tbuckley/cabot-search huggingface dataset:
Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Christophe Le Tourneau, Yungan Tao, Carlos Gomez-Roca, Valerie Cristina, Edith Borcoman, Eric Deutsch, Rastislav Bahleda, Valentin Calugaru, Anouchka Modesto, Elisabeth Rouits, Kathrin Gollmer, Gregoire Vuagniaux, Philippa Crompton, Claudio Zanna, Sergio Szyldergemajn, Jean-Pierre Delord, Jean Bourhis
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported. Patients and Methods: Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment. Results: Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3–4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%. Conclusions: The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.
Cyanine conjugates in cancer theranostics
Authors: Yang Li, Yiming Zhou, Xiuli Yue, Zhifei Dai
Journal: Bioactive Materials (2020)

Cyanine is a meritorious fluorogenic core for the construction of fluorescent probes and its phototherapeutic potential has been enthusiastically explored as well. Alternatively, the covalent conjugation of cyanine with other potent therapeutic agents not only boosts its therapeutic efficacy but also broadens its therapeutic modality. Herein, we summarize miscellaneous cyanine-therapeutic agent conjugates in cancer theranostics from literature published between 2014 and 2020. The application scenarios of such theranostic cyanine conjugates covered common cancer therapeutic modalities, including chemotherapy, phototherapy and targeted therapy. Besides, cyanine conjugates that serve as nanocarriers for drug delivery are introduced as well. In an additional section, we analyze the potential of these conjugates for clinical translation. Overall, this review is aimed to stimulate research interest in exploring unattempted therapeutic agents and novel conjugation strategies and hopefully, accelerate clinical translation in this field.
Abstract A31: A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype
Authors: Martin Rosenberg, Jennifer R. Bethard, Linda Aronoff, George Lipkin
Journal: Cancer Research (2020)

Abstract Knowledge of the molecular basis for contact inhibition of growth, an in vitro property differentiating benign from malignant cells and correlated with in vivo growth control, could provide new targets for reestablishing control of malignant cell proliferation. We previously reported a soluble Contact Inhibitory Factor (CIF) in culture medium from a revertant contact inhibited melanoma cell line that restored contact-, serum-, and anchorage-dependent growth control to melanoma cells, closely linked to reversal of multiple malignant properties and whose contact inhibitory effects extended to a wide spectrum of other cancers. We now report identification, purification, and synthesis of the molecule, CIF, responsible for restoring contact inhibition: a structurally novel cyclic decapeptide dimer. Its discovery has both clinical and theoretical implications. Availability of CIF should not only facilitate evaluation of its therapeutic potential but also may provide the key to its target and the sequence of molecular events linking contact inhibition to broad phenotypic reversal. CIF may be the ligand for a widely distributed contact inhibitory checkpoint, one that is defective in cancer cells but pharmacologically correctible by CIF, and controlling replication at a single locus, potentially simplifying treatment. CIF is the first cell-derived peptide that restores contact inhibition of growth to melanoma and a wide spectrum of other cancers, with an obligatory link in melanoma to reversal of multiple aspects of the malignant phenotype. It suggests the possibility of an alternative approach to treatment of intractable melanoma and other cancers: broad-spectrum, endogenous peptide-based control of malignancy through phenotypic reversal that tilts the biologic balance to favor host recapture of control over tumor. Citation Format: Martin Rosenberg, Jennifer R. Bethard, Linda Aronoff, George Lipkin. A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A31.
Abstract IA07: Impact of tumor-resident dendritic cells on antitumor immune responses
Authors: Stefani Spranger
Journal: Cancer Research (2020)

