tbuckley/cabot-search huggingface dataset:
Abstract 1614: The effect of tumor mutation burden on immune checkpoint inhibitors in non-small cell lung cancer
Authors: Jie Zhao, Yiting Dong, Hua Bai, Jianchun Duan, Guoqiang Wang, Jiachen Xu, Zhijie Wang, Jie Wang
Journal: Cancer Research (2021)

Abstract Backgroud: Tumor mutation burden (TMB) remains a promising but ambiguous biomarker for the efficacy of immune checkpoint inhibitors (ICIs)-based regimens. We conducted multifaceted systematic review and meta-analysis, and public cohort validation, to provide pooled evidence of the prediction value of TMB for ICIs in advanced non-small cell lung cancer (NSCLC). Methods: Mirror-based meta-analysis balancing the confounding factors was applied in Part1, and Bayesian network meta-analysis was conducted in Part2. PubMed, Embase, and Cochrane Central were searched and abstracts from conference were reviewed. All randomized controlled trials (RCTs) that investigated the predictive value of TMB in advanced NSCLC patients receiving ICIs were included. Baseline characteristics, hazard ratios (HRs) with 95% confidence intervals (95% CIs) for progression-free survival (PFS) and overall survival (OS) stratified by TMB status were extracted. Furthermore, public cohorts of advanced NSCLC treated with ICIs with genomic sequencing were analyzed in Part 3. Results: 10 RCTs covering 4443 patients and 5 public cohorts with 573 patients as validation were included. 9 RCTs were included in Part1a. TMB-high subgroup exhibited significantly superior PFS than TMB-low subgroup (HR 0.56, 95% CI 0.47-0.67) in NSCLC treated with ICIs compared with chemotherapy, and such superiority was consistent in the preplanned subgroup analysis based on the line of therapy, regimen modality, test method of TMB and PD-L1 expression. 7 RCTs were included in Part1b. No significant difference of PFS or OS was observed between anti-PD-L1 and anti-PD-1 according to TMB status. 7 RCTs were included in Part2. Among all first-line regimens in TMB-high group, platinum-based doublet chemotherapy combined with anti-PD-1 was most likely to rank first for PFS (probability of ranking best 48.29%, surface under the cumulative ranking curve 0.83), anti-PD-L1 plus anti-cytotoxic T-lymphocyte A antigen-4 (CTLA-4) provided the most favorable OS (63.89%, 0.86), and platinum-based chemotherapy ranked worst for PFS (0.03%, 0.11) and OS (0.02%, 0.09). In Part3, TMB was validated to be an independent predictor, which could further distinguish beneficiaries of ICIs in those with PD-L1 expression less than 50%. Conclusions: TMB could be used to identify beneficiaries of ICIs contained therapies and played a crucial role in determining the optimal first-line treatment among various available strategy for advanced NSCLC patients. Citation Format: Jie Zhao, Yiting Dong, Hua Bai, Jianchun Duan, Guoqiang Wang, Jiachen Xu, Zhijie Wang, Jie Wang. The effect of tumor mutation burden on immune checkpoint inhibitors in non-small cell lung 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 1614.
Abstract LB099: The inhibitory effect of pemetrexed disodium heptahydrate on the growth of A549 cells
Authors: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara
Journal: Cancer Research (2021)

