tbuckley/cabot-search huggingface dataset:
Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies
Authors: Maciej Szydłowski, Filip Garbicz, Ewa Jabłońska, Patryk Górniak, Dorota Komar, Beata Pyrzyńska, Kamil Bojarczuk, Monika Prochorec-Sobieszek, Anna Szumera-Ciećkiewicz, Grzegorz Rymkiewicz, Magdalena Cybulska, Małgorzata Statkiewicz, Marta Gajewska, Michał Mikula, Aniela Gołas, Joanna Domagała, Magdalena Winiarska, Agnieszka Graczyk-Jarzynka, Emilia Białopiotrowicz, Anna Polak, Joanna Barankiewicz, Bartosz Puła, Michał Pawlak, Dominika Nowis, Jakub Golab, Andrea M. Tomirotti, Krzysztof Brzózka, Mariana Pacheco-Blanco, Kristyna Kupcova, Michael R. Green, Ondrej Havranek, Bjoern Chapuy, Przemysław Juszczyński
Journal: Cancer Research (2021)

Abstract The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase–associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition–induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. Significance: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
Sapanisertib plus Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive/HER2-Negative Advanced Breast Cancer after Progression on Aromatase Inhibitor
Authors: José Á. García-Sáenz, Noelia Martínez-Jáñez, Ricardo Cubedo, Yolanda Jerez, Ainhara Lahuerta, Santiago González-Santiago, Nieves Ferrer, Manuel Ramos, Jose L. Alonso-Romero, Antonio Antón, Eva Carrasco, Jingjing Chen, Rachel Neuwirth, Kevin Galinsky, Sylvie Vincent, E. Jane Leonard, Dennis Slamon
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant. Patients and Methods: Postmenopausal women with estrogen receptor–positive (ER+)/HER2-negative (HER2−) advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion. Results: Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin-dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47–1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53–1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively). Conclusions: Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2− advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.
Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial
Authors: Francisco Bautista, Xavier Paoletti, Jonathan Rubino, Caroline Brard, Keyvan Rezai, Souad Nebchi, Nicolas Andre, Isabelle Aerts, Emilie De Carli, Natasha van Eijkelenburg, Estelle Thebaud, Nadege Corradini, Anne-Sophie Defachelles, Stephane Ducassou, Raphael J. Morscher, Gilles Vassal, Birgit Geoerger
Journal: Journal of Clinical Oncology (2021)

PURPOSE AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m 2 once a day, temozolomide 100 mg/m 2 once a day, and topotecan 0.5 mg/m 2 once a day (arm A) and ribociclib 175 mg/m 2 once a day and everolimus 2.5 mg/m 2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.
First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study
Authors: Heinz-Josef Lenz, Eric Van Cutsem, Maria Luisa Limon, Ka Yeung Mark Wong, Alain Hendlisz, Massimo Aglietta, Pilar García-Alfonso, Bart Neyns, Gabriele Luppi, Dana B. Cardin, Tomislav Dragovich, Usman Shah, Sandzhar Abdullaev, Joseph Gricar, Jean-Marie Ledeine, Michael James Overman, Sara Lonardi
Journal: Journal of Clinical Oncology (2021)

PURPOSE Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study. PATIENTS AND METHODS Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1). RESULTS Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events. CONCLUSION Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.
Renal Infarction Imaged With [18F]Prostate-Specific Membrane Antigen–1007 PET/CT
Authors: Niloefar Ahmadi Bidakhvidi, Amaryllis H. Van Craenenbroeck, Raymond Oyen, Koen Van Laere, Karolien Goffin
Journal: Clinical Nuclear Medicine (2021)

Abstract A 61-year-old post–renal transplant man developed pain in the region of the allograft 4 days after transplantation. Contrast-enhanced CT scan revealed multiple small perfusion defects in the renal graft cortex. Multifocal renal cortical infarction was suspected. A [ 99m Tc]Tc-DMSA SPECT/CT showed several small regions with decreased uptake. In addition, an [ 18 F]PSMA-1007 PET/CT confirmed these uptake defects and revealed additional defects. The renal cortical infarctions presumably originated from intraoperative emboli emerging from the arterial anastomosis. Treatment with acetylsalicylic acid 100 mg led to favorable evolution of the renal function biochemically. Follow-up DMSA scintigraphy 3 months later showed resolution of the renal cortical defects.
Incidental Finding of Endometrioid Adenocarcinoma of the Ovary on 131I Whole-Body Scan
Authors: Mohd Fazrin Mohd Rohani, Siti Zarina Amir Hassan
Journal: Clinical Nuclear Medicine (2021)

