tbuckley/cabot-search huggingface dataset:
Efficacy and limitations of senolysis in atherosclerosis
Authors: Abel Martin Garrido, Anuradha Kaistha, Anna K Uryga, Sebnem Oc, Kirsty Foote, Aarti Shah, Alison Finigan, Nichola Figg, Lina Dobnikar, Helle Jørgensen, Martin Bennett
Journal: Cardiovascular Research (2021)

Abstract Aims Traditional markers of cell senescence including p16, Lamin B1, and senescence-associated beta galactosidase (SAβG) suggest very high frequencies of senescent cells in atherosclerosis, while their removal via ‘senolysis’ has been reported to reduce atherogenesis. However, selective killing of a variety of different cell types can exacerbate atherosclerosis. We therefore examined the specificity of senescence markers in vascular smooth muscle cells (VSMCs) and the effects of genetic or pharmacological senolysis in atherosclerosis. Methods and results We examined traditional senescence markers in human and mouse VSMCs in vitro, and in mouse atherosclerosis. p16 and SAβG increased and Lamin B1 decreased in replicative senescence and stress-induced premature senescence (SIPS) of cultured human VSMCs. In contrast, mouse VSMCs undergoing SIPS showed only modest p16 up-regulation, and proliferating mouse monocyte/macrophages also expressed p16 and SAβG. Single cell RNA-sequencing (scRNA-seq) of lineage-traced mice showed increased p16 expression in VSMC-derived cells in plaques vs. normal arteries, but p16 localized to Stem cell antigen-1 (Sca1)+ or macrophage-like populations. Activation of a p16-driven suicide gene to remove p16+ vessel wall- and/or bone marrow-derived cells increased apoptotic cells, but also induced inflammation and did not change plaque size or composition. In contrast, the senolytic ABT-263 selectively reduced senescent VSMCs in culture, and markedly reduced atherogenesis. However, ABT-263 did not reduce senescence markers in vivo, and significantly reduced monocyte and platelet counts and interleukin 6 as a marker of systemic inflammation. Conclusions We show that genetic and pharmacological senolysis have variable effects on atherosclerosis, and may promote inflammation and non-specific effects respectively. In addition, traditional markers of cell senescence such as p16 have significant limitations to identify and remove senescent cells in atherosclerosis, suggesting that senescence studies in atherosclerosis and new senolytic drugs require more specific and lineage-restricted markers before ascribing their effects entirely to senolysis.
Cancer beliefs and screening across three NYC neighborhoods.
Authors: Tracy M. Layne, Parul Agarwal, Lina Jandorf, Bruce Rapkin, Nina A. Bickell
Journal: Journal of Clinical Oncology (2021)

e22512 Background: Differences in breast cancer screening exist between the NYC neighborhoods of East Harlem (EH) and Central Harlem (CH), and the Upper East Side (UES). Here we assess the relationship between six cancer beliefs and breast cancer screening among women in these neighborhoods. Methods: We include women aged ≥40 who responded to the Community Cancer Needs Survey between 2018-2019 and were eligible to undergo screening mammography within 2 years (“recommended screening”). All estimates use weighted data generated using raking techniques. We compared categorical variables using Chi-square tests &amp; estimated odds ratios (OR) and 95% confidence intervals (CI) from logistic regression model associating beliefs and reported mammography receipt (results and covariates listed in Table). For each belief, we compared women who reported “agree” (combined strongly or somewhat agree) to those who “disagree” (combined strongly or somewhat disagree). Results: Of the weighted sample of 76,610 (41.3% CH, 34.4% EH, and 24.3% UES) women eligible to undergo screening mammography, 75.1%, 81.2%, and 90.3% of women in CH, EH, and UES, respectively reported recommended screening. There was no difference by neighborhood in prolonged (&gt;2 years ago) screening intervals: 10.6% in CH, 7.9% in EH, and 9.8% in the UES, while never use was reported by 11.3% in CH, 7.6% in EH, and none in the UES (p=&lt;0.0001). The table summarizes agreement between cancer beliefs and timely receipt of mammography. Conclusions: In this study, cancer beliefs are inconsistently associated with use of breast cancer screening across three NYC neighborhoods. Assessment of beliefs reveal important opportunities for breast cancer (and other cancer) prevention by promoting awareness of risk factors and screening in these communities.[Table: see text]
Melphalan Dose in Myeloma Patients over 65 Years of Age Undergoing High-Dose Therapy and Autologous Stem Cell Transplantation
Authors: Guido Ghilardi, Thomas Pabst, Barbara Jeker, Rouven Müller, Anne Cairoli, Antonia Mueller, Mario Bargetzi, Felicitas Hitz, Helen Baldomero, Dominik Heim, Davide Rossi, Michele Ghielmini, Erika Lerch, Urs Schanz, Jakob R. Passweg, Georg Stussi, Martina Kleber, Bernhard Gerber
Journal: Blood (2017)
Recognition, Prevention, and Management of Arrhythmias and Autonomic Disorders in Cardio-Oncology: A Scientific Statement From the American Heart Association
Authors: Michael G. Fradley, Theresa M. Beckie, Sherry Ann Brown, Richard K. Cheng, Susan F. Dent, Anju Nohria, Kristen K. Patton, Jagmeet P. Singh, Brian Olshansky
Journal: Circulation (2021)

