tbuckley/cabot-search huggingface dataset:
Abstract 962: Small-molecule NSC58874 releases and activates p73 via induction of mutant p53 degradation in cancer cells
Authors: Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2021)

Abstract The tumor suppressor p53 is the most frequently mutated gene in cancer. Mutant p53 is a challenge to target in cancer therapy due to its many mutations and the fact that it is an inactivated transcription factor. p73 is a member of the p53 family but very rarely mutated in cancer cells. Therefore, activation of p73 is one of the promising strategies to restore the p53 pathway signaling in cancer therapy. Our laboratory has reported that p73 can be activated by small molecules to restore p53 pathway signaling via induction of p73 expression or interruption of p73 interaction with mutant p53. In the present study, we explored a strategy for releasing p73 from a mutant p53 inhibitory complex by induction of mutant p53 degradation using small molecule NSC59984. We previously reported that NSC59984 induces mutant p53 degradation and restores p53 pathway signaling through p73 in p53-mutant cancer cells. To address the mechanism of whether p73 is released from a mutant p53 inhibitory complex to transcriptionally regulate p53 targets, we performed p53-RE-luc reporter assays and Chromatin Immunoprecipitation (ChIP)-PCR in cancer cells with overexpression of p73. We found NSC59984 enhances p73-mediated signaling based on p53 target (such as p21 and noxa) induction at the protein level and p53-RE-luc reporter assay. Further ChIP-PCR analysis showed that NSC59984 treatment increases p73-binding to the p21 and Noxa promoters. These results taken together suggest that NSC59984 enhances p73 transcriptional activity to restore the p53 pathway signaling. It is also well known that p73 activity is regulated through a complex mechanism such as post-translational modifications and protein-protein interactions. We found that NSC59984 can stimulate the ERK2 signaling pathway. The MEK1 inhibitor U0126 partially blocked p73 binding to the p21 and Noxa promoters and their gene expression in cells treated with NSC59984, and this correlated with the rescue of mutant p53 stabilization. These results suggest that p73 is released from mutant p53 inhibitory complex and further stimulated through ERK2 signaling, as a mechanism of tumor suppression in tumors with mutant p53. Citation Format: Shengliang Zhang, Wafik S. El-Deiry. Small-molecule NSC58874 releases and activates p73 via induction of mutant p53 degradation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 962.
Abstract 2893: Transmembrane Chloride Intracellular Channel 1 (tmCLIC1) protein as a potential target for colorectal cancer metastasis
Authors: Francesca Cianci, Valentina Carlini, Ivan Verduci, Matteo Ranucci, Michele Mazzanti
Journal: Cancer Research (2021)

Abstract Colorectal cancer (CRC) is the third most common tumor worldwide and the fourth cause of cancer-related death. The presence of distal metastasis at the time of the first diagnosis represents a worst prognosis factor for patients' long-term survival. Therefore, finding new targets to arrest the metastatic process is a main challenge for successful CRC therapy. Our laboratory focused its attention on the Chloride Intracellular Channel 1 (CLIC1), a metamorphic protein able to switch from a cytoplasmic to a transmembrane form associated to ion channel activity. Previous experiments demonstrated that transmembrane CLIC1 (tmCLIC1) functional activity is negligible in normal colon cells, while increases proportionally to CRC cells' aggressiveness. Moreover, we also revealed that tmCLIC1 supports CRC cells abnormal proliferation rate. Here, we show that tmCLIC1 pharmacological inhibition or its stable knock-down by gene silencing led to a significative reduction of CRC cells migrative and invasive potential, in vitro. To further confirm our hypothesis, we assessed in CLIC1 knock-down cells the downregulation of metalloproteinase-7 (MMP-7) protein and p38 mitogen-activated protein kinase (MAPK) signaling, both involved in migration and metastatic processes. Moreover, by injecting subcutaneously transfected cell lines in nude mice, we demonstrate that CLIC1 knock-down impairs tumor growth and limits cancer cells dissemination to lung. Our results suggest a role for tmCLIC1 in promoting CRC metastasis, making this protein a promising pharmacological target to arrest or slow-down CRC metastasis development. Moreover, thanks to its functional expression exclusively associated with malignant progression, tmCLIC1 could allow to limit side effects on healthy cell population. Citation Format: Francesca Cianci, Valentina Carlini, Ivan Verduci, Matteo Ranucci, Michele Mazzanti. Transmembrane Chloride Intracellular Channel 1 (tmCLIC1) protein as a potential target for colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2893.
Abstract LB244: The role of stromal <i>Per2</i> in regulation of tumorigenesis
Authors: Shimrit Mayer, Lee Shaashua, Chen Lior, Hagar Lavon, Alexander Novoselsky, Ruth Scherz-Shouval
Journal: Cancer Research (2021)