Abstract A 57-year-old woman was referred for radioactive iodine therapy 12 weeks after completion thyroidectomy and left modified radical neck dissection for pT2N1Mx follicular variant papillary thyroid carcinoma. After 4 weeks of l -thyroxine withdrawal, stimulated serum thyroglobulin level was less than 0.1 ng/mL with positive thyroglobulin antibody. Posttherapy 131 I scintigraphy with SPECT/CT of the head and abdominopelvic region showed thyroid residual in the neck, occipital bone metastasis, and heterogenous tracer uptake in a large peritoneal mass, likely arising from the left ovary. Left salpingo-oophorectomy was performed, and histopathologic examination revealed endometrioid carcinoma of left ovary.
165P Dynamic evolution of blood immune-inflammatory descriptors in advanced non-small cell lung cancer undergoing first-line immunotherapy-based regimens
Authors: G. Mazzaschi, M. Verzè, D. Tognazzi, B. Lorusso, R. Minari, M. Pluchino, F. Trentini, M. Manini, P. Bordi, A. Leonetti, F. Perrone, M. Corianò, M. Casali, I. Toscani, A. Cosenza, L. Ferri, S. Buti, N. Sverzellati, F. Quaini, M. Tiseo
Journal: Annals of Oncology (2022)
A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke
Authors: Natalie E. LeCouffe, Manon Kappelhof, Kilian M. Treurniet, Leon A. Rinkel, Agnetha E. Bruggeman, Olvert A. Berkhemer, Lennard Wolff, Henk van Voorst, Manon L. Tolhuisen, Diederik W.J. Dippel, Aad van der Lugt, Adriaan C.G.M. van Es, Jelis Boiten, Geert J. Lycklama à Nijeholt, Koos Keizer, Rob A.R. Gons, Lonneke S.F. Yo, Robert J. van Oostenbrugge, Wim H. van Zwam, Bob Roozenbeek, H. Bart van der Worp, Rob T.H. Lo, Ido R. van den Wijngaard, Inger R. de Ridder, Vincent Costalat, Caroline Arquizan, Robin Lemmens, Jelle Demeestere, Jeannette Hofmeijer, Jasper M. Martens, Wouter J. Schonewille, Jan-Albert Vos, Maarten Uyttenboogaart, Reinoud P.H. Bokkers, Julia H. van Tuijl, Hans Kortman, Floris H.B.M. Schreuder, Hieronymus D. Boogaarts, Karlijn F. de Laat, Lukas C. van Dijk, Heleen M. den Hertog, Boudewijn A.A.M. van Hasselt, Paul J.A.M. Brouwers, Tomas Bulut, Michel J.M. Remmers, Anouk van Norden, Farshad Imani, Anouk D. Rozeman, Otto E.H. Elgersma, Philippe Desfontaines, Denis Brisbois, Yves Samson, Frédéric Clarençon, G. Menno Krietemeijer, Alida A. Postma, Pieter-Jan van Doormaal, René van den Berg, Anouk van der Hoorn, Ludo F.M. Beenen, Daan Nieboer, Hester F. Lingsma, Bart J. Emmer, Jonathan M. Coutinho, Charles B.L.M. Majoie, Yvo B.W.E.M. Roos
Journal: New England Journal of Medicine (2021)

The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations.
Ayekoo! — Well done!
Authors: Rexford S. Ahima
Journal: Journal of Clinical Investigation (2022)

As the curtain draws on the 5-year term of the JCI editorial board at Johns Hopkins, I am filled with gratitude and would like to extend a warm ayekoo (Ghanaian salutation meaning “well done”) to our editors, staff, reviewers, and scientists for supporting the Journal. I am delighted to welcome the next JCI Editor in Chief, Elizabeth McNally — the first woman to lead the JCI since it was founded almost a century ago — and her team from Northwestern University.
Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy
Authors: Weixi Jiang, Li Chen, Xun Guo, Chen Cheng, Yuanli Luo, Jingxue Wang, Junrui Wang, Yang Liu, Yang Cao, Pan Li, Zhigang Wang, Haitao Ran, Zhiyi Zhou, Jianli Ren
Journal: Theranostics (2022)

Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy.The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD).On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells.Methods: In this study, silver nanoparticles (Ag NPs) and peptide-functionalized doxorubicin ( P DOX) were used to prepare a theranostic nanocomposite (Ag-TF@ P DOX), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration.Results: The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect.It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones.In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation.Moreover, surface TA-Fe 3+ engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux.Ag-TF@ P DOX has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance.Conclusion: This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level.Key words: ER stress, cell
The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals
Authors: Jean-Eudes Fahrner, Imran Lahmar, Anne-Gaëlle Goubet, Yacine Haddad, Agathe Carrier, Marine Mazzenga, Damien Drubay, Carolina Alves Costa Silva, Eric de Sousa, Cassandra Thelemaque, Cléa Melenotte, Agathe Dubuisson, Arthur Geraud, Gladys Ferrere, Roxanne Birebent, Camille Bigenwald, Marion Picard, Luigi Cerbone, Joana R. Lérias, Ariane Laparra, Alice Bernard-Tessier, Benoît Kloeckner, Marianne Gazzano, François-Xavier Danlos, Safae Terrisse, Eugenie Pizzato, Caroline Flament, Pierre Ly, Eric Tartour, Nadine Benhamouda, Lydia Meziani, Abdelhakim Ahmed-Belkacem, Makoto Miyara, Guy Gorochov, Fabrice Barlesi, Alexandre Trubert, Benjamin Ungar, Yeriel Estrada, Caroline Pradon, Emmanuelle Gallois, Fanny Pommeret, Emeline Colomba, Pernelle Lavaud, Marc Deloger, Nathalie Droin, Eric Deutsch, Bertrand Gachot, Jean-Philippe Spano, Mansouria Merad, Florian Scotté, Aurélien Marabelle, Frank Griscelli, Jean-Yves Blay, Jean-Charles Soria, Miriam Merad, Fabrice André, Juliette Villemonteix, Mathieu F. Chevalier, Sophie Caillat-Zucman, Florence Fenollar, Emma Guttman-Yassky, Odile Launay, Guido Kroemer, Bernard La Scola, Markus Maeurer, Lisa Derosa, Laurence Zitvogel
Journal: Cancer Discovery (2022)

Abstract Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873
Abstract 039: Association Of A Cumulative Exposure To Sleep Disordered Breathing From Childhood Through Young Adulthood With Carotid Intima-media Thickness
Authors: Julio Fernandez-Mendoza, Zhaohui Gao, Baadal Vachhani, Kristen Brandt, Kreesha Shah, Jason Liao, Fan He, Susan Calhoun, Alexandros N Vgontzas, Duanping Liao, Edward O Bixler
Journal: Circulation (2022)

Introduction: Commensurate with studies in middle-aged adults, we have previously shown that a cumulative exposure to sleep disordered breathing (SDB) since childhood is associated, independent of obesity, with endothelial dysfunction in young adulthood. There is a lack of population-based studies that have examined the association of SDB with atherosclerosis using such a developmental approach. Hypothesis: Exposure to SDB since childhood is associated with long-term increased carotid intima-media thickness (CIMT) in young adulthood. Methods: We tested this hypothesis in a subsample of the Penn State Child Cohort, a population-based study of 700 children (median age 9y), of whom 421 were followed-up 7.4 years later during adolescence (median age 16y), and 204 have been followed-up 15.4 years later during young adulthood (median age 24y). Subjects (53% female, 23% racial/ethnic minority) underwent in-lab polysomnography to ascertain the apnea/hypopnea index (AHI) at all three time points, and ultrasound to assess CIMT in young adulthood. Based on the AHI truncated at ≥5 events/hour of sleep to include subjects already on positive airway pressure therapy, we averaged the exposure to AHI over the three time points (cAHI). The study outcome was total CIMT from right and left carotids as a continuous measure. Stepwise linear regression models first adjusted for sex, age, race/ethnicity, and length of follow-up and, thereafter, for body mass index (BMI). To test the robustness of the analysis, we applied the same linear models with the square root of CIMT (sqrt-CIMT) as the outcome. Results: The mean cAHI was 1.16 (standard deviation=0.99) ranging from 0 to 5 and the mean CIMT was 0.51 (0.07) ranging from 0.37 to 0.79. Although cAHI was positively associated with higher CIMT in young adulthood (β = 0.015; 95% CI = 0.005, 0.025; p = 0.003), the association was significantly diminished after further adjusting for BMI (β = 0.004; 95% CI = -0.004, 0.014; p = 0.424). The results were similar when using sqrt-CIMT (β = 0.010; 95% CI = 0.004, 0.017; p = 0.002 before BMI adjustment; β = 0.003; 95% CI = -0.004, 0.010; p = 0.415 after BMI adjustment). Conclusions: In contrast to endothelial dysfunction, the preliminary data of this ongoing longitudinal study indicates that obesity plays a key role in the association between SDB and atherosclerosis in young adulthood.