tbuckley/cabot-search huggingface dataset:
Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer
Authors: Christos Fountzilas, David L. Bajor, Sarbajit Mukherjee, Joel Saltzman, Agnieszka K. Witkiewicz, Orla Maguire, Hans Minderman, Ram Nambiar, Hanna R. Rosenheck, Erik S. Knudsen, Jason B. Muhitch, Scott I. Abrams, Chong Wang, Alan D. Hutson, Kristopher Attwood, Karen A. Hicks, Jennifer A. Jurcevic, Pawel Kalinski, Renuka Iyer, Patrick M. Boland
Journal: Clinical Cancer Research (2021)

We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC).In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence.Forty-four patients were evaluable for efficacy. The study was negative for the primary efficacy endpoint [overall response rate: 2.6%, 6-month progression-free survival (PFS): 31%; P = 0.52]. Median PFS was 4.1 months [95% confidence interval (CI): 3.9-5.5 months]. No increase in adverse effects was identified. We observed favorable immunomodulation with 47% increase in the number of intratumoral CTLs posttreatment (P = 0.035). These changes were more pronounced in patients with tumor shrinkage (P = 0.05). The TME was characterized by high numbers of TIM3+ and CTLA4+ cells; there were few activated OX40+ cells. PD-L1 expression was higher in pretreatment tumor cells from metastatic sites versus primary tumor samples (P < 0.05). Higher numbers of PD-L1+ tumor cells at baseline were associated with tumor shrinkage (P = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1+ memory effector cells (P = 0.04) and granulocytic myeloid-derived suppressor cells (P = 0.03), with simultaneous increases in CD4+/CTLA4+ cells (P = 0.01).The combination of cetuximab and pembrolizumab is inactive in patients with RASwt mCRC, despite its partial local immunologic efficacy. Further development of immuno-oncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.
Polyphenol-based hydrogels: Pyramid evolution from crosslinked structures to biomedical applications and the reverse design
Authors: Zimu Li, Zhidong Chen, Hongzhong Chen, Kebing Chen, Wei Tao, Xiao-kun Ouyang, Lin Mei, Xiaowei Zeng
Journal: Bioactive Materials (2022)

As a kind of nature-derived bioactive materials, polyphenol-based hydrogels possess many unique and outstanding properties such as adhesion, toughness, and self-healing due to their specific crosslinking structures, which have been widely used in biomedical fields including wound healing, antitumor, treatment of motor system injury, digestive system disease, oculopathy, and bioelectronics. In this review, starting with the classification of common polyphenol-based hydrogels, the pyramid evolution process of polyphenol-based hydrogels from crosslinking structures to derived properties and then to biomedical applications is elaborated, as well as the efficient reverse design considerations of polyphenol-based hydrogel systems are proposed. Finally, the existing problems and development prospects of these hydrogel materials are discussed. It is hoped that the unique perspective of the review can promote further innovation and breakthroughs of polyphenol-based hydrogels in the future.
Rare Sequences Make Sense of CAR T-cell Therapy Outcomes
Authors: Sara Ghorashian, Jack Bartram
Journal: Blood Cancer Discovery (2021)

In this issue, Pulsipher and colleagues used next-generation sequencing to detect leukemia-specific sequences following tisagenlecleucel therapy of acute lymphoblastic leukemia. A challenge for the field currently is to identify which patients will have therapy failure and to do so early enough to allow planning for further treatment, for example, stem cell transplantation. Detection of disease below the standard detection level for this technique (less than one per million cells) at day 28 was associated with poorer outcomes and potentially therefore could be used to identify those that might benefit from adjunctive therapies.See related article by Pulsipher et al., p. 66.
Counterintuitive production of tumor-suppressive secretomes from Oct4- and c-Myc-overexpressing tumor cells and MSCs
Authors: Kexin Li, Xun Sun, Rongrong Zha, Shengzhi Liu, Yan Feng, Tomonori Sano, Uma K. Aryal, Akihiro Sudo, Bai-Yan Li, Hiroki Yokota
Journal: Theranostics (2022)

