tbuckley/cabot-search huggingface dataset:
Abstract 1945: Modulation of intracellular redox milieu regulates Mcl-1 levels and sensitizes venetoclax resistant cancer cells
Authors: Jolin Xiao Lai, Shazib Pervaiz
Journal: Cancer Research (2021)

Abstract Mcl-1, a member of the Bcl-2 family of anti-apoptotic proteins is commonly amplified in malignant cancers and has been implicated in chemotherapy resistance. More recently, it has been reported to mediate resistance to the Bcl-2 specific BH3 mimetic, venetoclax (ABT199). The protein stability of Mcl-1 is regulated largely by post-translational modifications (PTMs) such as phosphorylation and ubiquitination. Where phosphorylation of Thr163 residue at the PEST domain region by kinases result in Mcl-1 stability and extended protein half-life, phosphorylation of Ser159 residue leads to protein degradation via proteasome pathway. Given the importance of PTMs in regulating Mcl-1, identification of signaling pathways that could modulate PTMs of Mcl-1 to thereby sensitize tumors to chemotherapy have been explored extensively. The intracellular redox milieu has been widely reported to modulate protein-protein signaling as well as inducing PTMs, where different reactive oxygen species (ROS) have also been shown to mediate differential effects. For example, enhanced production of O2- (by either inhibition or downregulation of SOD1/SOD2) could mediate tumorigenicity and chemoresistance. To that end, our group and others have also previously reported the oncogenicity of superoxide (O2-), where an elevated O2- level mediates enhanced anti-apoptotic activity against chemotherapeutic agents through sustained Bcl-2 phosphorylation and the inhibition of O2- production conversely sensitized cells to chemotherapy. Nonetheless, the exact mechanisms of how O2- exerts its pro-survival effects remain elusive. Our preliminary findings now suggest that elevated intracellular O2- levels induces Mcl-1 stability in cancer cells through PTMs as a potential mechanism of chemotherapy resistance. Increased intracellular O2- levels induced Mcl-1 through phosphorylation of Thr163 residue of Mcl-1, which in turn reduced ubiquitination dependent degradation of Mcl-1. Importantly, increased O2- level increased resistance to cell death induced by Mcl-1 specific BH3 mimetic, S63845 and conversely, reducing O2- levels resulted in sensitization of intrinsically venetoclax resistant leukemia cells to venetoclax induced cell death. These results provide a novel insight into how the intracellular redox state could impact upon cancer cell viability and therapy resistance. Citation Format: Jolin Xiao Lai, Shazib Pervaiz. Modulation of intracellular redox milieu regulates Mcl-1 levels and sensitizes venetoclax resistant 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 1945.
Impact of original, B.1.1.7, and B.1.351/P.1 SARS-CoV-2 lineages on vaccine effectiveness of two doses of COVID-19 mRNA vaccines: Results from a nationwide case-control study in France
Authors: Tiffany Charmet, Laura Schaeffer, Rebecca Grant, Simon Galmiche, Olivia Chény, Cassandre Von Platen, Alexandra Maurizot, Alexandra Rogoff, Faïza Omar, Christophe David, Alexandra Septfons, Simon Cauchemez, Alexandre Gaymard, Bruno Lina, Louise H Lefrancois, Vincent Enouf, Sylvie van der Werf, Alexandra Mailles, Daniel Levy-Bruhl, Fabrice Carrat, Arnaud Fontanet
Journal: The Lancet Regional Health - Europe (2021)
Potential Benefits of Expanded COVID-19 Surveillance in the US
Authors: David R. Holtgrave, Sten H. Vermund, Leana S. Wen
Journal: JAMA (2021)

