tbuckley/cabot-search huggingface dataset:
Abstract OT1-08-05: Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM)
Authors: Jose P Leone, Lorenzo Trippa, Lindsey Milisits, Chelsea Andrews, Jennifer Ligibel, Heather Parsons, Wenya L Bi, Jean Zhao, Eric P Winer, Nancy U Lin
Journal: Cancer Research (2020)

Abstract Background: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. Methods: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha &amp;lt;10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983. Citation Format: Jose P Leone, Lorenzo Trippa, Lindsey Milisits, Chelsea Andrews, Jennifer Ligibel, Heather Parsons, Wenya L Bi, Jean Zhao, Eric P Winer, Nancy U Lin. Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-05.
Reply
Authors: Alok K. Verma, Chandrashekhar R. Gandhi
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. We appreciate the important points raised by Weiss et al.(1) Our data indicate that the loss of 21/23 kDa Augmenter of liver regeneration (ALR) , in mice and humans, renders the liver compromised to develop NASH.(2) Administration of 21/23 kDa ALR to hepatocyte‐specific ALR‐knockout (ALR‐H‐KO) mice between 1 and 2 weeks postpartum mitigated steatohepatitis.(3) The 15 kDa ALR is absent (Fig. 8)(2)(Ref. 71 in (4)) or expressed at a very low level(5) in human liver and absent in mouse liver.(2,4,6) However, further investigation of ALR isoform(s) that can be of therapeutic intervention is important. Hepatic ALR is down‐regulated in steatosis regardless of its etiology in wild‐type (WT) mice, which do not develop inflammation or fibrosis.(2,3,5,6) Only a subset of humans with nonalcoholic fatty liver (NAFL) develop NASH, and some of these progress to cirrhosis, suggesting that inherent deficiency or anomaly in ALR could be an important predisposing factor. However, it will be of interest to examine forkhead box A2 or nuclear erythroid 2 p45‐related factor 2 during NAFL disease progression caused by diet‐induced or inherent ALR deficiency. In the papers identified by Weiss et al.,(4) ALR is less stable (and probably also less efficient) because of the rare mutation(s) in the Growth factor, ERV1‐like (GFER) gene in the patients who were affected. The mutations were associated with congenital cataract, muscular hypotonia, and developmental delay. Note that a liver biopsy of only one patient was performed, which showed mitochondrial damage and fibrosis. Although studying the effect of HF diet in mice with these mutation(s) in an organ‐specific manner is interesting, they are unlikely to be present in NASH, a global epidemic. Other mutations identified in the GFER gene in the general population(6) are being investigated. Our conclusion that inherent ALR deficiency or anomaly could be critical in NASH progression to cirrhosis was based on (1) HF diet‐induced excessive steatosis, inflammation, and fibrosis in otherwise normal ALR‐hepatocyte‐heterozygous mice and augmented inflammation and cirrhosis in ALR‐H‐KO mice with pre‐existing underlying pathology; and (2) lower ALR levels in human NASH and NASH cirrhosis.(2,5,6) However, the high ALR expression observed in some NASH‐cirrhotic livers (Supporting Fig. S10; Supporting Table S4)(2) indicates heterogeneity in human NASH. Patients expressing higher hepatic ALR had non‐NASH cirrhosis,(Ref. 71 in (4)) which may be attributed to etiological differences from NASH cirrhosis.
Abstract P4-13-10: An evaluation of patient reported outcomes following oncoplastic breast conserving surgery with a crescent modification of the chest wall perforated flap utilizing Breast Q
Authors: Amtul R Carmichael, Amtul Shafee Sami, Kefah Mokbel
Journal: Cancer Research (2020)

Abstract Background: An increasing acceptance of chest wall perforator flaps has provided additional options for enhancing the cosmetic appearance of the conserved breast after breast cancer surgery. Traditional lateral intercostal anterior perforator (LICAP) flap involves a lateral chest wall scar. To enhance the cosmetic results of LICAP flap, we propose the crescent modification of the LICAP flap to conceal the scar in the inframammary crease. Aim: The aim of our study was to investigate patient satisfaction and cosmetic outcome by using the BREAST-Q after undergoing crescent-modification of LICAP flap partial breast reconstruction. Methods: All eighteen consecutive patients with who underwent crescent modification of LICAP flap reconstruction for partial breast reconstruction after wide local excision of breast cancer between June 2017 and July 2019 were invited to complete the BREAST-Q questionnaire. All patients were prospectively evaluated and their demographic, clinical and pathological details were recorded on a database. Results: The median psychological, physical and sexual well-being scores were 93 (IQR 63-100), 82 (IQR 69-95) and 70 (IQR 46-96) respectively. The median satisfaction score with breast was 88 (IQR 66-100) Conclusions: In a carefully selected group of women with breast cancer, our study demonstrates that the crescent-modification of the LICAP flap for partial breast reconstruction provides a safe and effective technique with preservation of satisfaction with breast, physical, psychological and sexual well-being. Citation Format: Amtul R Carmichael, Amtul Shafee Sami, Kefah Mokbel. An evaluation of patient reported outcomes following oncoplastic breast conserving surgery with a crescent modification of the chest wall perforated flap utilizing Breast Q [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-13-10.
Interactions of commensal and pathogenic microorganisms with the mucus layer in the colon
Authors: Rui Cai, Chen Cheng, Jianwei Chen, Xiaoqiang Xu, Chao Ding, Bing Gu
Journal: Gut Microbes (2020)