Abstract The tumor microenvironment (TME) comprised of multiple proteins, extracellular matrix(ECM) and various cell types that together promote tumor initiation, progression andhomeostasis in a cell-cell communication manner. In this study, we set to understand howthe stromal circadian clock supports the cancer cells, specifically the contribution of thecore clock gene Per2 to tumor initiation and progression. The circadian clock is anendogenous, evolutionally conserved and ubiquitously expressed pacemaker, consisting ofcell autonomous clocks and a central pacemaker located in the hypothalamussuperchiasmatic nucleus (SCN). Together these clocks synchronize numerous biologicalprocesses between the organism and its environment. Amongst these processes are DNAdamage repair, metabolism, and cell cycle. Several studies showed that disruption ofcircadian rhythms has been associated with various forms of cancer in humans and mice.While Per2 was previously suggested to be a tumor suppressor, in this study we found thatthe core clock gene Per2 in the TME is essential for tumor initiation and metastaticcolonization. Another core gene, Per1, is dispensable. We further showed that lossof Per2 in the TME leads to transcriptional rewiring at early stages of metastasesformation, and suppresses subsequent metastatic tumor progression. Thus, our resultsunravel an unexpected protumorigenic role for the core clock gene Per2 in the TME. Thesefindings may imply a non-circadian role for Per2, differentiating it from Per1 withpotential implications for therapeutic dosing strategies and treatment regimens. Citation Format: Shimrit Mayer, Lee Shaashua, Chen Lior, Hagar Lavon, Alexander Novoselsky, Ruth Scherz-Shouval. The role of stromal Per2 in regulation of tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB244.
Abstract 18334: Prolonged Use of Clopidogrel and Risk of Death and Myocardial Infarction 4 Years after Coronary Stenting in Diabetes: the VA DES Study
Authors: Scott Kinlay, Michael Gaziano, Melissa Young, Elizabeth Lawler, David P Faxon
Journal: Circulation (2011)

Clopidogrel is recommended with aspirin for up to one year after coronary drug-eluting stent (DES) placement but the value beyond this time is controversial. Patients with diabetes mellitus (DM) are at higher risk of cardiovascular events than patients without DM, and may benefit from more prolonged clopidogrel treatment. Methods: We assessed all DM patients in the National VA Healthcare System who received a coronary stent from 2002- 2006. Baseline factors and comorbities, pharmacy data, and adverse events during follow-up were collected. We estimated crude and adjusted hazard ratios for prolonged versus 12 or less months of clopidogrel on the risk of death, and death or myocardial infarction (MI), stroke, major bleeding, and repeat revascularization up to 4 years after stenting using Cox proportional hazards. We used a landmark analysis that excluded all events up to 12 months after stenting with DES or bare-metal stents (BMS). Results: Of 42,254 patients who received a coronary stent, 13,657 had diabetes on treatment. 2,808 received a DES and 2,782 a BMS. 39% of DES pts and 23% of BMS pts were on clopidogrel &gt;12months. The results of the landmark analysis showed no differences for stroke, major bleeding or repeat revascularization in either group. Conclusion: In this large unrestricted veteran population, prolonged clopidogrel use of more than 12 months in patients with diabetes receiving coronary stenting associated with lower risk of death and death and MI particularly after DES. These data suggest that prolonged use more than one year may be of benefit in DM patients receiving a DES. Figure: Risk of Outcomes After the 12 Month Landmark for Prolonged vs 12 or Less Months Clopidogrel Use † Adjusted for age, diabetes, ACS during index admission, hypertension, PVD, heart failure, warfarin within 7-days of index discharge, year of stent, occurrence of another outcome within 12-months of index procedure
Abstract LB005: High quality neoantigens are immunoedited in long term survivors of pancreatic cancer
Authors: Marta Luksza, Zachary Sethna, Luis Rojas, Kevin Soares, Yuval Elhanati, Jayon Lihm, David Hoyos, Rajya Kappagantula, Alvin M. Moore, Erin Patterson, Christine Iacobuzio-Donahue, Benjamin Greenbaum, Vinod P. Balachandran
Journal: Cancer Research (2021)

