
Journal: Clinical Nuclear Medicine (2022)

Abstract Adenoid cystic carcinoma (ACC) is a rare and slow-growing tumor, originating from salivary glands. Locoregional recurrence and distant metastasis of ACC can be visualized not only with 18 F-FDG but also with 68 Ga-PSMA PET/CT due to its high prostate-specific membrane antigen (PSMA) expression. We report 2 cases of metastatic ACC who underwent first 18 F-FDG and then 68 Ga-PSMA for staging and restaging.
Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial
Authors: Yukihide Kanemitsu, Yasuhiro Shimizu, Junki Mizusawa, Yoshitaka Inaba, Tetsuya Hamaguchi, Dai Shida, Masayuki Ohue, Koji Komori, Akio Shiomi, Manabu Shiozawa, Jun Watanabe, Takeshi Suto, Yusuke Kinugasa, Yasumasa Takii, Hiroyuki Bando, Takaya Kobatake, Masafumi Inomata, Yasuhiro Shimada, Hiroshi Katayama, Haruhiko Fukuda
Journal: Journal of Clinical Oncology (2021)

Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC.In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis.Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration.DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.
Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche
Authors: Cui Liu, Qiuyun Chen, Yinghui Shang, Lechuang Chen, Jay Myers, Amad Awadallah, Jinger Sun, Shuiliang Yu, Katharine Umphred-Wilson, Danian Che, Yingtong Dou, Luoyi Li, Pamela Wearsch, Diana Ramírez-Bergeron, Rose Beck, Wei Xin, Ge Jin, Stanley Adoro, Lan Zhou
Journal: Theranostics (2022)

The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL).Methods: in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL.We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis.We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4.We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function.Results: we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche.The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration.Further, targeting endothelial PERK significantly improved T-ALL outcome.EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival.Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia.Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts.Conclusion: our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.
Clinical Activity of Single-Agent Cabozantinib (XL184), a Multi-receptor Tyrosine Kinase Inhibitor, in Patients with Refractory Soft-Tissue Sarcomas
Authors: Geraldine O'Sullivan Coyne, Shivaani Kummar, James Hu, Kristen Ganjoo, Warren A. Chow, Khanh T. Do, Jennifer Zlott, Ashley Bruns, Lawrence Rubinstein, Jared C. Foster, Lamin Juwara, Robert Meehan, Richard Piekarz, Howard Streicher, Elad Sharon, Naoko Takebe, Andrea Regier Voth, Donald Bottaro, Rene Costello, John J. Wright, James H. Doroshow, Alice P. Chen
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population. Patients and Methods: We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints. Results: Six (11.1%; 95% CI, 4.2%–22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%–67.3%), with a median time on study of 4 cycles (range, 1–99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome. Conclusions: Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.
Mechanical Left Ventricular Unloading in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation
Authors: E Wilson Grandin, Jose I Nunez, Brooks Willar, Kevin Kennedy, Peter Rycus, Joseph E Tonna, Navin K Kapur, Shahzad Shaefi, A Reshad Garan
Journal: Journal of the American College of Cardiology (2022)
Maintaining face mask use before and after achieving different COVID-19 vaccination coverage levels: a modelling study
Authors: Sarah M Bartsch, Kelly J O'Shea, Kevin L Chin, Ulrich Strych, Marie C Ferguson, Maria Elena Bottazzi, Patrick T Wedlock, Sarah N Cox, Sheryl S Siegmund, Peter J Hotez, Bruce Y Lee
Journal: The Lancet Public Health (2022)

Face mask wearing has been an important part of the response to the COVID-19 pandemic. As vaccination coverage progresses in countries, relaxation of such practices is increasing. Subsequent COVID-19 surges have raised the questions of whether face masks should be encouraged or required and for how long. Here, we aim to assess the value of maintaining face masks use indoors according to different COVID-19 vaccination coverage levels in the USA.
Global Patterns of Subgenome Evolution in Organelle-Targeted Genes of Six Allotetraploid Angiosperms
Authors: Joel Sharbrough, Justin L. Conover, Matheus Fernandes Gyorfy, Corrinne E. Grover, Emma R. Miller, Jonathan F. Wendel, Daniel B. Sloan
Journal: Molecular Biology and Evolution (2022)

