tbuckley/cabot-search huggingface dataset:
R-Loop Associated Mitotic Stress Confers Vulnerabilities in Splicing Factor Mutant Leukemia
Authors: Martina Cusan, Meiling Jin, Bo Zhang, Mike Fernandez, Aijun Liao, Lu Yang, Yiming Wu, Prajish Iyer, Kevyn Hart, Catherine Gutierrez, Jeremy Stark, Teresa V. Bowman, Catherine J. Wu, Ren-Jang Lin, Lili Wang
Journal: Blood (2021)
27P Plasma-derived exosomes as biomarkers for therapy monitoring in head and neck cancer patients treated with surgery and (chemo)radiotherapy
Authors: L. Hofmann, S. Laban, E.K. Jackson, R. Lotfi, P.J. Schuler, C. Brunner, T.K. Hoffmann, T.L. Whiteside, M-N. Theodoraki
Journal: Annals of Oncology (2021)
Omitted Nonauthor Collaborators
Authors: Ping Liu, Carlee Thorsen, Pietro Ravani
Journal: JAMA Internal Medicine (2021)

Alex C. Spyropoulos, MD; Mark Goldin, MD; Dimitrios Giannis, MD, MSc; Wassim Diab, MD; Janice Wang, MD; Sameer Khanijo, MD; Andrea Mignatti, MD; Eugenia Gianos, MD; Marc Cohen, MD; Gulru Sharifova, MD; Jeet M. Lund, DO; Alfonso Tafur, MD, MSc, RPVI; Paul A. Lewis, MD, CPE; Kevin P. Cohoon, DO; Husneara Rahman, PhD; Cristina P. Sison, PhD; Martin L. Lesser, PhD; Kanta Ochani, MBBS; Nirav Agrawal, MBBS; Judith Hsia, MD; Victoria E. Anderson, MPH; Marc Bonaca, MD, MPH; Jonathan L. Halperin, MD; Jeffrey I. Weitz, MD; HEP-COVID Investigators; Lori Ohanesian; Michelle Glater; Christopher Ho; Annamaria Iakovou; Daniel Ying; Manile Dastagir; Alex Convissar; Seerat Aujla; Elizabeth Mathew; Vani Thiyagarajan; Tricia Lewis; Luis Gruberg; Paul Maccaro; Dana Kuziw; Bhumi Pandhi; George Surguladze; Ashley M. Eapen; Alexandra Pantea; Phyllis Suen; John Flynt; Michael Krzyzak; Kamal Sharma; Amanda Steadham; Sherry L. McLean; Karen Herring; Karen Maroney; Kambiz Zorriasateyn; Bernardo Vargas; Marisa Durante; Ujala Bhokary; Linda Pierchala; Elizabeth A. Fisher; Debi L. Oxenberg; Alison Sabados; Omair A. Chaudhary; Shelley Schultz; Sue Cotey; Connie Hess; Hope Cruse; Daniel Uy; Sunita Sharma; Kevin Molina; Daliya Jagat; Bandyopadhyay Dehali
WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models
Authors: Takahiro Kishikawa, Hiroshi Higuchi, Limei Wang, Nivedita Panch, Valerie Maymi, Sachem Best, Samuel Lee, Genso Notoya, Alex Toker, Lydia E. Matesic, Gerburg M. Wulf, Wenyi Wei, Motoyuki Otsuka, Kazuhiko Koike, John G. Clohessy, Yu-Ru Lee, Pier Paolo Pandolfi
Journal: Journal of Clinical Investigation (2021)

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pervasive event in tumorigenesis due to PI3K mutation and dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Pharmacological inhibition of PI3K has resulted in variable clinical outcomes, however, raising questions regarding the possible mechanisms of unresponsiveness and resistance to treatment. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase frequently amplified and mutated in multiple cancers, as well as in the germ lines of patients predisposed to cancer, and was recently found to activate PI3K signaling through PTEN inactivation. Here, we demonstrate that PTEN dissociated from the plasma membrane upon treatment with PI3K inhibitors through WWP1 activation, whereas WWP1 genetic or pharmacological inhibition restored PTEN membrane localization, synergizing with PI3K inhibitors to suppress tumor growth both in vitro and in vivo. Furthermore, we demonstrate that WWP1 inhibition attenuated hyperglycemia and the consequent insulin feedback, which is a major tumor-promoting side effect of PI3K inhibitors. Mechanistically, we found that AMPKα2 was ubiquitinated and, in turn, inhibited in its activatory phosphorylation by WWP1, whereas WWP1 inhibition facilitated AMPKα2 activity in the muscle to compensate for the reduction in glucose uptake observed upon PI3K inhibition. Thus, our identification of the cell-autonomous and systemic roles of WWP1 inhibition expands the therapeutic potential of PI3K inhibitors and reveals new avenues of combination cancer therapy.
Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study
Authors: David M. O'Malley, Maryna Neffa, Bradley J. Monk, Tamar Melkadze, Marilyn Huang, Anna Kryzhanivska, Iurie Bulat, Tarek M. Meniawy, Andrea Bagameri, Edward W. Wang, Bernard Doger de Speville Uribe, Roberto Hegg, Waldo Ortuzar Feliu, Marek Ancukiewicz, Iwona Lugowska
Journal: Journal of Clinical Oncology (2021)

Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte-associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy.
The role of endoscopic ultrasound investigation in the diagnosis of submucosal neoplasms of the stomach and duodenum (literature review and our clinical observations)
Authors: Yu.M. Stepanov, N.V. Prolom, I.S. Konenko, S.O. Tarabarov, N.P. Dementii, I.M. Adamska
Journal: GASTROENTEROLOGY (2021)

Submucosal neoplasms of the stomach and duodenum include a group of diseases with different etiology, clinical symptoms, diagnosis and management. Conventional gastroduodenoscopy helps detect submucosal formations in 0.36–4% of cases, while the stomach is the most common site of submucosal lesions (up to 60%). Endoscopy and ultrasound endoscopic examination are important tools for the diagnosis of submucosal tumors of the esophagus, stomach, duodenum, both benign (polyps, submucosal formations, extraorganic compression, cysts) and malignant neoplasms of the gastrointestinal tract, especially small and accidentally detected. It is important not only to diagnose the tumor, but also to determine from which layers it comes, what level germinates, whether there is damage to regional lymph nodes. Only endoscopic ultrasonography (EUS) can answer these questions. EUS combines the capabilities of two studies: endoscopic and ultrasound, which significantly increased the informativeness of endoscopic examination, as it was possible to determine the site of the pathological process and the degree of intramural invasion, and also made it possible to carry out the differential diagnosis of submucosal tumors and pathological processes in organs adjacent to the esophagus, stomach, duodenum. The article presents examinations of patients with submucous formations of the stomach and duodenum at the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine. With the help of EUS, the diagnosis was confirmed in one patient, and in another one, the submucosal neoplasms was excluded.
Clonal Hematopoiesis Prevalence Increases throughout Treatment of Newly Diagnosed Multiple Myeloma Patients
Authors: Tarek H. Mouhieddine, Chidimma Nzerem, Robert A. Redd, Andrew Dunford, Matthew Joseph Leventhal, Romanos Sklavenitis-Pistofidis, Sabrin Tahri, Habib El-Khoury, David P. Steensma, Benjamin L. Ebert, Robert J. Soiffer, Jonathan J Keats, Shaadi Mehr, Daniel Auclair, Adam S. Sperling, Chip Stewart, Gad Getz, Irene M. Ghobrial
Journal: Blood (2021)
Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis
Authors: G. Curigliano, V. Mueller, V. Borges, E. Hamilton, S. Hurvitz, S. Loi, R. Murthy, A. Okines, E. Paplomata, D. Cameron, L.A. Carey, K. Gelmon, G.N. Hortobagyi, I. Krop, S. Loibl, M. Pegram, D. Slamon, J. Ramos, W. Feng, E. Winer
Journal: Annals of Oncology (2021)

In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB.HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized.Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events.With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.
Ofatumumab: A Review in Relapsing Forms of Multiple Sclerosis
Authors: Connie Kang, Hannah A. Blair
Journal: Drugs (2021)

Ofatumumab (Kesimpta®) is a fully human anti-CD20 monoclonal antibody that can be self-administered by patients and is approved in several countries worldwide for the treatment of relapsing forms of multiple sclerosis (MS). In two identical phase III trials in adults with relapsing forms of MS, subcutaneous ofatumumab was more effective than oral teriflunomide in reducing the annualized relapse rate, as well as reducing MRI-detected lesion activity and limiting worsening of disability. Ofatumumab had a generally manageable tolerability profile; the most common adverse events (AEs) included nasopharyngitis, headache, upper respiratory tract infections and urinary tract infections. AEs of special interest (AESIs) included infections and injection-related reactions, which were generally manageable. There was no apparent association between changes in immunoglobulin G or M levels and the risk of serious infections after 3.5 years of ofatumumab treatment. Thus, ofatumumab is a convenient treatment option that is effective and has a generally manageable tolerability profile in adults with relapsing forms of MS. MS is an incurable disease that affects ≈ 2.8 million people worldwide. Limiting the progression of disability associated with this disease is crucial, and treatments such as teriflunomide or monoclonal antibodies can prevent the relapses which define MS. Ofatumumab (Kesimpta®), a monoclonal antibody, works by reducing the level of B cells which contribute to the development and progression of MS. Ofatumumab is approved in several countries worldwide to treat adults with certain relapsing forms of MS. It is administered by subcutaneous injection once per month and is the first therapy of its kind that patients can self-inject at home. In clinical trials, ofatumumab was more effective than teriflunomide in reducing the annual relapse rate, as well as slowing both the progression of disability and formation of new MS lesions in the brain. Ofatumumab had a generally manageable tolerability profile, although treatment resulted in infections and injection-related reactions; these were generally manageable with treatment. Thus, ofatumumab is an effective and convenient treatment option, with a generally manageable tolerability profile, in adults with relapsing forms of MS.
Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
Authors: Young Min Chung, Pragya P Khan, Hong Wang, Wen-Bin Tsai, Yanli Qiao, Bo Yu, James W Larrick, Mickey C-T Hu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Stimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy. Methods We assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity. Results We showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors. Conclusion We show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors.
Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors
Authors: Yang Zhou, Fan Tong, Weilong Gu, Siqin He, Xiaotong Yang, Jiamei Li, Yue-Dong Gao, Huile Gao
Journal: Acta Pharmaceutica Sinica B (2021)