Abstract Cancer immunoediting, a hallmark of cancer, predicts that lymphocytes recognize tumor-specific mutations (neoantigens) to kill immunogenic tumor cells and select less immunogenic clones to survive in immunocompetent hosts. Yet, though proven in mice, whether immunoediting governs how human tumors evolve naturally, and the principles of how the immune system edits tumors remain unclear. Here, we report that T cell rich tumors of rare long-term survivors of human pancreatic ductal adenocarcinoma longitudinally lose immunogenic features predicted by a fitness model based on immune recognition of high quality neoantigens. We find that compared to T cell poor tumors in short-term survivors, long-term survivors evolve less immunogenic recurrent tumors over 10 years with fewer clones, fewer neoantigens, and new neoantigens of markedly lower quality, to indicate that the immune system edits lower fitness clones with high-quality neoantigens. To explore if the immune system more broadly selects against non-self-like changes in host genomes, we define a minimal amino acid substitution distance sufficient for T cell receptors to discriminate self from non-self mutations. We find that both primary and recurrent tumors in long but not short-term survivors are enriched in self-like mutations, to suggest that the immune system depletes non-self-like mutations. Thus, we submit longitudinal evidence that the immune system edits neoantigens to sculpt recurrent human pancreatic ductal adenocarcinomas, a lethal tumor largely considered resistant to endogenous immune attack. Furthermore, we demonstrate that the neoantigen quality fitness model predicts how immune pressure changes tumor cell populations over time, with significant implications for cancer biology and immunotherapy. More broadly, our results argue that cancer immunoediting is a fundamental principle of how human cancers evolve in immunocompetent hosts. Citation Format: Marta Luksza, Zachary Sethna, Luis Rojas, Kevin Soares, Yuval Elhanati, Jayon Lihm, David Hoyos, Rajya Kappagantula, Alvin M. Moore, Erin Patterson, Christine Iacobuzio-Donahue, Benjamin Greenbaum, Vinod P. Balachandran. High quality neoantigens are immunoedited in long term survivors of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB005.
Male infertility and the effect of seminal and urinary infections on sperm DNA fragmentation, reactive oxygen species and WHO semen parameters
Authors: C.L.T. Ho, D.R. Vaughan-Constable, J. Ramsay, C. Jayasena, T. Tharakan, T. Yap, S. Minhas, S. Homa
Journal: European Urology (2021)
Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices — United States, June 2021
Authors: Julia W. Gargano, Megan Wallace, Stephen C. Hadler, Gayle Langley, John R. Su, Matthew E. Oster, Karen R. Broder, Julianne Gee, Eric Weintraub, Tom Shimabukuro, Heather M. Scobie, Danielle Moulia, Lauri E. Markowitz, Melinda Wharton, Veronica V. McNally, José R. Romero, H. Keipp Talbot, Grace M. Lee, Matthew F. Daley, Sara E. Oliver
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine and the Moderna COVID-19 (mRNA-1273) vaccine,† and the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for their use in persons aged ≥16 years and ≥18 years, respectively.§ In May 2021, FDA expanded the EUA for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12-15 years; ACIP recommends that all persons aged ≥12 years receive a COVID-19 vaccine. Both Pfizer-BioNTech and Moderna vaccines are mRNA vaccines encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. Both mRNA vaccines were authorized and recommended as a 2-dose schedule, with second doses administered 21 days (Pfizer-BioNTech) or 28 days (Moderna) after the first dose. After reports of myocarditis and pericarditis in mRNA vaccine recipients,¶ which predominantly occurred in young males after the second dose, an ACIP meeting was rapidly convened to review reported cases of myocarditis and pericarditis and discuss the benefits and risks of mRNA COVID-19 vaccination in the United States. Myocarditis is an inflammation of the heart muscle; if it is accompanied by pericarditis, an inflammation of the thin tissue surrounding the heart (the pericardium), it is referred to as myopericarditis. Hereafter, myocarditis is used to refer to myocarditis, pericarditis, or myopericarditis. On June 23, 2021, after reviewing available evidence including that for risks of myocarditis, ACIP determined that the benefits of using mRNA COVID-19 vaccines under the FDA's EUA clearly outweigh the risks in all populations, including adolescents and young adults. The EUA has been modified to include information on myocarditis after receipt of mRNA COVID-19 vaccines. The EUA fact sheets should be provided before vaccination; in addition, CDC has developed patient and provider education materials about the possibility of myocarditis and symptoms of concern, to ensure prompt recognition and management of myocarditis.
Error in Number of Eligible Patients in Survey of Self-reported Prognostic Expectations of People Undergoing Dialysis
Authors: Ann M. O'Hare
Journal: JAMA Internal Medicine (2021)