Abstract Background: Pemetrexed disodium heptahydrate (pemetrexed) is currently used for the treatment of patients with advanced non-small cell lung cancer (NSCLC). More than 30% of lung cancer cases involve KRAS mutations. In this study, we examined the anticancer ability of pemetrexed in KRAS-dependent A549 lung cancer cells. Methods: A549 cells were treated with pemetrexed for 72 h and then evaluated by a TUNEL assay, ROS assay and Western blotting. Results: The apoptotic effect of pemetrexed was observed through increased levels of cleaved caspase-9 (Asp 315), cleaved caspase-3 (Asp 175) and cleaved PARP. Furthermore, pemetrexed increased ROS-mediated DNA damage and enhanced the proapoptotic Bax protein expression, leading to the loss of mitochondrial membrane potential (MMP). The increased expression of the β-galactosidase protein was correlated with the induction of cellular senescence. Significantly, pemetrexed induced cytotoxicity without inhibiting the RAS/RAF/MEK/ERK signaling pathway, while pemetrexed induced autophagy, which activated the AMPK/mTOR signaling pathway. Conclusion: Taken together, these findings indicate that, in addition to apoptosis, pemetrexed-induced autophagy and cellular senescence, providing a promising direction for the development of KRAS-targeted therapy. Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. The inhibitory effect of pemetrexed disodium heptahydrate on the growth of A549 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 LB099.
Abstract LB212: The VGLL4 tumor suppressor inhibits transglutaminase-2 dependent YAP1-TEAD signaling to attenuate the cancer phenotype
Authors: McKayla B. Mickle, Gautam Adhikary, Wen Xu, Suruchi Shrestha, Richard L. Eckert
Journal: Cancer Research (2021)

Abstract Epidermal squamous cell carcinoma (SCC) is among the most common and aggressive forms of cancer. We previously showed that the pro-cancer transcription factor, YAP1, drives an aggressive SCC cancer phenotype by binding to nuclear TEAD transcription factors to activate pro-cancer gene expression. Vestigial-like protein 4 (VGLL4) is a tumor suppressor that is downregulated in epithelial cancers. It binds to TEAD factors to displace YAP1 binding to reduce YAP1-dependent transcription and target gene expression. The present study shows that VGLL4 overexpression reduces SCC cell TEAD-dependent transcription to reduce expression of mRNA and protein encoding YAP1-target genes (CTGF, CYR61, CCND1), and pro-cancer collagen genes (COL1A2, COL3A1) leading to reduced cell proliferation, spheroid formation, invasion and migration. Identical results were observed in response to transient and stable VGLL4 overexpression. Similarly, VGLL4 expression reduces YAP1 activity in tumors leading to reduced YAP1 target and pro-cancer collagen gene expression and reduced and EMT marker proteins levels which is associated with reduced tumor formation. Loss of YAP1 responsive gene expression appears to be essential for VGLL4 attenuation of the aggressive phenotype, as forced overexpression of CCND1 or COL1A2 antagonizes VGLL4 action. These findings suggest VGLL4 functions as a tumor suppressor in SCC by repressing YAP1/TEAD signaling and consequently attenuating the SCC phenotype. Citation Format: McKayla B. Mickle, Gautam Adhikary, Wen Xu, Suruchi Shrestha, Richard L. Eckert. The VGLL4 tumor suppressor inhibits transglutaminase-2 dependent YAP1-TEAD signaling to attenuate the cancer phenotype [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 LB212.
Complete Remission of Basal Cell Carcinoma Following Treatment With Cemiplimab After 2 Years
Authors: Konstantin Dumann, Niklas Artz, Mirjana Ziemer
Journal: JAMA Dermatology (2021)

This case report describes a man in his early 80s with a locally advanced ulcerated cutaneous squamous cell carcinoma on the left temple, 2 pulmonary metastases, and 2 infiltrative basal cell carcinomas that presented with erythematosquamous ulcerated plaques.
Abstract CT227: A phase 1 multiple ascending dose study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of KD033 in subjects with metastatic or locally advanced solid tumors
Authors: Jason J. Luke, Anthony J. Olszanski, Igor Puzanov, Dan Lu, Adrian Hackett, Stella Martomo, Jeegar Patel, Olivier Schueller, Alessandro Mora, Miranda L. Schlitt, Linghui Li
Journal: Cancer Research (2021)