Potential Benefits of Expanded COVID-19 Surveillance in the USWhen public health officials assert that a new vaccine, drug, or policy is "safe," the public needs to have full confidence in that assertion.This trust is boosted when the public knows that health officials tried hard to find flaws in their proposed strategies and "pressure tested" their assumptions.Public health strategies should be evaluated longafterprogramshavebeendeployedtoensurethatanticipatedconsequencesoccurasplannedandunanticipated ones are detected early.This is the rationale used when the US Food and Drug Administration grants Emergency Use Authorization and requires postmarketing surveillance for adverse events before full product approval.By June 2021, public health agencies (especially the Centers for Disease Control and Prevention [CDC] 1 ) had gathered substantial data relevant to the COVID-19 response.There are, however, some key epidemiologic blind spots.This Viewpoint proposes several important areas of surveillance expansion. Enhance COVID-19 Testing EffortsAt its peak in the US (November 2020 to January 2021), the number of COVID-19 tests performed often exceeded an estimated 2 million per day. 2 The number of daily tests in June 2021, however, declined to well under 1 million tests per day, estimated at approximately 577 000 tests per day during the week of June 20 through June 26. 2Some of this decline may be among fully vaccinated persons without a need for frequent testing.However, a reenergizing of testing efforts is needed because without vigorous testing the nation cannot be sure whether declining cases are a function of decreased numbers of infections or reduced numbers of tests.The test positivity rate is still approximately 2% in the US (as of mid-June 2021), 2 so testing continues to identify cases.As the pandemic phases unfold, testing may take on enhanced roles such as further aiding in the reopening of businesses, schools, and other organizations.Furthermore, as the highly transmissible SARS-CoV-2 delta variant arises in the US, a new focus on widespread testing of unvaccinated and partially vaccinated persons takes on additional urgency.Vaccination status should be obtained along with each COVID-19 test.
Government must boost spending on drug dependency services, says landmark review
Authors: Richard Hurley
Journal: BMJ (2021)

An extra £550m (€642m; $761m) for local authorities to tackle drug dependency should be ringfenced over five years to reverse huge recent cuts, a major review of UK drug policy has concluded.The call is one of over 30 recommendations made in the independent review of UK drug misuse from Carol Black, which examined prevention, treatment, and recovery among people who take drugs, with the aim of reducing misuse.
Abstract 1929: Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells <i>in vitro</i>
Authors: Latoya Mcglorthan, Ana Paucarmayta, Yovanni Casablanca, George L. Maxwell, Viqar Syed
Journal: Cancer Research (2021)

Abstract Previously we have shown that progesterone and calcitriol induce apoptosis of cancer cells. However, the apoptotic mechanisms of the two agents have not been well characterized yet. Herein, we investigated the molecular mechanisms of how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12 h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24h. Caspase 9 activity was increased in all cell lines after 24h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells. Citation Format: Latoya Mcglorthan, Ana Paucarmayta, Yovanni Casablanca, George L. Maxwell, Viqar Syed. Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro [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 1929.
Abstract 1182: The NEDD8 inhibitor pevonedistat blocks the repair of topoisomerase I (TOP1)-induced replication damage and synergizes with TOP1 inhibitors
Authors: Yilun Sun, Andrea Baechler, Valentina Factor, Kanako Okamoto, Yves Pommier
Journal: Cancer Research (2021)

Abstract Genomic DNA is constantly challenged by various genotoxic substances, resulting in an array of DNA lesions including DNA-protein crosslinks (DPCs), one of the most detrimental forms of DNA damage. Topoisomerase I (TOP1) is the molecular target of anti-cancer agents camptothecin derivatives and indenoisoquinolines, which act by trapping TOP1 on genomic DNA. The resulting TOP1-DPCs interfere with DNA replication and transcription and trigger cell death if left unrepaired. In this work, we found that the ubiquitin-like protein NEDD8 plays a pivotal role in the repair of TOP1-DPCs by activating the cullin 4 (CUL4)-RING ubiquitin ligases (CRL4) for K48-linked polyubiquitylation of TOP1-DPCs and their subsequent proteasomal degradation. We identified DCAF13, an understudied family member of DDB1- and CUL4-asscoiated factors, as the receptor of TOP1-DPCs for CRL4. DCAF13 colocalizes with TOP1-DPCs at nascent replication forks and binds the TOP1 core domain with its WD40 domains, linking TOP1 to DDB1-CRL4 for ubiquitylation upon TOP1-induced replication damage. Prompted by these findings, we hypothesized that targeting this NEDD8-activated repair pathway can be developed as a strategy to overcome resistance to TOP1 inhibitors. To test this hypothesis, we performed pharmacological analyses using CellMiner (http://discover.nci.nih.gov/cellminercdb) and found that the activities of TOP1 inhibitors and pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor in clinical trial, are highly correlated across cancer cell lines and with the expression of SLFN11. We also assessed the sensitivity of cultured cancer cells to combination of clinical TOP1 inhibitors and pevonedistat. The combination exhibited synergy in multiple cell lines particularly in human colon cancer cells HCT116 independently of SLFN11. We next investigated the efficacy of combination with TOP1 inhibitor topotecan and pevonedistat in HCT116 xenografts and observed supra-additive effect on tumor growth inhibition. Taken together, our work not only identifies a novel pathway for the repair of TOP1-DPCs but also provides translational evidence to support pevonedistat in combination with TOP1 inhibitors as a rationale therapeutic combination for cancer treatments. Citation Format: Yilun Sun, Andrea Baechler, Valentina Factor, Kanako Okamoto, Yves Pommier. The NEDD8 inhibitor pevonedistat blocks the repair of topoisomerase I (TOP1)-induced replication damage and synergizes with TOP1 inhibitors [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 1182.
Abstract 2326: Differential lipid metabolism in mammary cancer cell progression
Authors: Chaylen Andoline, Parik Pawar, Dorothy Teegarden
Journal: Cancer Research (2021)