Abstract The responsiveness of tumor towards checkpoint blockade therapy but also other immunotherapies is highly associated with the presence of CD8+ infiltrating T cells. Further, an increasing amount of recent studies revealed a critical role for cross-presenting CD103+ dendritic cells (DC1) in both the induction and maintenance of CD8+ T-cell immunity in the tumor. We have shown that exclusion of DC1 from the tumor microenvironment (TME) can result in both blunted T-cell priming and impaired recruitment of effector T cells into the TME. Thus, exclusion of DC1 represents a mechanism of immune evasion by the tumor and resistance towards immunotherapy. Therefore, elucidating the contributions of different DC subsets to the local tumor microenvironment will be instrumental for the improvement of current immunotherapies. In more recent data we compare models of strong and poor antitumor immune responses with a specific focus on tumor-resident dendritic cells. These experiments reveal the absence of several immune-potentiating dendritic cell subsets in tumors with impaired antitumor immunity. Citation Format: Stefani Spranger. Impact of tumor-resident dendritic cells on antitumor immune responses [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA07.
Ex-GP climate activist says her new role is as important as being a doctor
Authors: Jacqui Thornton
Journal: BMJ (2020)

A GP turned climate change activist who spent four weeks in prison on remand after being charged with conspiracy to cause criminal damage says that her new calling is no different from medicine, with the shared aim of saving lives.

Diana Warner, 61, who retired in 2019, was released on 22 September from Eastwood Park women’s prison in Falfield, Gloucestershire, after her arrest in August. She is now on bail before her trial next year.

She made the decision to devote her life to climate change, and specifically to change doctors’ conversation around the issue, when she was doing a six week check on a baby shortly after the Intergovernmental Panel on Climate Change published its report in October 2018.1 She …
Reducing the Global Burden of Alcohol‐Associated Liver Disease: A Blueprint for Action
Authors: Sumeet K. Asrani, Jessica Mellinger, Juan P. Arab, Vijay H. Shah
Journal: Hepatology (2020)

Alcohol‐associated liver disease (ALD) is a major driver of global liver related morbidity and mortality. There are 2.4 billion drinkers (950 million heavy drinkers) and the lifetime prevalence of any alcohol use disorder (AUD) is 5.1%‐8.6%. In 2017, global prevalence of alcohol‐associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively. Combined, alcohol‐associated cirrhosis and liver cancer account for 1% of all deaths worldwide with this burden expected to increase. Solutions for this growing epidemic must be multi‐faceted and focused on both population and patient‐level interventions. Reductions in ALD‐related morbidity and mortality require solutions that focus on early identification and intervention, reducing alcohol consumption at the population level (taxation, reduced availability and restricted promotion), and solutions tailored to local socioeconomic realities (unrecorded alcohol consumption, focused youth education). Simple screening tools and algorithms can be applied at the population level to identify alcohol misuse, diagnose ALD using non‐invasive serum and imaging markers, and risk‐stratify higher‐risk ALD/AUD patients. Novel methods of healthcare delivery and platforms are needed (telehealth, outreach, use of non‐healthcare providers, partnerships between primary and specialty care/tertiary hospitals) to proactively mitigate the global burden of ALD. An integrated approach that combines medical and AUD treatment is needed at the individual level to have the highest impact. Future needs include (1) improving quality of ALD data and standardizing care, (2) supporting innovative healthcare delivery platforms that can treat both ALD and AUD, (3) stronger and concerted advocacy by professional hepatology organizations, and (4) advancing implementation of digital interventions.
Embolic Stroke of Undetermined Source
Authors: Anthony S. Larson, Deena M. Nasr, Asim Rizvi, Muayad Alzuabi, Seyed Mohammad Seyedsaadat, Giuseppe Lanzino, John Huston, Vance T. Lehman, Luis E. Savastano, Waleed Brinjikji
Journal: JACC. Cardiovascular imaging (2020)
Abstract IA08: Elevated endogenous SDHA drives pathologic metabolism in highly metastatic uveal melanoma
Authors: Chandrani Chattopadhyay, Junna Oba, Jason Roszik, Scott E. Woodman, Elizabeth A. Grimm
Journal: Cancer Research (2020)