Considering that photodynamic therapy (PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac (Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species (ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A (LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1α (HIF-1α) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.
14. Children and Adolescents: <i>Standards of Medical Care in Diabetes—2022</i>
Journal: Diabetes Care (2021)

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
2. Classification and Diagnosis of Diabetes:<i>Standards of Medical Care in Diabetes—2022</i>
Journal: Diabetes Care (2021)

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
NCOG-08. BIOPSY-ONLY GLIOBLASTOMA (BO-GBM) AS A HETEROGENEOUS GROUP OF PATIENTS
Authors: Vincent Harlay, Anderson Loundou, Céline Boucard, Gregorio Petrirena, Maryline Barrie, Chantal Campello, Didier Autran, Laeticia Padovani, Dominique Figarella, Sébastien Boissonneau, Henry Dufour, Karine Baumstark, Emeline Tabouret, Olivier Chinot
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND “Biopsy-only” glioblastoma is associated with a heterogeneous functional and survival outcome. It is an understudied group of patients which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients. Our objective was to explore treatment and prognosis of BO-GBM. MATERIAL AND METHODS Patients with BO-GBM included in a prospective regional glioma SIRIC cohort in 2014-2017 were retrospectively reviewed for patient characteristics, MRI finding, treatment allocation and delivery. PFS and OS were analyzed. RESULTS Of 535 patients included in the cohort, 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. Of 158 patients, 18 were excluded for missing data leaving 139 patients for the present analysis. Fifty-four (39%) were referred to RT-TMZ, 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF), 17 (12%) were referred to palliative care. Groups differed at baseline for age (mean 60 and 68 years, for RT-TMZ, CT-UF respectively); KPS (70, 60 for RT-TMZ, CT-UF); mean tumor surface (793, 1420 mm2 for RT-TMZ, CT-UF); and tumor extension (bilateral in 6.4% and 29.3% for RT-CT and CT-UF respectively). Median OS was 14 months (95% CI, 9.65-18.71) and 8 months (95% CI, 4.62-7.67) for RT-TMZ, CT-UF respectively. CONCLUSION Inoperable GBM constitute a large and heterogeneous population in which one third of patients are amenable to standard of care, with survival outcome close to the one of patients who underwent surgery. Patients considered unfit for RT-CT at diagnosis exhibit a poor survival outcome. Thus, reliable criteria are needed to help selecting patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT.
Novel 15-mm-long lumen-apposing metal stent for endoscopic ultrasound-guided drainage of pancreatic fluid collections located ≥10 mm from the luminal wall
Authors: Linda Y. Zhang, Rastislav Kunda, Maridi Aerts, Nouredin Messaoudi, Rishi Pawa, Swati Pawa, Carlos Robles-Medranda, Roberto Oleas, Mohammad A. Al-Haddad, Itegbemie Obaitan, Thiruvengadam Muniraj, Carlo Fabbri, Cecilia Binda, Andrea Anderloni, Ilaria Tarantino, Michael Bejjani, Bachir Ghandour, Vikesh Singh, Mouen A. Khashab
Journal: Endoscopy (2021)

Abstract Background Endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) by cautery-enhanced lumen-apposing metal stents (LAMS) has largely been limited to collections located &lt; 10 mm from the luminal wall. We present outcomes of the use of a novel 15-mm-long cautery-enhanced LAMS for drainage of PFCs located ≥ 10 mm away. Methods This international, multicenter study analyzed all adults with PFCs located ≥ 10 mm from the luminal wall who were treated by EUS-guided drainage using the 15-mm-long cautery-enhanced LAMS. The primary outcome was technical success. Secondary outcomes included clinical success (decrease in PFC size by ≥ 50 % at 30 days and resolution of clinical symptoms without surgical intervention), complications, and recurrence. Results 35 patients (median age 57 years; interquartile range [IQR] 47–64 years; 49 % male) underwent novel LAMS placement for drainage of PFCs (26 walled-off necrosis, 9 pseudocysts), measuring 85 mm (IQR 64–117) maximal diameter and located 11.8 mm (IQR 10–12.3; range 10–14) from the gastric/duodenal wall. Technical and clinical success were high (both 97 %), with recurrence in one patient (3 %) at a median follow-up of 123 days (58–236). Three complications occurred (9 %; one mild, two moderate). Conclusions The 15-mm-long cautery-enhanced LAMS was feasible and safe for drainage of PFCs located 10–14 mm from the luminal wall.