Abstract There is an association between increased lipid accumulation and aggressive breast cancer phenotypes, and therefore poorer clinical outcomes. The mechanism by which dysregulated lipid metabolism may promote metastasis remains incompletely understood. Several potential mechanisms by which the neutral lipid storage organelles, cytoplasmic lipid droplets, may promote metastasis include utilization of fatty acids (FAs) for oxidation, protection against lipotoxcity, and production of lipid signaling mediators. We have previously demonstrated that metastatic MCF10CA1a mammary cancer cells rely on fatty acid oxidation (FAO) compared to non-metastatic MCF10A-ras cells, using etomoxir to inhibit the rate-limiting enzyme of FAO, carnitine palmitoyltransferase 1 (CPT1). Previous literature indicates that there is an increase in various lipid metabolism pathways, including FA uptake, de novo lipogenesis, and FA storage in neutral lipid. We found that there is no significant difference between palmitic acid uptake between the non-metastatic and metastatic cells. In the current study, we show that MCF10CA1a cells have significantly higher levels of carbon incorporation into palmitic and oleic FAs from 13C-acetate (25% and 20% greater), 13C-glucose (21% and 11% greater), and 13C-lactate (29% and 22% greater) respectively, compared to the MCF10A-ras cells, as detected by LC-MS/MS. In order to determine the source of FAs that contributes to the migration-dependent FAO, we assessed MCF10CA1a cell migration following inhibition of lipolysis (adipose triglyceride lipase—ATGL; ATGListatin) alone or in combination with the FAO inhibitor, etomoxir. We determined that inhibition of ATGL, the initial enzyme of triglyceride lipolysis pathway, significantly reduces MCF10CA1a cell migration (20% decrease compared to vehicle). Inhibition of FAO and lipolysis did not induce additional reduction in cell migration. We also showed that MCF10CA1a cells are more dependent on FA metabolism than the non-metastatic MCF10A-ras cells, demonstrated by MCF10CA1a cells having a greater decrease in cell viability compared to the MCF10A-ras cells given each FA metabolism inhibition (p&amp;lt;0.05: 22% greater decrease for FAO inhibition and 16% greater decrease for dual FAO and lipolysis inhibition, p=0.05: 17% greater decrease for FA synthesis inhibition). These data suggest that metastatic MCF10CA1a cells rely on their increased FA metabolism to survive and migrate, and specifically that the catabolism of FAs from triglyceride supports the FAO-driven migration of metastatic cancer cells. Citation Format: Chaylen Andoline, Parik Pawar, Dorothy Teegarden. Differential lipid metabolism in mammary cancer cell progression [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 2326.
Direct in vivo reprogramming with non-viral sequential targeting nanoparticles promotes cardiac regeneration
Authors: Qiaozi Wang, Yanan Song, Jing Chen, Qiyu Li, Jinfeng Gao, Haipeng Tan, Yuefei Zhu, Zhengmin Wang, Minghui Li, Hongbo Yang, Ning Zhang, Xiaomin Li, Juying Qian, Zhiqing Pang, Zheyong Huang, Junbo Ge
Journal: Biomaterials (2021)
PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca <sup>2+</sup> Content
Authors: David C. Hutchings, Charles M. Pearman, George W.P. Madders, Lori S. Woods, David A. Eisner, Katharine M. Dibb, Andrew W. Trafford
Journal: Circulation Research (2021)

[Figure: see text].
Abstract LB031: Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST)
Authors: Chandrashekhar Honrao, Srihari Raghavendra Rao, Nathalie Teissier, S. Greg Call, Elizabeth M. ODay, Filip Janku
Journal: Cancer Research (2021)