Background: Advanced breast cancer frequently metastasizes to bone, but inhibiting tumor progression in chemotherapy may occasionally enhance tumorigenesis.Here, we employed a counterintuitive approach of overexpressing Yamanaka factors (Oct4, c-Myc, Sox2, and Klf4) and examined a conditioned medium (CM)-based treatment option with induced tumor-suppressing cells (iTSCs).Methods: In vitro proliferation and migration assays were conducted using tumor cell lines derived from breast cancer, as well as prostate and pancreatic cancers, and osteosarcoma.The tumor-suppressing capability of iTSC-derived CM was evaluated using freshly isolated breast cancer tissues and a mouse model of mammary tumors and tumor-induced osteolysis.The regulatory mechanism was evaluated using Western blotting, immunoprecipitation, pull-down, gene overexpression, and RNA interference based on mass spectrometrybased proteomics data. Results:The overexpression of Oct4 and c-Myc in tumor cells and MSCs, but not Sox2 or Klf4, generated anti-tumor CM, which suppressed the progression of mammary tumors and tumor-induced bone loss.Notably, CM downregulated histone demethylase, and PDL-1, a blocker of T-cell-based immune responses.Whole-genome proteomics predicted enolase 1 (Eno1), Hsp90ab1, Eef2, and vinculin as extracellular tumor suppressors.Specifically, CD44 was co-immunoprecipitated with Eno1 and the silencing of CD44 suppressed Eno1's anti-tumor action.The overexpression of Oct4 and c-Myc also generated secretomes that inhibited the development of bone-resorbing osteoclasts.Conclusions: In analogous to cell competition in which Myc-overexpressing cells in Drosophila and mouse embryos remove neighboring cells with a lower level of Myc, this study presented the possibility of eliminating tumor cells by the secretory proteomes derived from Myc/Oc4-overexpressing iTSCs.
Disentangling paradigm and method can help bring qualitative research to post-positivist psychology and address the generalizability crisis
Authors: Moin Syed, Kate C. McLean
Journal: Behavioral and Brain Sciences (2022)

Abstract For decades, psychological research has heavily favored quantitative over qualitative methods. One reason for this imbalance is the perception that quantitative methods follow from a post-positivist paradigm, which guides mainstream psychology, whereas qualitative methods follow from a constructivist paradigm. However, methods and paradigms are independent, and embracing qualitative methods within mainstream psychology is one way of addressing the generalizability crisis.
Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel
Authors: Dror Mevorach, Emilia Anis, Noa Cedar, Michal Bromberg, Eric J Haas, Eyal Nadir, Sharon Olsha-Castell, Dana Arad, Tal Hasin, Nir Levi, Rabea Asleh, Offer Amir, Karen Meir, Dotan Cohen, Rita Dichtiar, Deborah Novick, Yael Hershkovitz, Ron Dagan, Iris Leitersdorf, Ronen Ben-Ami, Ian Miskin, Walid Saliba, Khitam Muhsen, Yehezkel Levi, Manfred S Green, Lital Keinan-Boker, Sharon Alroy-Preis
Journal: New England Journal of Medicine (2021)

BackgroundApproximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance.MethodsWe retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons.ResultsAmong 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637.ConclusionsThe incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.
Rational framing effects: A multidisciplinary case
Authors: José Luis Bermúdez
Journal: Behavioral and Brain Sciences (2022)

Frames and framing make one dimension of a decision problem particularly salient. In the simplest case, frames &lt;i&gt;prime&lt;/i&gt; responses (as in, e.g., the Asian disease paradigm, where the gain frame primes risk-aversion and the loss frame primes risk-seeking). But in more complicated situations frames can function reflectively, by making salient particular reason-giving aspects of a thing, outcome, or action. For Shakespeare's Macbeth, for example, his feudal commitments are salient in one frame, while downplayed in another in favor of his personal ambition. The role of frames in reasoning can give rise to &lt;i&gt;rational framing effects&lt;/i&gt;. Macbeth can prefer fulfilling his feudal duty to murdering the king, while also preferring bravely taking the throne to fulfilling his feudal duty, knowing full well that bravely taking the throne just is murdering the king. Such patterns of &lt;i&gt;quasi-cyclical&lt;/i&gt; preferences can be correct and appropriate from the normative perspective of how one ought to reason. The paper explores three less dramatic types of rational framing effects: (1) Consciously framing and reframing long-term goals and short-term temptations can be important tools for self-control. (2) In the prototypical social interactions modeled by game theory, allowing for rational framing effects solves longstanding problems, such as the equilibrium selection problem and explaining the appeal of non-equilibrium solutions (e.g., the cooperative solution in the Prisoner's Dilemma). (3) Processes for resolving interpersonal conflicts and breaking discursive deadlock, because they involve internalizing multiple and incompatible ways of framing actions and outcomes, in effect create rational framing effects.
2MO Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC
Authors: S. Lu, J. Fang, X. Li, L. Cao, J. Zhou, Q. Guo, Z. Liang, Y. Cheng, L. Jiang, N. Yang, Z. Han, J. Shi, Y. Chen, H. Xu, H. Zhang, G. Chen, R. Ma, S. Sun, Y. Fan, S. Weiguo
Journal: Annals of Oncology (2022)
Abstract P012: Orthostatic Hypo- And Hyper-tension Are Associated With Cognitive Decline: The S.ages Cohort
Authors: Strumia Mathilde, Olivier Hanon, Jean-Sébastien Vidal, Laure Rouch
Journal: Circulation (2022)