Abstract Whole-genome duplications (WGDs) are a prominent process of diversification in eukaryotes. The genetic and evolutionary forces that WGD imposes on cytoplasmic genomes are not well understood, despite the central role that cytonuclear interactions play in eukaryotic function and fitness. Cellular respiration and photosynthesis depend on successful interaction between the 3,000+ nuclear-encoded proteins destined for the mitochondria or plastids and the gene products of cytoplasmic genomes in multi-subunit complexes such as OXPHOS, organellar ribosomes, Photosystems I and II, and Rubisco. Allopolyploids are thus faced with the critical task of coordinating interactions between the nuclear and cytoplasmic genes that were inherited from different species. Because the cytoplasmic genomes share a more recent history of common descent with the maternal nuclear subgenome than the paternal subgenome, evolutionary “mismatches” between the paternal subgenome and the cytoplasmic genomes in allopolyploids might lead to the accelerated rates of evolution in the paternal homoeologs of allopolyploids, either through relaxed purifying selection or strong directional selection to rectify these mismatches. We report evidence from six independently formed allotetraploids that the subgenomes exhibit unequal rates of protein-sequence evolution, but we found no evidence that cytonuclear incompatibilities result in altered evolutionary trajectories of the paternal homoeologs of organelle-targeted genes. The analyses of gene content revealed mixed evidence for whether the organelle-targeted genes are lost more rapidly than the non-organelle-targeted genes. Together, these global analyses provide insights into the complex evolutionary dynamics of allopolyploids, showing that the allopolyploid subgenomes have separate evolutionary trajectories despite sharing the same nucleus, generation time, and ecological context.
TYPE 2 DIABETES AND RISK OF MAJOR CARDIOVASCULAR EVENTS IN PERIPHERAL ARTERY DISEASE VERSUS CORONARY ARTERY DISEASE PATIENTS
Authors: Christoph H. Saely, Alexander Vonbank, Barbara Larcher, Arthur Mader, Maximilian Maechler, Lukas Sprenger, Valentin Grabher, Andreas Leiherer, Axel Muendlein, Heinz Drexel
Journal: Journal of the American College of Cardiology (2022)
Escaping from the IIT Munchausen method: Re-establishing the scientific method in the study of consciousness
Authors: Paul Verschure
Journal: Behavioral and Brain Sciences (2022)

Abstract Integrated information theory (IIT) is an example of “ironic science” and obstructs the scientific study of consciousness. By confusing the ontological status of a method to quantify network complexity with that of a theory of consciousness, IIT has to square the circle and spirals toward its panpsychism conclusion. I analyze the consequences of this fallacy and suggest how the study of consciousness can be brought back into the realm of rational, empirical science.
Focal Liver 18F-FDG Uptake in a Patient Who Underwent Thrombolysis for Brachiocephalic and Subclavian Thrombosis: A Potential Pitfall: Reply
Authors: Alexis Huot Daneault, Éric Turcotte, Étienne Rousseau
Journal: Clinical Nuclear Medicine (2022)

Huot Daneault, Alexis MD; Turcotte, Éric MD, FRCPC; Rousseau, Étienne MD, BEng, FRCPC Author Information
Multistate Outbreak of Melioidosis Associated with Imported Aromatherapy Spray
Authors: Jay E. Gee, William A. Bower, Amber Kunkel, Julia Petras, Jenna Gettings, Maria Bye, Melanie Firestone, Mindy G. Elrod, Lindy Liu, David D. Blaney, Allison Zaldivar, Chelsea Raybern, Farah S. Ahmed, Heidi Honza, Shelley Stonecipher, Briana J. O’Sullivan, Ruth Lynfield, Melissa Hunter, Skyler Brennan, Jessica Pavlick, Julie Gabel, Cherie Drenzek, Rachel Geller, Crystal Lee, Jana M. Ritter, Sherif R. Zaki, Christopher A. Gulvik, W. Wyatt Wilson, Elizabeth Beshearse, Bart J. Currie, Jessica R. Webb, Zachary P. Weiner, María E. Negrón, Alex R. Hoffmaster
Journal: New England Journal of Medicine (2022)

Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an uncommon infection that is typically associated with exposure to soil and water in tropical and subtropical environments. It is rarely diagnosed in the continental United States. Patients with melioidosis in the United States commonly report travel to regions where melioidosis is endemic. We report a cluster of four non-travel-associated cases of melioidosis in Georgia, Kansas, Minnesota, and Texas. These cases were caused by the same strain of B. pseudomallei that was linked to an aromatherapy spray product imported from a melioidosis-endemic area.
Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months
Authors: Einav G Levin, Yaniv Lustig, Carmit Cohen, Ronen Fluss, Victoria Indenbaum, Sharon Amit, Ram Doolman, Keren Asraf, Ella Mendelson, Arnona Ziv, Carmit Rubin, Laurence Freedman, Yitshak Kreiss, Gili Regev-Yochay
Journal: New England Journal of Medicine (2021)

BackgroundDespite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear.MethodsWe conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months.ResultsThe study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman's rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46).ConclusionsSix months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.
Artificial intelligence deployment in diabetic retinopathy: the last step of the translation continuum
Authors: Amy Yuan, Aaron Y Lee
Journal: The Lancet Digital Health (2022)