Abstract Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs). In addition, unlike IL-2, IL-15 does not mediate activation-induced cell death and is expected to have an improved therapeutic index compared to IL-2. KD033 is a fusion antibody molecule generated by combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies to understand the pharmacology, pharmacokinetic (PK) and toxicology properties. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free-IL-15. The increased safety and efficacy of PD-L1-targeted IL-15 observed in pre-clinical studies warranted evaluation of KD033 in humans. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. KD033 is administered as an IV infusion over 30 minutes every 14 days (i.e., a cycle equals 2 weeks). The starting dose of KD033 is 3 µg/kg, with step-up dosing to 12.5 µg/kg in the first cohort of 3 subjects. After the first cohort, the dose escalation will use a standard 3+3 design with planned doses from 25 µg/kg to 600 µg/kg. The dose escalation phase will be followed by one expansion cohort, which will enroll patients who received PD-1/PD-L1 inhibitor but have either progressed or are refractory to therapy. Secondary objectives include characterization of PK and immunogenicity, evaluation of immune correlates that will potentially differentiate the impact of KD033 versus monotherapy as well as investigate IL-15 biology and determine best overall response and duration of response. (NCT04242147) Citation Format: Jason J. Luke, Anthony J. Olszanski, Igor Puzanov, Dan Lu, Adrian Hackett, Stella Martomo, Jeegar Patel, Olivier Schueller, Alessandro Mora, Miranda L. Schlitt, Linghui Li. A phase 1 multiple ascending dose study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of KD033 in subjects with metastatic or locally advanced solid tumors [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 CT227.
Ablation of Akt2 and AMPKα2 rescues high fat diet-induced obesity and hepatic steatosis through Parkin-mediated mitophagy
Authors: Shuyi Wang, Jun Tao, Huaguo Chen, Machender R. Kandadi, Mingming Sun, Haixia Xu, Gary D. Lopaschuk, Yan Lu, Junmeng Zheng, Hu Peng, Jun Ren
Journal: Acta Pharmaceutica Sinica B (2021)

Given the opposing effects of Akt and AMP-activated protein kinase (AMPK) on metabolic homeostasis, this study examined the effects of deletion of Akt2 and AMPKα2 on fat diet-induced hepatic steatosis. Akt2-Ampkα2 double knockout (DKO) mice were placed on high fat diet for 5 months. Glucose metabolism, energy homeostasis, cardiac function, lipid accumulation, and hepatic steatosis were examined. DKO mice were lean without anthropometric defects. High fat intake led to adiposity and decreased respiratory exchange ratio (RER) in wild-type (WT) mice, which were ablated in DKO but not Akt2-/- and Ampkα2-/- mice. High fat intake increased blood and hepatic triglycerides and cholesterol, promoted hepatic steatosis and injury in WT mice. These effects were eliminated in DKO but not Akt2-/- and Ampkα2-/- mice. Fat diet promoted fat accumulation, and enlarged adipocyte size, the effect was negated in DKO mice. Fat intake elevated fatty acid synthase (FAS), carbohydrate-responsive element-binding protein (CHREBP), sterol regulatory element-binding protein 1 (SREBP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor-α (PPARα), PPARγ, stearoyl-CoA desaturase 1 (SCD-1), phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and diglyceride O-acyltransferase 1 (DGAT1), the effect was absent in DKO but not Akt2-/- and Ampkα2-/- mice. Fat diet dampened mitophagy, promoted inflammation and phosphorylation of forkhead box protein O1 (FoxO1) and AMPKα1 (Ser485), the effects were eradicated by DKO. Deletion of Parkin effectively nullified DKO-induced metabolic benefits against high fat intake. Liver samples from obese humans displayed lowered microtubule-associated proteins 1A/1B light chain 3B (LC3B), Pink1, Parkin, as well as enhanced phosphorylation of Akt, AMPK (Ser485), and FoxO1, which were consolidated by RNA sequencing (RNAseq) and mass spectrometry analyses from rodent and human livers. These data suggest that concurrent deletion of Akt2 and AMPKα2 offers resilience to fat diet-induced obesity and hepatic steatosis, possibly through preservation of Parkin-mediated mitophagy and lipid metabolism.
Abstract ND10: Discovery of RMC-5552: A selective bi-steric inhibitor of mTORC1 that suppresses 4EBP1 phosphorylation, for the treatment of mTORC1-activated tumors including RAS pathway escape
Authors: G. Leslie Burnett
Journal: Cancer Research (2021)