Abstract Purpose: Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. Experimental Design: We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9,858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. Results: We identified UM as having among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the TCA cycle with OxPhos by oxidizing (lowering) succinate. We show that SDHA-high M3 UM has elevated expression of key OxPhos molecules, exhibits abundant mitochondrial reserve respiratory capacity, and is resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. Conclusions: Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediates resistance to therapy that is reversible with targeted treatment. Citation Format: Chandrani Chattopadhyay, Junna Oba, Jason Roszik, Scott E. Woodman, Elizabeth A. Grimm. Elevated endogenous SDHA drives pathologic metabolism in highly metastatic uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA08.
Understanding the impact of antibiotic perturbation on the human microbiome
Authors: Drew J. Schwartz, Amy E. Langdon, Gautam Dantas
Journal: Genome Medicine (2020)

Abstract The human gut microbiome is a dynamic collection of bacteria, archaea, fungi, and viruses that performs essential functions for immune development, pathogen colonization resistance, and food metabolism. Perturbation of the gut microbiome’s ecological balance, commonly by antibiotics, can cause and exacerbate diseases. To predict and successfully rescue such perturbations, first, we must understand the underlying taxonomic and functional dynamics of the microbiome as it changes throughout infancy, childhood, and adulthood. We offer an overview of the healthy gut bacterial architecture over these life stages and comment on vulnerability to short and long courses of antibiotics. Second, the resilience of the microbiome after antibiotic perturbation depends on key characteristics, such as the nature, timing, duration, and spectrum of a course of antibiotics, as well as microbiome modulatory factors such as age, travel, underlying illness, antibiotic resistance pattern, and diet. In this review, we discuss acute and chronic antibiotic perturbations to the microbiome and resistome in the context of microbiome stability and dynamics. We specifically discuss key taxonomic and resistance gene changes that accompany antibiotic treatment of neonates, children, and adults. Restoration of a healthy gut microbial ecosystem after routine antibiotics will require rationally managed exposure to specific antibiotics and microbes. To that end, we review the use of fecal microbiota transplantation and probiotics to direct recolonization of the gut ecosystem. We conclude with our perspectives on how best to assess, predict, and aid recovery of the microbiome after antibiotic perturbation.
SAT0152 Effects of raloxifene on bone mineral density and on serum lipids in postmenopausal women with severe osteopenia and/or osteoporosis
Authors: A Matsoyka, E Kantaxaki, S Zerboudis, A Georgiadis
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Raloxifene (RLX) is a selective oestrogen receptor modulator (SERM) and exerts a positive estrogenic activity on bone and on serum lipids. The purpose of this randomised study was to access the effect of RLX on Bone Mineral Density (BMD) and on serum lipids in postmenopausal (PM) women with severe osteopenia and/or osteoporosis according to WHO criteria. <h3>Objectives</h3> 100 PM women were randomly assigned to either RLX 60 mg/day+600 mg Calcium Carbonate (CC) (70 women) or 600 mg of CC alone (30 women), as controls, for 12 months. The two groups of women had similar anthropometric data, mean age (56,98 ± 5,1 yrs) and mean postmenopausal age (9,4 ± 5,2 yrs). <h3>Methods</h3> BMD was measured at baseline and at 12 months of therapy, using DEXA (Hologic 1000 QDR) at Lumbar Spine (LS) and Lft Femur (FN)(neck). Serum total Cholesterol, LDL, HDL, triglycerides were measured at baseline, 6 and 12 months (photometric method). Results are expressed as percentage change from baseline. Statistics were done using t-test (unpaired). <h3>Results</h3> Bone loss prevented only in the group of RLX. The BMD increased at LS = +2,3(± 2,8)% and at FN = 1,4 (± 2,6)%. In the group of controls the BMD diminished at LS -1,2(± 1,1)% and at FN -1,5(± 2,4)%. The difference in BMD changes between the two groups was significant (p &lt; 0,05). There was no change in HDL, LDL and triglycerides in either group. Only Total Cholesterol decreased significantly (p &lt; 0,05) in RLX group. No clinically relevant effects on safety parameters (liver enzymes, hematologic variables and vital signs) were recorded. <h3>Conclusion</h3> We conclude that RLX proved to be effective and safe in the prophylaxis and treatment of postmenopausal severe osteopenia and/or osteoporosis.
Protein Arginine Methyltransferase 5 Promotes pICln-Dependent Androgen Receptor Transcription in Castration-Resistant Prostate Cancer
Authors: Elena Beketova, Shuyi Fang, Jake L. Owens, Sheng Liu, Xufeng Chen, Qingfu Zhang, Andrew M. Asberry, Xuehong Deng, Jonathan Malola, Jiaoti Huang, Chenglong Li, Roberto Pili, Bennett D. Elzey, Timothy L. Ratliff, Jun Wan, Chang-Deng Hu
Journal: Cancer Research (2020)