Introduction: The association between orthostatic hypotension (OHYPO) and cognition has reported conflicting results. Although orthostatic hypertension (OHYPER) is an emerging cardiovascular risk factor, only very few studies investigated its association with cognition. We aimed to assess the impact of OHYPO and OHYPER on cognitive performances in non-institutionalized subjects aged ≥ 65 years. Method: The S.AGES (Sujets Ågés) cohort followed for three years non-institutionalized subjects aged ≥ 65 years without major neurocognitive impairment at inclusion. OHYPO was defined as a decrease in systolic blood pressure (SBP) of at least 20 mmHg and/or diastolic blood pressure (DBP) of at least 10 mmHg from a sitting to a standing position. In contrast, OHYPER was defined as an increase in SBP of at least 20 mmHg and/or DBP of at least 10 mmHg under the same measurement conditions. Cognition was assessed using the Mini-Mental State Examination (MMSE). Linear mixed models were used for the analyses. Results: We included 3,170 subjects (mean age 78 years, 56% women). 209 (6.5%) had OHYPO at inclusion and 226 (7.1%) had OHYPER. Over time, MMSE was on average 0.5 points lower in patients with OHYPO compared to those without OHYPO or OHYPER (adjusted β [IC95%] = -0.52 [-0.97 ; -0.08], p=0.021) after adjustment for age, sex, education, baseline body mass index, smoking, alcohol intake, atrial fibrillation, congestive heart failure, transient ischemic attack or stroke, coronary artery disease, type 2 diabetes, dyslipidemia, seated SBP/DBP and antihypertensive treatment. Similarly, patients with OHYPER had, on average, poorer cognitive performances over time compared to those without pathological blood pressure (BP) postural changes (adjusted β [IC95%] = -0.54 [-0.98; -0.09], p = 0.017). Conclusion: Both OHYPO and OHYPER were associated with cognitive decline. Considering that BP postural changes are common in the elderly and easy to detect, orthostatic BP measurements could help identify patients with greater risk of cognitive impairment.
BRAF Mutations: The Discovery of Allele- and Lineage-Specific Differences
Authors: Aphrothiti J. Hanrahan, David B. Solit
Journal: Cancer Research (2022)

Abstract Cancer treatment is increasingly guided by molecular analyses designed to identify clinically actionable genomic alterations in individual patients. The discovery of BRAF mutations in human cancer, and the subsequent development and FDA authorization of selective BRAF inhibitors highlight the potential clinical impact and current limitations of precision oncology paradigms. In 2002, Brose and colleagues reported that the distribution of BRAF mutations differed in melanoma and lung cancer and that not all BRAF mutations were functionally equivalent. Here, we discuss this landmark paper, which foreshadowed subsequent research elucidating how biochemical differences among mutant alleles within the same gene and lineage-specific differences among cancer types impact drug sensitivity. Such translational studies provided a road map for the development of novel RAF inhibitors and rational combination strategies that promise greater clinical activity and/or more favorable toxicity profiles. See related article by Brose and colleagues, Cancer Res 2002;62:6997–7000
Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in <i>RAS</i> Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212)
Authors: Dominik Paul Modest, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Lothar Müller, Alexander Otto König, Ludwig Fischer von Weikersthal, Karel Caca, Albrecht Kretzschmar, Eray Goekkurt, Siegfried Haas, Annika Kurreck, Arndt Stahler, Swantje Held, Armin Jarosch, David Horst, Anke Reinacher-Schick, Stefan Kasper, Volker Heinemann, Sebastian Stintzing, Tanja Trarbach
Journal: Journal of Clinical Oncology (2021)