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Abstract 2817: Metabolic heterogeneity in breast cancer integrative clusters to screen metabolic vulnerabilities for diagnosis and treatment response
Authors: Susana Ros, Alan J. Wright, Flaviu Bulat, Wendy Greenwood, De-en Hu, Maurizio Callari, Ming Li Chia, Violeta Serra, Oscar Rueda, Alejandra Bruna, Carlos Caldas, Kevin M. Brindle
Journal: Cancer Research (2021)

Abstract Introduction: Metabolic adaptation occurs in transformed cells and can be exploited clinically for diagnosis and disease monitoring. Metabolic profiles can be influenced by genetic heterogeneity, both within and between tumors. Breast tumors show considerable intra and inter tumor genomic heterogeneity, which partly accounts for the variable clinical course of the disease and response to treatment. Imaging tumor metabolism may provide a metabolic signature that can be used to stratify patients. Methods: We have investigated eight patient-derived xenograft (PDX) models of breast cancer to determine whether metabolic imaging can be linked to different “integrative clusters” (Int-Cluster), which are defined by their distinctive genomic profiles and clinical outcomes. Metabolic imaging was performed using PET measurements of the uptake, phosphorylation, and trapping of the glucose analog, 2-deoxy-2-[18F]fluorodeoxyglucose ([18F]FDG), catalyzed by hexokinase II, and 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized 13C label exchange between [1-13C]pyruvate and the endogenous tumor lactate pool, catalyzed by lactate dehydrogenase A. Results: Lactate labelling was higher in Int-Clusters dominated by ER- basal-like PDXs from patients with a poor short-term prognosis. Lower levels of lactate labelling were observed in Int-Clusters dominated by estrogen receptor positive (ER+) PDXs and the Pam50 subtypes, Luminal A and B, from patients which have an intermediate to good prognosis. More importantly, tumors that had a similar genomic profile nevertheless showed differences in lactate labeling, that was not observed in the [18F]FDGPET measurements. Although lactate labelling was low in the ER+ tumor models, decreases in lactate labeling could be used to detect treatment response, for example to drugs targeted at the most frequently mutated oncogene in this tumor subtype, PI3KCA. Discussion: These results illustrate the potential importance of metabolism-based stratification of breast cancer and demonstrate that metabolic imaging can provide diagnostic information that could be important for non-invasive diagnosis and for designing and monitoring therapeutic strategies. Citation Format: Susana Ros, Alan J. Wright, Flaviu Bulat, Wendy Greenwood, De-en Hu, Maurizio Callari, Ming Li Chia, Violeta Serra, Oscar Rueda, Alejandra Bruna, Carlos Caldas, Kevin M. Brindle. Metabolic heterogeneity in breast cancer integrative clusters to screen metabolic vulnerabilities for diagnosis and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2817.
Covid-19: Vaccine corruption allegations spark protests across Brazil
Authors: Luke Taylor
Journal: BMJ (2021)