Abstract Background: Discovery of oncogenic mutations as targets for cancer therapy revolutionized treatment of GIST and other cancers. However, nearly all patients ultimately progress, which emphasizes the need for development of new tools to assess cancer prognosis and factors associated with benefit of cancer therapies. Altered metabolism is a hallmark of cancer, enabling tumors to proliferate, survive and metastasize. By measuring the complete set of metabolites in an individual (metabolome) it is possible to identify biomarkers that correlate with disease status, prognosis, and therapeutic response. Methods: We performed untargeted NMR and MS-based machine learning metabolomic analysis (Olaris, Waltham, MA) of serial plasma samples collected at baseline and during experimental systemic therapies in 39 patients with advanced/metastatic GIST. Results were compared to clinical outcomes. Results: In serial plasma samples from 39 patients with advanced/metastatic GIST using untargeted NMR and MS-based machine learning (ML) metabolomic analysis, we identified metabolic signatures to build Biomarker-of-Response (BoR) ML models that could accurately differentiate patients with response, intrinsic and adaptive resistance to experimental systemic therapies. The BoR ML model also correlated with tumor growth or tumor reduction in patients with response, intrinsic and adaptive resistance. Finally, we identified metabolic pathways associated with response and resistance. Conclusions: Comprehensive metabolomic profiling of serially collected plasma is feasible and detects metabolic signatures associated with therapeutic response in advanced GIST. Citation Format: Chandrashekhar Honrao, Srihari Raghavendra Rao, Nathalie Teissier, S. Greg Call, Elizabeth M. ODay, Filip Janku. Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST) [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 LB031.
Preventing microalbuminuria with benazepril, valsartan, and benazepril–valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study
Authors: Piero Ruggenenti, Monica Cortinovis, Aneliya Parvanova, Matias Trillini, Ilian P. Iliev, Antonio C. Bossi, Antonio Belviso, Maria C. Aparicio, Roberto Trevisan, Stefano Rota, Annalisa Perna, Tobia Peracchi, Nadia Rubis, Davide Martinetti, Silvia Prandini, Flavio Gaspari, Fabiola Carrara, Salvatore De Cosmo, Giancarlo Tonolo, Ruggero Mangili, Giuseppe Remuzzi
Journal: PLoS Medicine (2021)

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy.VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion.Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients.EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152.
Abstract 1013: Mechanistic role of nelfinavir as drug-repurposing strategy against high-grade serous ovarian cancer
Authors: Mahbuba R. Subeha, Alicia A. Goyeneche, Carlos M. Telleria
Journal: Cancer Research (2021)

Abstract Platinum-based therapy following tumor-debulking surgery has been the backbone of treatment for high-grade serous ovarian cancer (HGSOC) since the 1970s; however, high recurrence of platinum-resistant disease necessitates the development of improved alternative therapies. Repurposing market-available drugs as cancer therapeutics carries the prospect of reducing the timeframe and cost of drug development, posing potential benefits to drug-resistant as well as financially underprivileged patients. Nelfinavir (NFV), an orally available anti-HIV drug, has shown promising effects against diverse cancers as demonstrated through a myriad of pre-clinical studies and clinical trials; however, its remedial benefits against HGSOC are still unclear. In this study, we explored the therapeutic efficacy of NFV on HGSOC cells generated from patients when platinum sensitive or resistant. Acute drug toxicity was assessed by total cell count, percent viability, and the level of hypo-diploid DNA content following 72 h of treatment with NFV. Living cells that tolerated 72 h of NFV treatment were subjected to further drug-free re-incubation for 14-21 days, to assess the residual anti-clonogenic potential of the drug. NFV triggered a dose-depended reduction of total cell number and viability, with a parallel increased hypo-diploid DNA content in both platinum-sensitive and resistant HGSOC cells. A dose-dependent reduction in the number of colonies - originating from cells that evaded acute toxicity - suggested long-term residual toxicity of NFV. Western blot analysis of underlying molecular mechanisms revealed phosphorylation of γH2AX, which suggested NFV-mediated induction of DNA damage. NFV also inhibited proliferation signals by reducing the phosphorylation of Akt and ERK. Moreover, NFV stimulated endoplasmic reticulum (ER) stress in a dose-dependent manner, which was evident from the enhanced expression of GRP78, IRE1α, ATF4, CHOP, and phosphorylated eIF2α. A time-dependent steady increase of ATF4 and CHOP suggested a progressive temporal apoptotic shift during NFV treatment. Finally, the cleavage of caspases-3 and -7 and their downstream effector PARP, in association with increased pro-apoptotic protein BAX, indicated caspase-associated cell-death during NFV-mediated cytotoxicity. In summary, we demonstrated that HGSOC cells of differential platinum sensitivities could be therapeutically targeted by NFV via multipronged mechanistic approaches, encouraging its prospective repurposing benefit against HGSOC. Citation Format: Mahbuba R. Subeha, Alicia A. Goyeneche, Carlos M. Telleria. Mechanistic role of nelfinavir as drug-repurposing strategy against high-grade serous ovarian 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 1013.