The intestinal mucosal barrier, which is composed of epithelial cells and mucus layers secreted by goblet cells and contains commensal bacteria, constitutes the first line of defense against pathogenic gut microbiota. However, homeostasis between the microbiota and mucus layer is easily disrupted by certain factors, resulting in alteration of the gut microbiota and entry of pathogens to the intestinal mucosal barrier. In this review, we describe the structures and functions of the mucus layer, expound several crucial influencing factors, including diet styles, medications and host genetics, and discuss how pathogenic microorganisms interact with the mucus layer and commensal microbiota, with the understanding that unraveling their complex interactions under homeostatic and dysbiosis conditions in the colon would help reveal some underlying pathogenic mechanisms and thus develop new strategies to prevent pathogenic microbiological colonization.
Abstract 112: Survival of In-Hospital Cardiac Arrest Patients Before and After the Implementation of the Act on Decisions on Life-Sustaining Treatment; The Well-Dying Law
Authors: Minjung K Chae, Chae-Won Jeong, Sung Eun Lee
Journal: Circulation (2019)

Objective: The act on decisions on life-sustaining treatment; the well-dying law(WDL) was implemented in Korea since February of 2018 so that a patient may cease with dignity in his or her death bed. However in the contrary, we have observed increase of in-hospital cardiac arrest patients resulting in poor outcomes due to strict regulations of withdrawal of life support. The objective of this study is to analyze the survival of in-hospital cardiac arrest patients before and after implementation of the WDL. Methods: We retrospectively reviewed our in-hospital cardiac arrest data registry from our in-hospital cardiac arrest committee and electronic medical records. Baseline characteristics, cardiac arrest variables and cardiac arrest outcomes were compared before and after the implementation of the WDL. Multivariate logistic regression was done to analyze the association of the implementation of the WDL and return of spontaneous circulation(ROSC) of in-hospital cardiac arrest patients. Results: There were 183 patients before and 346 patients after the implementation of the WDL. ROSC (158[45.7%] vs. 115[62.8%]), 24 hour survival (60[17.3%] vs. 53[29.0%]) and survival discharge (29[8.4%] vs. 25[13.7%]) was lower in the after period versus the before period. In the multivariate logistic regression analysis implementation of the WDL was associated with lower ROSC (Odds ratio 0.56, 95% Confidence interval 0.37-0.85, p&lt;0.01) and lower survival at 24 hours (Odds ratio 0.53, 95% Confidence interval 0.31-0.93, p=0.03). Conclusion: Implementation of the WDL was associated with lower ROSC and lower survival at 24 hours in in-hospital cardiac arrest patients.
Abstract P3-01-16: Utilizing a decellularized patient-derived xenograft tumor model for the evaluation of triple negative breast cancer
Authors: Maryl Wright, Margarite Matossian, Connor King, Khoa Nguyen, Steven Elliott, Madlin Alzoubi, Elizabeth Martin, Bridgette Collins-Burow, Matthew Burow
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is an aggressive and heterogeneous disease with poorer prognoses compared to other breast cancer (BC) subtypes. This is due, in part, to the lack of clinically approved targeted therapeutics. The mechanisms underlying the process of recurrence in TNBC remain elusive. Traditional 2D BC models do not accurately mimic the cell-matrix interactions and extracellular matrix (ECM) composition that are vital to maintaining the tumor microenvironment and are unique to individual patient tumors. Here we introduce and utilize our novel decellularized patient-derived xenograft (PDX) TNBC model, TU-BcX-4IC (“4IC”), to address this knowledge discrepancy. In this study, we seeded TU-BcX-4IC PDX-derived cells onto TU-BcX-4IC PDX decellularized tumor scaffold (“4IC + 4IC scaffold”) and implanted our model into SCID/beige mice. Concordantly, mice were inoculated with TU-BcX-4IC cells mixed with Matrigel and PBS (“4IC + Matrigel”), or PBS alone (“4IC + PBS”). We demonstrate that our decellularized model, along with the injected cells, can form tumors in vivo. We also show that the “4IC + 4IC scaffold” model retains aberrant mitotic figures seen in the original 4IC PDX. However, due to inconsistent tumor growth in the experimental group, optimization of cell seeding onto our decellularized scaffold model is needed to produce consistent tumor propagation in vivo. We compared the number and area of metastases in the lungs and livers excised from the mice. The area and number of lung metastases were lower in mice implanted with “4IC + 4IC scaffold,” albeit not significantly. There was little difference in the area of liver metastases in all groups. The number of liver metastases was lower in the “4IC + Matrigel” and “4IC + 4IC scaffold” groups; however, there was no significance. All groups had a greater propensity to metastasize to the livers. We also compared differences in human and mouse ECM gene expression amongst all groups. Our decellularized scaffold model can be used as a platform to evaluate ECM onco-architecture and composition. The data presented here will help enhance our understanding of the breast tumor microenvironment and elucidate the mechanisms underlying tumorigenesis and recurrence in TNBC. Citation Format: Maryl Wright, Margarite Matossian, Connor King, Khoa Nguyen, Steven Elliott, Madlin Alzoubi, Elizabeth Martin, Bridgette Collins-Burow, Matthew Burow. Utilizing a decellularized patient-derived xenograft tumor model for the evaluation of triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-16.
Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype
Authors: Hongliang Dong, Yueyao Yang, Chenhui Gao, Hehe Sun, Hongmin Wang, Chao Hong, Jun Wang, Fangyuan Gong, Xiaoming Gao
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Tumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy. Methods A mouse IgG 1 (kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14 + monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models. Results Through coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues. Conclusions LTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.
Outcome of living donor liver transplantation for secondary biliary cirrhosis in adult: Single center experience
Authors: Young In Yoon, Sung Gyu Lee, Hwang Shin, Ki Hun Kim, Chul Soo Ahn, Deok Bog Moon, Tae Yong Ha, Gi Won Song, Dong Hwan Jung, Gil Chun Park
Journal: International Journal of Surgery (2020)
Cellular cytotoxicity is a form of immunogenic cell death
Authors: Luna Minute, Alvaro Teijeira, Alfonso R Sanchez-Paulete, Maria C Ochoa, Maite Alvarez, Itziar Otano, Iñaki Etxeberrria, Elixabet Bolaños, Arantza Azpilikueta, Saray Garasa, Noelia Casares, Jose Luis Perez Gracia, Maria E Rodriguez-Ruiz, Pedro Berraondo, Ignacio Melero
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown. Methods In this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient in Batf3 , Ifnar1 and Sting1 were used to study mechanistic requirements. Results We observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA + EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient in Batf3 -dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8 + T lymphocytes. Conclusion These results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.
Anterior sector outflow reconstruction in right lobe living donor liver transplantation: A single center experience with polytetrafluoroethylene (PTFE) graft
Authors: Ashish Singhal, Kausar Makki, Vishal Chorasiya, Arif Khan, Mohd Qaleem, Furqan Ahmed, Ajitabh Srivastava, Vivek Vij
Journal: International Journal of Surgery (2020)
Abstract 14056: Ventricular-Arterial Coupling Mismatch in Obese Children With Metabolic Syndrome
Authors: Kenji Harada, Yukiko Harada, Manatomo Toyono
Journal: Circulation (2017)