With the advent of novel cancer therapeutics and improved screening, more patients are surviving a cancer diagnosis or living longer with advanced disease. Many of these treatments have associated cardiovascular toxicities that can manifest in both an acute and a delayed fashion. Arrhythmias are an increasingly identified complication with unique management challenges in the cancer population. The purpose of this scientific statement is to summarize the current state of knowledge regarding arrhythmia identification and treatment in patients with cancer. Atrial tachyarrhythmias, particularly atrial fibrillation, are most common, but ventricular arrhythmias, including those related to treatment-induced QT prolongation, and bradyarrhythmias can also occur. Despite increased recognition, dedicated prospective studies evaluating true incidence are lacking. Moreover, few studies have addressed appropriate prevention and treatment strategies. As such, this scientific statement serves to mobilize the cardio-oncology, electrophysiology, and oncology communities to develop clinical and scientific collaborations that will improve the care of patients with cancer who have arrhythmias.
CD38-specific Chimeric Antigen Receptor Expressing Natural Killer KHYG-1 Cells: A Proof of Concept for an “Off the Shelf” Therapy for Multiple Myeloma
Authors: Arwen Stikvoort, Jort van der Schans, Subhashis Sarkar, Renée Poels, Ruud Ruiter, Jyoti Naik, Huipin Yuan, Joost D. de Bruijn, Niels W. C. J. van de Donk, Sonja Zweegman, Maria Themeli, Richard Groen, Michael O’Dwyer, Tuna Mutis
Journal: HemaSphere (2021)

Chimeric antigen receptor (CAR) T cells are highly successful in the treatment of hematologic malignancies. We recently generated affinity-optimized CD38CAR T cells, which effectively eliminate multiple myeloma (MM) cells with little or no toxicities against nonmalignant hematopoietic cells. The lack of universal donors and long manufacturing times however limit the broad application of CAR T cell therapies. Natural killer (NK) cells generated from third party individuals may represent a viable source of “off the shelf” CAR-based products, as they are not associated with graft-versus-host disease unlike allogeneic T cells. We therefore explored the preclinical anti-MM efficacy and potential toxicity of the CD38CAR NK concept by expressing affinity-optimized CD38CARs in KHYG-1 cells, an immortal NK cell line with excellent expansion properties. KHYG-1 cells retrovirally transduced with the affinity-optimized CD38CARs expanded vigorously and mediated effective CD38-dependent cytotoxicity towards CD38 high MM cell lines as well as primary MM cells ex vivo. Importantly, the intermediate affinity CD38CAR transduced KHYG-1 cells spared CD38 neg or CD38 int nonmalignant hematopoietic cells, indicating an optimal tumor nontumor discrimination. Irradiated, short living CD38CAR KHYG-1 cells also showed significant anti-MM effects in a xenograft model with a humanized bone marrow-like niche. Finally, CD38CAR KHYG-1 cells effectively eliminated primary MM cells derived from patients who are refractory to CD38 antibody daratumumab. Taken together, the results of this proof-of-principle study demonstrate the potential value of engineering affinity-optimized CD38CARs in NK cells to establish effective anti-MM effects, with an excellent safety profile, even in patients who failed to response to most advanced registered myeloma therapies, such as daratumumab.
Tumor-associated immune cells and progression-free survival in advanced endometrial cancer (EC), results from the PHAEDRA trial (ANZGOG 1601).
Authors: Deborah Smith, Kristy Robledo, Sonia Yip, Michelle Cummins, Peey-Sei Kok, Yeh Chen Lee, Michael Friedlander, Sally E. Baron-Hay, Catherine M. Shannon, Jermaine Coward, Philip James Beale, Geraldine Goss, Tarek Meniawy, Janine Margaret Lombard, Amanda B. Spurdle, John Andrews, Martin R. Stockler, Linda R. Mileshkin, Yoland Catherine Antill
Journal: Journal of Clinical Oncology (2021)

