tbuckley/cabot-search huggingface dataset:
PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting v integrin/FAK/Src signaling in oral squamous cell carcinoma cells
Authors: Gulnara Tuguzbaeva, Er Yue, Xi Chen, Lina He, Xinlei Li, Jiaming Ju, Ying Qin, Valentin Pavlov, Yanjie Lu, Wenting Jia, Yunlong Bai, Yumei Niu, Baofeng Yang
Journal: Acta Pharmaceutica Sinica B (2019)

Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies. In oral squamous cell carcinoma (OSCC), αv integrin is a crucial mediator of multicellular clustering and collective movement in vitro; however, its contribution to metastatic spread remains to be addressed. According to the emerging therapeutic concept, dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas. This study aimed to investigate the anti-OSCC potential of novel endostatin-derived polypeptide PEP06 as a cluster-dissociating therapeutic agent in vitro. Firstly, we found marked enrichment of αv integrin in collectively invading multicellular clusters in human OSCCs. Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of αv integrin in cancerous lesions. Following PEP06 treatment, cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC were significantly inhibited. Moreover, PEP06 suppressed αv integrin/FAK/Src signaling in OSCC cells. PEP06-induced loss of active Src and E-cadherin from cell-cell contacts contributed to diminished collective migration of OSCC in vitro. Overall, these results suggest that PEP06 polypeptide 30 inhibiting αv integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent.
Mesenchymal Stem Cells Gene Signature in High-Risk Myeloma Bone Marrow Linked to Suppression of Distinct IGFBP2-Expressing Small Adipocytes
Authors: Syed J. Mehdi, Sarah K Johnson, Joshua Epstein, Maurizio Zangari, Pingping Qu, Antje Hoering, Frits van Rhee, Carolina D. Schinke, Sharmilan Thanendrarajan, Faith E. Davies, Gareth Morgan, Shmuel Yaccoby
Journal: Blood (2018)
Abstract 939: Mdm2 Induces Vascular Calcification Through Its E3 Ligase Activity
Authors: Hyun Kook, Duk-Hwa Kwon, Nakwon Choe, Sera Shin, Hosouk Joung, Juhee Ryu, Young-Kuk Kim
Journal: Circulation Research (2019)

Rationale: Calcium deposition to the vascular smooth muscle matrix, or vascular calcification (VC), makes vessels rigid, increasing morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we suggested that histone deacetylase (HDAC) 1 prevents VC, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), exaggerates VC by inducing the polyubiquitination of HDAC1. Objective: In the present study, we extend our results to investigate whether MDM2-induced VC is dependent on its ubiquitination activity. Methods and Results: Using cellular and animal models with genetically engineered mice, we observed that vascular smooth muscle cell-specific conditional knockout of Mdm2 blunted vitamin D3-induced VC. We generated both MDM2 Y489A, which lacks ubiquitination activity, and MDM2 ΔR, a RING domain-deleted truncated mutant. Compared with the activity of wild-type (WT) MDM2, the HDAC1-ubiquitination activities of both Y489A and ΔR were significantly reduced. WT MDM2 potentiated inorganic phosphate-induced VC by inducing runt-related transcription factor 2 (Runx2), whereas Y489A and ΔR failed to do so. We generated three different transgenic lines to overexpress WT, Y489A, and ΔR MDM2. TgMDM2 WT elicited calcium deposition, whereas TgMDM2 Y489A and TgMDM2 ΔR did not. Conclusions: Taken together, our results suggest that MDM2-induced VC is dependent on the ubiquitination activity of MDM2 to degrade HDAC1. Accordingly, blockade of MDM2 ubiquitination activity might have beneficial effects in the treatment of VC.
Pathophysiology of Obstructive Sleep Apnea (OSA) - Blood Cells’ Reactive Oxygen Species and Inflammation Prevent Polycythemia
Authors: Jihyun Song, Krishna M Sundar, Christensen Robert, Monika Horvathova, Barbora Kralova, Vladimir Divoky, Tomas Ganz, Josef T. Prchal
Journal: Blood (2018)
Cancer screening: more convenient access will boost early diagnosis, says review
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The NHS should provide more convenient access to cancer screening services to increase early diagnosis and improve survival rates, a major government commissioned review has recommended.1

Women should be able to access screening for breast, cervical, and other cancers at health centres or other locations close to their work, and local screening services should provide extra evening and weekend appointments, says the review by Mike Richards, a leading cancer expert.