Background: Obesity is associated with structural and functional changes in the heart, however, little is known about ventricular-arterial stiffness/coupling in metabolic syndrome. To clarify this,...
Abstract P3-05-05: Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways
Authors: Santosh Timilsina, Subapriya Rajamanickam, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia Kaklamani, Manjeet K Rao
Journal: Cancer Research (2020)

Abstract Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective targeted therapies with the main therapeutic option being cytotoxic chemotherapies, which have toxic side effects on patient’s health. Less toxic alternatives that could target key pathways that are altered in TNBCs could lead to better outcomes for the patients. Important distinguishing traits of TNBCs is the high amounts of genomic instability and high number of alterations in key proteins in DNA repair and cell proliferation that helps the cancer grow, survive and progress. Previous findings from our lab indicate that Imipramine Blue, a derivative of anti-depressant imipramine, is a potent inhibitor of proliferation and DNA repair pathways in TNBC. Therefore, we tested the therapeutic efficacy of Imipramine on TNBCs using various in vitro assays for viability, migration, invasion as well as in vivo xenograft assays for tumor growth. Our results demonstrate that Imipramine inhibits cancer cell viability and progression in vitro. Similarly, in vivo xenograft assays showed reduced tumor growth in pre-clinical models upon imipramine treatment. Importantly, at the molecular level, Imipramine treatment suppressed key players in both cell proliferation, and DNA repair pathways, including FOXM1; a proto-oncogene that is a master regulator of both cell proliferation and DNA Repair pathways. These findings suggest that Imipramine may be a potential therapeutic option for TNBC patients. A clinical trial is ongoing to test the efficacy of Imipramine in Triple Negative Breast Cancer patients. Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia Kaklamani, Manjeet K Rao. Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-05.
How Un-POPular Is Bleeding in Patients with TAVI?
Authors: Frederick Feit
Journal: New England Journal of Medicine (2020)

For years, bleeding complications in patients undergoing transcatheter procedures, predominantly percutaneous coronary interventions (PCIs), were not included in the primary outcome of clinical trials. It was not until the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2) trial, which assessed two anticoagulant strategies for PCI, that bleeding became a component of the primary outcome and was found to be a predictor of death at 1 year that was as powerful as myocardial infarction.1 As the population ages, increasing numbers of patients have indications for oral anticoagulants, either a vitamin K antagonist or direct-acting oral anticoagulants. Not . . .