Abstract The PI3K/mTOR and RAS signaling pathways are hyperactivated in a wide range of human cancers. Several points of cross-talk and intersecting feedback mechanisms have been described and activation of mTOR signaling frequently mediates escape from RAS pathway inhibition. Revolution Medicines has developed a novel class of selective mTORC1 inhibitors, termed ‘bi-steric inhibitors', that interact with both the ATP- and FKBP12/FRB-binding sites of mTORC1. These compounds potently and selectively inhibit mTORC1 over mTORC2 and other lipid kinases. Unlike rapalogs, such as everolimus, these bi-steric inhibitors suppress 4EBP1 phosphorylation in vivo and induce growth suppression and apoptosis in various genetically-defined preclinical models of human cancer. We will describe our SAR investigations and findings for our preclinical tool compound, RMC-6272 (also known as RM-006) and for RMC-5552, our clinical candidate. We will demonstrate that mTORC1-selective bi-steric inhibitors show combinatorial activity with both KRASG12C(OFF) and KRASG12C(ON) inhibitors, in KRASG12C STK11deficient NSCLC models and can forestall resistance to KRASG12C inhibitor monotherapy. In addition, we will show single agent activity of bi-steric mTORC1 inhibitors in preclinical models of tumors bearing PI3K/mTOR pathway alterations as primary drivers, including PTEN-deficient glioblastoma multiforme, TSC1/2-deficient renal cystadenoma cancer, and hepatocellular cancers harboring mTOR-activating β-catenin mutations. RMC-5552, through reactivation of 4EBP1 and inhibition of cap-dependent translation, has the potential to benefit cancer patients with genetically-defined tumors with activating mutations in the RAS and PI3K/mTOR pathways both as a single agent or in combination with RAS inhibitors. Citation Format: G. Leslie Burnett. Discovery of RMC-5552: A selective bi-steric inhibitor of mTORC1 that suppresses 4EBP1 phosphorylation, for the treatment of mTORC1-activated tumors including RAS pathway escape [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 ND10.
Rectourethral Fistula Induced by Localised Prostate Cancer Treatment: Surgical and Functional Outcomes of Transperineal Repair with Gracilis Muscle Flap Interposition
Authors: Marc Sbizzera, Nicolas Morel-Journel, Alain Ruffion, Sébastien Crouzet, Philippe Paparel, Damien Carnicelli, Paul Neuville
Journal: European Urology (2021)
The effectiveness of adapted psychological interventions for people from ethnic minority groups: A systematic review and conceptual typology
Authors: Laura-Louise Arundell, Phoebe Barnett, Joshua E.J. Buckman, Rob Saunders, Stephen Pilling
Journal: Clinical Psychology Review (2021)