The disproportionate burden of diabetes worldwide on low-income and middle-income countries (LMICs) is a predicament keenly felt in the field of ophthalmology.1 Globally, the prevalence of visual impairment due to diabetic retinopathy is rising,2 attributed to growing rates of diabetic macular oedema, which is now more common than the historically more feared proliferative diabetic retinopathy and is the predominant cause of moderate or severe vision loss in patients with diabetes.3 Blindness from diabetic retinopathy is rendered all the more poignant by well established data about its preventability with early detection and intervention.
Single-cell analysis of somatic mutation burden in mammary epithelial cells of pathogenic BRCA1/2 mutation carriers
Authors: Shixiang Sun, Kristina Brazhnik, Moonsook Lee, Alexander Y. Maslov, Yi Zhang, Zhenqiu Huang, Susan Klugman, Ben H. Park, Jan Vijg, Cristina Montagna
Journal: Journal of Clinical Investigation (2022)

Inherited germline mutations in the breast cancer gene 1 (BRCA1) or BRCA2 genes (herein BRCA1/2) greatly increase the risk of breast and ovarian cancer, presumably by elevating somatic mutational errors as a consequence of deficient DNA repair. However, this has never been directly demonstrated by a comprehensive analysis of the somatic mutational landscape of primary, noncancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1/2 germline mutations. Here, we used an accurate, single-cell whole-genome sequencing approach to first show that telomerized primary mammary epithelial cells heterozygous for a highly penetrant BRCA1 variant displayed a robustly elevated mutation frequency as compared with their isogenic control cells. We then demonstrated a small but statistically significant increase in mutation frequency in mammary epithelial cells isolated from the breast of BRCA1/2 mutation carriers as compared with those obtained from age-matched controls with no genetically increased risk for breast cancer.
Abstract MP58: Eating Behaviors Influence Diet Quality: Impact Of Sleep Restriction
Authors: Rocio Barragan, Victoria Tam, Samantha Scaccia, Justin Cochran, Arindam RoyChoudhury, Marie-Pierre St-Onge
Journal: Circulation (2022)

Background: Eating behavior is an important construct with predictive value for energy intake and is associated with health. Two characteristics of eating behavior, eating window and eating frequency, are consistently associated with cardiometabolic risk across populations and have been shown to be related to sleep patterns. Both lifestyle factors have been related to cardiometabolic diseases but no long-term study has analyzed the association between sleep and eating behavior. Objective: To analyze the link between eating behavior and diet quality in a randomized, crossover study of sleep restriction (SR) vs adequate sleep (AS). Methods: Sixty-one participants (68% women, 20-73y) underwent 2 phases of 6 wk each, AS (sleep ≥7 h/night) and SR (-1.5 h/night relative to AS). Energy intake, diet quality, number of eating occasions (any eating/drinking episode providing at least 210kJ separated by &gt;15min) and eating window (time elapsed between the first and last eating occasion) were assessed at baseline, wk 3 and wk 6 of each phase using 3-d food records. Linear regression models were used to evaluate associations of eating behavior with diet quality by sleep condition, adjusting for confounding variables. Results: Participants had more eating occasions during SR compared to AS (β= 0.27±0.12, P=0.028). Duration of eating window also tended to be longer during SR compared to AS (β= 0.38±0.22, P=0.090). We then assessed the impact of these dietary behaviors on diet quality separately by condition. During AS, greater number of eating occasions was associated with greater energy intakes (β= 106.5±41.8, P=0.013), carbohydrates (β= 14.0±5.5, P=0.013), protein (β= 4.6±2.2, P=0.040), monounsaturated fat (β= 1.9±0.9, P=0.028), and fiber intakes (β= 2.1±0.8, P=0.010). Dietary glycemic index was also higher in those with greater eating occasions (β= 70.9±27.9, P=0.013). During SR, greater number of eating occasions was associated with greater energy intakes (β= 168.5±36.8, P&lt;0.001), fat (β= 6.3±2.1, P=0.004), carbohydrates (β= 19.7±4.7, P&lt;0.001), protein (β= 6.9±2.0, P&lt;0.001), saturated fat (β= 1.6±0.8, P=0.043), monounsaturated fat (β= 2.9±0.9, P=0.002), sugar (β= 6.5±1.8, P&lt;0.001), and fiber intakes (β= 2.2±0.7, P=0.003). Dietary glycemic index was also higher in those with greater eating occasions (β= 92.8±23.7, P&lt;0.001). Findings were similar but less pronounced for eating window duration. Conclusions: Higher eating frequency is associated with higher intakes of energy and several macronutrients. However, in the context of SR, more frequent eating occasions is associated with a worse dietary profile, namely greater intakes of saturated fat and sugar.