The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer.Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873).Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%).In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.
Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma
Authors: Victor E Ortega, Michelle Daya, Stanley J Szefler, Eugene R Bleecker, Vernon M Chinchilli, Wanda Phipatanakul, Dave Mauger, Fernando D Martinez, Esther Herrera-Luis, Maria Pino-Yanes, Gregory A Hawkins, Elizabeth J Ampleford, Susan J Kunselman, Corey Cox, Leonard B Bacharier, Michael D Cabana, Juan Carlos Cardet, Mario Castro, Loren C Denlinger, Celeste Eng, Anne M Fitzpatrick, Fernando Holguin, Donglei Hu, Daniel J Jackson, Nizar Jarjour, Monica Kraft, Jerry A Krishnan, Stephen C Lazarus, Robert F Lemanske, John J Lima, Njira Lugogo, Angel Mak, Wendy C Moore, Edward T Naureckas, Stephen P Peters, Jacqueline A Pongracic, Satria P Sajuthi, Max A Seibold, Lewis J Smith, Julian Solway, Christine A Sorkness, Sally Wenzel, Steven R White, Esteban G Burchard, Kathleen Barnes, Deborah A Meyers, Elliot Israel, Michael E Wechsler, Tarig Ali-Dinar, Lisa Bartnikas, Sachin Baxi, Avraham Beigelman, Mindy Benson, Kathryn V. Blake, Elizabeth Burke-Roberts, Manuela Cernadas, James F. Chmiel, Ronina Covar, Emily DiMango, Jonathan Gaffin, Deborah Gentile, Nicole Grossman, Marissa Hautpman, David Kantor, Harsha Kumar, Craig F. LaForce, Jason Lang, Dayna Long, Margee Louisias, Wayne Morgan, James Moy, Ross E. Myers, J. Tod Olin, Perdita Permaul, Loretta Que, Hengameh Raissy, Rachel G. Robison, Kristie Ross, William Sheehan, Lisa Sullivan-Vedder, Lakeia Wright
Journal: The Lancet Child & Adolescent Health (2021)
Abstract 10810: CMR Feature Tracking Can Estimate Right Ventricular Functional Reserve in Rats with Pulmonary Arterial Hypertension
Authors: Haruka Sato, Kazunori Kumasaka, Wakako Satoh, Chiyohiko Shindoh, Hideki Ota, Kawashima Ryuta, Masahito Miura
Journal: Circulation (2021)

Introduction: Patient survival with pulmonary arterial hypertension (PAH) is determined from right ventricular (RV) function. CMR feature tracking (CMR-FT) is used to assess RV function. It is not determined, however, whether CMR-FT can assess RV functional reserve in patients with PAH. Hypothesis: We assessed the hypothesis that CMR-FT can estimate RV functional reserve in rats with PAH. Methods: Rats were received injections with monocrotaline (MCT-rats, n=19) or solvent (Ctr-rats, n=5). After four weeks, retrospective ECG-gated cine MR (16 phases/beat) was imaged using a 7-T MRI scanner, and RVEF, RV global longitudinal strain (RVGLS) and RV global circumferential strain (RVGCS) were measured before and after addition of 0.5~3 nmol endothelin-1 (ET-1). After the measurements, trabeculae were dissected from the RVs and electrically stimulated with 2-s intervals ([Ca 2+ ] o 2.0 mM, 24°C). Force and maximum dF/dt (dF/dt max ) were obtained using a silicon strain gauge in the absence and presence of 0.1 μM ET-1. Results: MCT-rats showed higher RV pressure (RVP), lower RVEF, lower RVGLS, lower developed force and lower dF/dt max . RVGLS showed a liner correlation with dF/dt max (r=0.53, p&lt;0.05) and had already been reduced in 5 MCT-rats with preserved RVEF (&gt;50%), suggesting that RVGLS reflects RV contractile properties and is reduced earlier than RVEF. Addition of ET-1 increased RVP in MCT-rats (49.0±19.3 to 59.7±16.8 mmHg, n=6) and Ctr-rats (17.3±7.5 to 20.4±7.8 mmHg, n=2) and increased developed force and dF/dt max in MCT-rats (12.2±5.7 to 17.4±3.1 mN/mm 2 , 0.08±0.03 to 0.14±0.06 mN/mm 2 /sec, n=6). When MCT-rats with preserved-RVEF (&gt;50%) were divided into 2 groups depending on RVGCS, addition of ET-1 further reduced RVGCS in reduced-RVGCS (&gt;-20%) group but not in increased-RVGCS (&lt;-30%) group, suggesting that RVGCS can reflect RV functional reserve. In addition, ET-1 killed MCT-rats with reduced-RVGCS and reduced-RVEF just after its addition. In contrast, ET-1 did not change RVGCS and RVEF in Ctr-rats. Conclusions: CMR-FT can estimate RV functional reserve earlier and more accurately with RVGLS and RVGCS in rats with PAH. Therefore, RV strain with CMR may become an important parameter to assess RV functional reserve in patients with PAH.