This review assessed the efficacy of adapted psychological interventions for Black and minority ethnic (BME) groups. A conceptual typology was developed based on adaptations reported in the literature, drawing on the common factors model, competence frameworks and distinctions between types of cultural adaptations. These distinctions were used to explore the efficacy of different adaptations in improving symptoms of a range of mental health problems for minority groups. Bibliographic searches of MEDLINE, Embase, PsycINFO, HMIC, ASSIA, CENTRAL, CDSR and CINAHL spanned the period from 1965 to December 2020. Adaptations to interventions were categorised: i) treatment specific: therapist-related, ii) treatment-specific: content-related and iii) organisation-specific. Meta-analyses of RCTs found a significant effect on symptom reduction when adapted interventions were compared to non-adapted active treatments (K = 30, Hedge's g = -0.43 [95% CI: -0.61, -0.25], p < .001). Studies often incorporated multiple adaptations, limiting the exploration of the comparative effectiveness of different adaptation types, although inclusion of organisation-specific adaptations may be associated with greater benefits. Future research, practitioner training and treatment and service development pertaining to adapted care for minority groups may benefit from adopting the conceptual typology described.
Venous Thromboembolism (VTE) in Adults with Non Hodgkin Lymphoma (NHL) a Retrospective Cohort Study
Authors: Carlos Martinez Murillo, Karen Flores Ordoñez, Efreen Montaño Figueroa, Humberto Baldemar Castellanos Sinco, Guadalupe Leon Gonzalez, Julio Kassack Ipiña, Juan Collazo Jaloma, Christian Ramos Peñafiel, Hugo Leyton Rivera, Angélica Vazquez Gonzalez
Journal: Blood (2017)
Planning prostate cancer radiotherapy following male to female gender affirming surgery
Authors: N. Bedi, A. Dusoye, F. Hosking-Jervis, H. Gresty, K.A. Bell, K. Sahota, M. Bertoncelli Tanaka, M.J. Hyder Junejo, P.J. Eyskens, R.L. Oliver, C. Dunford, R. Crawford, U. Walters, J.B Burn, P. Bridge, T. Rashid
Journal: European Urology (2021)
Abstract LB198: Inhibition of the RAC Activator VAV3 by the small molecule IODVA1 impedes RAC signaling &amp; overcomes resistance to tyrosine kinase inhibition in lymphoblastic leukemia
Authors: Nicolas N. Nassar, Shailaja Hegde, Kark Wunderlich, Yuan Lin, Reza Ahmadian, William Seibel, Yi Zheng, Benjamin E. Mizukawa, Lisa Privette Vinnedge, Jose A. Cancelas
Journal: Cancer Research (2021)

Abstract Aberrant activation of RHO guanine nucleotide exchange factors (RhoGEFs) is a chief mechanism driving abnormal activation of their RhoGTPase targets in transformation and tumorigenesis. Consequently, a small molecule inhibitor of RhoGEF activities can be used as an anti-cancer drug. Herein, we used cellular, mouse, and humanized models of RAC-dependent BCR-ABL1-driven and Ph-like lymphoblastic leukemia to identify VAV3, a tyrosine phosphorylation-dependent RacGEF, as the target of the small molecule IODVA1. We show that IODVA1 binds tightly to VAV3, inhibits RAC activation and signaling, and increases pro-apoptotic activity in BCR-ABL1-transformed cells only. Consistent with this mechanism of action, both VAV3-deficient leukemic cells and mouse models of BCR-ABL1 leukemia do not respond to IODVA1. IODVA1 eradicates leukemic propagating activity of TKI-resistant BCR-ABL1(T315I) B-ALL cells after treatment withdrawal by decreasing RAC signaling in vivo. Importantly, IODVA1 is superior to standard of care dasatinib and ponatinib at prolonging the survival of PDX models of relapsed pediatric Ph+ and TKI-resistant Ph+ B-ALL with commonly found genetic mutations especially after treatment withdrawal. Cells representing pediatric ALL patients with diverse genetic lesions are highly sensitive to IODVA1 ex vivo and this sensitivity is VAV3-dependent. IODVA1 thus spearheads a novel class of drugs that inhibits a RacGEF and holds promise as an anti-tumor therapeutic agent. Citation Format: Nicolas N. Nassar, Shailaja Hegde, Kark Wunderlich, Yuan Lin, Reza Ahmadian, William Seibel, Yi Zheng, Benjamin E. Mizukawa, Lisa Privette Vinnedge, Jose A. Cancelas. Inhibition of the RAC Activator VAV3 by the small molecule IODVA1 impedes RAC signaling &amp; overcomes resistance to tyrosine kinase inhibition in lymphoblastic leukemia [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 LB198.
Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1–Selected NSCLC
Authors: Jacek Jassem, Filippo de Marinis, Giuseppe Giaccone, Alain Vergnenegre, Carlos H. Barrios, Masahiro Morise, Enriqueta Felip, Cristina Oprean, Young-Chul Kim, Zoran Andric, Simonetta Mocci, Ida Enquist, Kimberly Komatsubara, Mark McCleland, Hiroshi Kuriki, Monette Villalobos, See Phan, David R. Spigel, Roy S. Herbst
Journal: Journal of Thoracic Oncology (2021)