5584 Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H&amp;E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the individual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p &lt; 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.
Genetic alterations in MSS and TMB-H Chinese colorectal cancer patients.
Authors: Shuangyi Ren, Taiyan Guo, Xia You, Qianru He, Qin Zhang, Chuang Qi
Journal: Journal of Clinical Oncology (2021)

e15524 Background: Efforts by previous study had provided molecular profile of MSS &amp; TMB-H gastrointestinal (GI) cancers, however, Asian patients were underrepresented in this study. We aim to investigate specific molecular features of Chinese MSS &amp; TMB-H colorectal cancer patients. Methods: FFPE tumor samples from 249 Chinese colorectal cancer patients with MSS &amp; TMB-H (Chinese cohort) were sequencing using a panel targeting 539 cancer-related genes of the human genome. Genomic data from our cohort was compared with publicly available data from 508 MSS &amp; TMB-H colorectal cancer patients from the TCGA dataset (TCGA cohort). TMB was calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 48 (19%) MSS &amp; TMB-H patients were found in Chinese cohort, and 55 (10%) were found in TCGA cohort. Based on the analysis of the genetic alteration profile from our cohort, in MSS &amp; TMB-H colorectal cancer patients, APC (85%), TP53 (81%), KRAS (44%), and LRP1B (378%) as the most commonly altered genes. In TCGA cohort, TTN (84%), APC (80%), TP53 (64%), SYNE1 (51%), and MUC16 (51%) as the most commonly altered genes. On the other hand, the most difference genes between MSS &amp; TMB-H group and MSS/TMB-L group in TCGA cohort were TNN (84% vs. 52%; p = 0.000008), SYNE1 (56% vs. 24%; p = 0.000003), MUC16 (51% vs. 23%; p = 0.00006), FAT4 (47% vs. 16%; p = 0.000002), RYR2 (44%vs. 16%; p = 0.00001). Compared with TCGA cohort, LRP1B (38% vs. 13%; p = 0.0005), TCF7L2 (33% vs. 8%; p = 0.00003), SPTA1 (29% vs. 6%; p = 0.00005), PREX2 (19% vs. 3%; p = 0.0006) were the most difference genes between MSS &amp; TMB-H group and MSS/TMB-L group in Chinese cohort. Conclusions: Our study contributes to the understanding of specific genetic alterations harbored by MSS &amp; TMB-H colorectal cancer patients that could potentially be developed as markers of precision medicine.
The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia.
Authors: Xingchen Ding, Jinming Yu, Man Hu
Journal: Journal of Clinical Oncology (2021)