The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation. SIGNIFICANCE: This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.
A microfluidic cell-migration assay for the prediction of progression-free survival and recurrence time of patients with glioblastoma
Authors: Bin Sheng Wong, Sagar R. Shah, Christopher L. Yankaskas, Vivek K. Bajpai, Pei-Hsun Wu, Deborah Chin, Brent Ifemembi, Karim ReFaey, Paula Schiapparelli, Xiaobin Zheng, Stuart S. Martin, Chen-Ming Fan, Alfredo Quiñones-Hinojosa, Konstantinos Konstantopoulos
Journal: Nature Biomedical Engineering (2020)
Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma
Authors: Byoung-San Moon, Mingyang Cai, Grace Lee, Tong Zhao, Xiaofeng Song, Steven L. Giannotta, Frank J. Attenello, Min Yu, Wange Lu
Journal: Journal of Clinical Investigation (2020)

Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O6-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl–histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence.
It is never too late to start: adherence to physical activity recommendations for 11–22 years and risk of all-cause and cardiovascular disease mortality. The HUNT Study
Authors: Trine Moholdt, Eivind Schjelderup Skarpsno, Børge Moe, Tom Ivar Lund Nilsen
Journal: British Journal of Sports Medicine (2020)

Objectives To examine associations between long-term (11–22 years) adherence to physical activity recommendations and mortality from all causes and from cardiovascular disease. Design Prospective population-based study with repeated assessments of self-reported physical activity (1984–86, 1995–97 and 2006–08) and follow-up until the end of 2013. Setting County of Nord-Trøndelag, Norway. Participants Men and women aged ≥20 years; 32 811 who participated in 1984–86 and 1995–97; 22 058 in 1984–86 and 2006–08; 31 948 in 1995–97 and 2006–09 and 19 349 in all three examinations (1984–1986, 1995–95 and 2006–08). Main outcome measures All-cause mortality and cardiovascular disease mortality from the national Cause of Death Registry. Results Compared with the reference category comprising individuals who adhered to the physical activity recommendations (≥150 min of moderate intensity or ≥60 min of vigorous intensity physical activity per week) over time, individuals who remained inactive (reporting no or very little physical activity) from 1984–86 to 1995–97 had HRs (95% CI) of 1.56 (1.40 to 1.73) for all-cause mortality and 1.94 (1.62 to 2.32) for cardiovascular disease mortality. Individuals who were inactive in 1984–86 and then adhered to recommendations in 2006–08 had HRs of 1.07 (0.85 to 1.35) for all-cause mortality and 1.31 (0.87 to 1.98) for cardiovascular disease mortality. In a subsample of individuals who participated at all three time points, those who were inactive or physically active below the recommended level across three decades (1984–86, 1995–97 and 2006–2008) had an HR of 1.57 (1.22 to 2.03) for all-cause mortality and 1.72 (1.08 to 2.73) for cardiovascular disease mortality. Conclusion Individuals who remained, or became, physically inactive had substantially greater risk of all-cause and cardiovascular disease mortality compared with those who met the physical activity recommendations throughout the lifespan.