Tens of thousands of people marched against Brazil’s president Jair Bolsonaro last weekend after the supreme court authorised a criminal investigation into alleged government corruption involving a covid-19 vaccine deal. Demonstrators gathered in more than 40 cities across the country to voice their anger at the outspoken leader’s mismanagement of the pandemic.

Bolsonaro’s popularity plummeted during the past year as the country’s public health crisis spiralled and it took a further hit on 2 July when supreme court approved requests to investigate a public servant’s claims that the government profited from a deal to buy Covaxin vaccines.1

Luis Ricardo Miranda, who leads the health ministry’s import division, told a separate inquiry into the …
Abstract 1187: Optimizing gemcitabine in metastatic TNBC by rational PI3K/AKT combination
Authors: Nathan M. Merrill, Nathalie M. Vandecan, Athena M. Apfel, Peter J. Ulintz, Liwei Bao, Xu Cheng, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner
Journal: Cancer Research (2021)

Abstract Metastatic triple-negative breast cancer (TNBC) has a median survival of 13 months, and only 5 months if brain metastases are present. Advances in immunotherapy are promising, but only add weeks to a few months of progression-free survival to this guarded prognosis. Thus, there is a large unmet need for innovations that improve patient outcomes in the metastatic setting when patients are refractory to first-line treatment. Recently, we published an innovative strategy to identify multi-omic molecular correlates of drug response in TNBC. From this work, we now apply the strategy to 3D cell culture models and patient derived xenografts (PDXs) that are more representative of in vivo drug response in real patients. In brief, we have tested the dose response for a panel of 387 investigational drugs and plotted this readout against molecular characterization in 35 TNBC cell lines and PDXs. Using linear regression, we have identified statistically significant positively and negatively correlating DNA, RNA, and protein predictors of drug efficacy. From this expanded multi-omic set, we have identified a multi-omic signature for sensitivity to gemcitabine, a drug widely used in TNBC, but at present, without any a priori knowledge of who is likely to benefit. Moreover, we noted a significant correlation of response with MERIT40, an AKT substrate. MERIT40 is critical for localization of BRCA1 to facilitate DNA damage repair. MERIT40 promotes resolution of DNA damage caused by chemotherapy, and thus, based on our published work and supporting literature, PI3K/AKT inhibition is a rational synergistic partner with gemcitabine. Moreover, further supporting our hypothesis, preliminary results indicate Chou-Talalay synergy at therapeutically relevant doses when gemcitabine is combined with PI3K/AKT inhibition. In future studies, we will evaluate the ability of the gemcitabine biomarker to predict response, and the efficacy of the prioritized combinations using ex vivo patient models of metastatic breast cancer established in our laboratory. Citation Format: Nathan M. Merrill, Nathalie M. Vandecan, Athena M. Apfel, Peter J. Ulintz, Liwei Bao, Xu Cheng, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner. Optimizing gemcitabine in metastatic TNBC by rational PI3K/AKT combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1187.
Abstract 16527: Gender Differences in Salt Sensitivity to Nitric Oxide-Dependent Vasodilation in Healthy Young Adults
Authors: John H Eisenach, Leah R Gullixson, Susan L Kost, Michael J Joyner, Stephen T Turner, Wayne T Nicholson
Journal: Circulation (2011)

Salt sensitivity may be associated with endothelial production of nitric oxide (NO). We therefore tested the hypothesis that dietary sodium influences the NO component of endothelium-dependent vaso...