e14043 Background: Hypoxia inducible factor-1α (HIF-1α) up-regulates the expression of programmed death ligand-1 (PD-L1) in some extracranial malignancies. However, whether it also increases PD-L1 expression in intracranial tumor is still unknown. Here we explored the relationship between HIF-1α and PD-L1 expression in glioma, and investigated their clinical significance. Methods: Tumor tissues from 120 patients with glioma, were analyzed for PD-L1 and HIF-1α expression using immunohistochemistry. And results were verified in vitro, using U251, U343 glioma cell lines. Gene expression were evaluated by quantitative PCR; protein levels were analyzed by Western blot; ChIP-qPCR (chromatin immunoprecipitation coupled with quantitative PCR) analysis showed the relationship between HIF-1α and PD-L1. Glioma in situ model were used to explore whether HIF-1α inhibitor (PX-478) can enhance anti-PD-L1 therapy responses. Tumor volume was measured twice weekly. Immune data were further analyzed by FACS DIVA 7.0 or Flow Jo 7.6.5 software. Results: In glioma patients, HIF-1α and PD-L1 were markedly overexpressed in high grade glioma (HGG) tissues and were both associated with poorer overall survival(OS) (PD-L1( &lt; 5% vs. ≥ 5%): 3, 5, 10-year OS: 78.1%, 50.5%, 27.2% vs. 45.4%, 11.8%, 0%, P = 0.0026; HIF-1α( &lt; 1% vs. ≥ 1%): 3, 5, 10-year OS:74.2%, 66.8%, 53.4% vs. 61.6%, 21.0%, 0%, P = 0.001). And the expression of PD-L1 was significantly positively correlated with the expression of HIF-1α in glioma patients ( r = 0.412, P &lt; 0.001). In glioma cell lines, PD-L1 expression was significantly induced under hypoxia condition, but the enhanced PD-L1 expression was abrogated by either HIF-1α knock-down or HIF-1α inhibitor treatment. Furthermore, ChIP-qPCR analysis showed the direct binding of HIF-1α to PD-L1 proximal promoter, providing evidence that HIF-1α up-regulate PD-L1 expression in glioma cells. In glioma murine model, combination treatment with HIF-1α inhibitor and anti-PD-L1 antibody caused a more pronounced suppressive effect on tumor growth compared to mice treated with either single agent. Immunologically, the combination treatment improved both dendritic cell (DC) and CD8 + T cell activation. Conclusions: Multiple findings demonstrated that positive relationship between HIF-1α and PD-L1 existed in glioma cells under hypoxia condition. These observations also provide invaluable information that hypoxia contributes to a key phase of glioma cells evading adaptive immunity, thereby promoting malignant progression and poorer clinical outcomes. Given these, it would be a potential strategy to target HIF-1α in combination with the blockage of PD-1/PD-L1 pathway for anti-cancer in the future.
Oral cancer proteomics for biomarker discovery
Authors: Shen Hu, Martha Arellano-Garcia, Pinmanee Boontheung, Joseph Loo, David Wong
Journal: Cancer Research (2007)

2463  The overall 5-year survival rates for oral squamous cell carcinoma (OSCC) have remained low at approximately 30-40% for the past decades. Delayed detection is one of the main reasons for the high morbidity rate of oral cancer, suggesting an imperative need for developing biomarkers to improve early detection of oral cancers. Proteomic analysis of body fluids (e.g., saliva and serum) over the course of oral cancer progression holds promise to identify early detection biomarkers for human oral cancer. In this study, we have conducted patient-based oral cancer proteomic studies towards the discovery of candidate saliva and serum biomarkers for OSCC detection. In the saliva study, we utilized a subtractive proteomic approach based on C4 HPLC prefractionation and LC-QqTOF MS to identify differentially expressed proteins in the whole saliva samples of 16 OSCCs or 16 matched control subjects. Many of the identified putative biomarkers for OSCC were regulatory proteins or glycoproteins, including Myc binding protein 2, angiomotin like 2, Ras-related protein Rab-7, Mac-2-binding protein (M2BP), Rho GDP-dissociation inhibitor 2, CD59 glycoprotein precursor, KRAB box family protein, hematopoietic lineage cell specific protein, peroxisome biogenesis factor 1, nuclear mitotic apparatus protein 1, swiprosin-2, PHD finger protein 3, histone H1.2 & H1.3 and calgranulin A. We further validated M2BP (n=32 for each group, p=0.000006) and calgranulin A (n=20 for each group, p=0.045) on a new patient cohort using ELISA. In the serum study, we mapped out serum proteins, individually, from 10 oral cancer and 10 control subjects using 2-D gel electrophoresis. The proteins at significantly differential levels were identified using in-gel tryptic digestion followed by LC-QqTOF MS analysis of the resulting peptides. The discovered candidate biomarkers included calgranulin A, serum amyloid A-4 protein and isoforms, haptoglobin-related protein, focolin 2, alpha-1-antitrypsin, complement C3 (fragment), splice isoform 1 of complement factor H-related protein 2 (up-regulated) and transthyretin, tetranectin, telomerase regulation-associated protein, alpha-1-acid glycoprotein 1 and 2, Apolipoprotein E, RalA binding protein 1 (down-regulated). Further validation of tetranectin by immunoblotting (n=25 for each group, p=0.00038) and calgranulin A by ELISA (n=20 for each group, p=0.039) was also demonstrated. Our study demonstrates that patient-based serum/saliva proteome analysis is a very promising approach to discovery of biomarkers for oral cancer detection. These promising candidate biomarkers, as a combination, may be used to improve the clinical detection of OSCC.  Supported by PHS Grants UO1- DE016275.
The predictive values of loss-of-function variants in histone methyltransferases for response to immune checkpoint inhibitors in solid tumors.
Authors: Naixin Liang, Yanling Niu, Xin Zhang, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

2586 Background: Dysregulation of histone methyltransferases (HMTs) has been reported to play critical roles in cancer development. Previous studies showed that many HMTs were recruited to DNA damage sites where they posttranslationally modified chromatin to regulate chromatin-based DNA damage repair (DDR) activities. We hypothesized that loss-of-function (LOF) variants of HMTs may associate with genome instability and tumor mutational burden (TMB). Thus, we explored the associations of LOF variants in some HMTs with TMB and benefit from immune checkpoint inhibitors (ICIs) in solid tumors. Methods: An ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was analyzed. The following solid tumor types were enrolled: NSCLC (n = 350), colorectal cancer (n = 110), bladder cancer (n = 215), breast cancer (n = 44), esophagogastric cancer (n = 126), head and neck cancer (n = 139), glioma (n = 117), melanoma (n = 320), and renal cell carcinoma (n = 151). We evaluated 15 HMTs (KMT2A, KMT2B, KMT2C, KMT2D, SETD2, SETD8, EZH1, EZH2, PRDM1, PRDM14, SMYD3, NSD1, WHSC1, WHSC1L1, and DOT1L). Results: The data revealed that LOF variants of KMT2D, SETD2, and KMT2C were more frequent in pan-cancer dataset. Furthermore, we found that LOF variants of 7 HMTs, including KMT2A, KMT2B, KMT2C, KMT2D, NSD1, SETD2, and EZH2, were associated with higher TMB (P &lt; 0.0001). Then we analyzed the associations between LOF variants and overall survival (OS) after ICIs therapy. The results indicated that LOF variants of KMT2A (P = 0.0295), KMT2B (P = 0.0329), KMT2C (P = 0.0122), and SETD2 (P = 0.0004) were significantly associated with prolonged median OS for all the enrolled patients. In this cohort, LOF variants of KMT2A, KMT2B, KMT2C, and SETD2 were most common in bladder cancer, colorectal cancer, colorectal cancer, and renal cell carcinoma, respectively. Then we assessed the predictive values of these four genes for each type of cancer. It was noteworthy that KMT2C LOF variants were significantly correlated with longer median OS in colorectal cancer (P = 0.0171), but not in other cancer types. Surprisingly, we did not observe the predictive roles of LOF variants in KMT2A, KMT2B, and SETD2 genes for response to ICIs therapy in any types of cancer. Conclusions: In pan-cancer dataset, we found that LOF variants of 4 HMTs, such as KMT2A, KMT2B, KMT2C, and SETD2, were correlated with better outcomes of ICIs treatment. However, for different types of cancer, only KMT2C LOF variants were associated with longer median OS in colorectal cancer, suggesting that it may be used as a predictive biomarker for ICIs efficacy in colorectal cancer. Because the sample sizes of patients with KMT2A, KMT2B, or SETD2 LOF variants were small, we did not find the predictive values of LOF variants in these three genes for different types of cancer. Next, we will enroll more patients to address this question.