The report was commissioned2 by Simon Stevens, NHS chief executive, and Matt Hancock, England’s health and social care secretary, to recommend how to overhaul national screening programmes. This is to help achieve the goal, set out in the NHS long …
Abstract 930: Aerobic Dose Intensity and the Human Exercise Plasma Proteome
Authors: James S Guseh, Timothy W Churchill, Ashish Yeri, Claire Lo, Marcel Brown, Anthony Rosenzweig, Aaron Baggish
Journal: Circulation Research (2019)

Aerobic exercise confers myriad benefits to human health but the mechanism by which it does so remain incompletely understood. We hypothesize that exercise works in part through circulating protein signaling. Healthy adult men (n, 12) participated in treadmill running sessions at both low (6 mph) and high intensity (maximal effort). We used pre- and post-exercise plasma and a high-throughput aptamer-based assay (SomaScan) to examine the acute impact of exercise on the plasma proteome. Acute aerobic exercise consistently alters the resting plasma proteome in an intensity-dependent fashion. Of 1,305 proteins assayed 184 (14%) and 598 (46%) change at low and high intensity respectively (FDR p &lt; 0.05). 159 protein species (12%) are common to both intensities. Gene ontology analysis revealed enrichment of pathways associated with leukocyte chemotaxis and chylomicron metabolism at low intensity and Wnt signaling, neuronal axonogenesis, and nitric oxide metabolism pathways at high intensity. We used human sequencing data from the GTEX Consortium (Broad, Cambridge MA) to computationally infer the sources of increasing proteins and found major contributions from the cardiovascular, gastrointestinal, and nervous systems. We identified 43 cis-SNPs that approximate the upregulated proteomic response to acute exercise and used Mendelian randomization to infer a causal relationship between the exercise proteome and decreased muscle wasting in a UK Biobank cohort. Although guidelines present low and high intensity exercise as equivalent alternatives for health, these data suggest that distinct exercise intensities might offer common and distinct exercise benefits.
Enhancing community capacity to deliver value-based cancer care at the end-of-life.
Authors: Manali I. Patel, David Ramirez, Richy Agajanian, Hilda H. Agajanian, Tumaini Coker
Journal: Journal of Clinical Oncology (2019)

4 Background: To improve value-based cancer care, we designed an intervention using lay health workers (LHWs) who we trained to assess patient's symptoms. LHWs referred patients to palliative care and/or behavioral health in response to positive assessments. We implemented the intervention in collaboration with a community oncology group and a Medicare Advantage payer for patients with all stages of cancer. At ASCO 2019 we demonstrated the associated reductions in patient-reported symptoms, acute care use, and total costs of care. This study evaluates the effect of the intervention on end-of-life cancer care, specifically healthcare use in the last month of life and total costs of care from diagnosis until death. Methods: We enrolled all newly diagnosed health plan beneficiaries with solid and hematologic malignancies from 11/2016 through 9/2018 and compared outcomes to all patients diagnosed with cancer in the year prior to the intervention (control arm). For all patients who died within 12-months follow-up, we compared risk of death using Cox Models and generalized linear regression to compare healthcare use in the last month of life, and total costs of care from diagnosis until death. All models were adjusted for age, stage, comorbidities, diagnosis, and length of follow-up. Results: 180 patients in the intervention and 156 in the control died during the study. In both groups, the mean age was 80 years; 49% were non-Hispanic White, 40% Hispanic, 5% Asian/Pacific Islander, and 4% black. There were no differences in survival (HR 0.96, p = 0.6). Intervention patients as compared to the control had lower mean inpatient admissions (0.3 +/- 0.04 versus 0.5 +/- 0.07, p = 0.02) and emergency department visits per thousand members per year (0.11 +/- 0.02 versus 0.49 +/- 0.06, p &lt; 0.001) in the last month of life, greater proportion of patients with hospice use (69% versus 48%, p &lt; 0.001), lower proportion of patients with acute care facility deaths (37.5% versus 62.5%, p = 0.02) and lower median total healthcare costs from diagnosis until death ($24,902 versus $33,145, p = 0.02). Conclusions: An LHW intervention significantly improved the value of end-of-life cancer care and may be a solution to improve burdensome and costly care for patients.
Expression of CRBN Signaling Pathway Proteins Assessed By Immunohistochemical Staining As Candidate Biomarkers for Outcome in Myeloma Patients Treated with IMiDs
Authors: Lijuan Chen, Qinglin Shi, Rong Wang, Xiupan Lu, Yan Gu, Xuxing Shen, Xiaoyan Qu, Jianyong Li
Journal: Blood (2018)
Cost Analysis of Hematopoietic Autologous Transplantation with and without DMSO Cryopreservation
Authors: Mauricio Sarmiento, Nicole Beffermann, Ximena Solar, Jara Veronica, Soto Katherine, Silvana Arellano, Pablo Bertin, Isabel Pizarro, Carla Lorca, Elizabeth Rivera, Mauricio Galleguillos, Isabel Rodriguez, Mauricio Ocqueteau
Journal: Blood (2018)
Imatinib Mesylate Is Safe and Effective in Maintaining Cytogenetic and Molecular Response Achieved with 1 Year Nilotinib First Line in Newly Diagnosed Chronic Myeloid Leukemia: Preliminary Results of a Prospective Clinical Trial
Authors: Nour Moukalled, Radwan Massoud, Rami Mahfouz, Jean Elcheikh, Ali Bazarbachi
Journal: Blood (2018)
Abstract 640: Indigo Naturalis, a Promising Herbal Medicine for Ulcerative Colitis, Can Induce Experimental Pulmonary Arterial Hypertension via Aryl Hydrocarbon Pathway
Authors: Takahiro Hiraide, Toshiaki Teratani, Masaharu Kataoka, Jin Endo, Motoaki Sano, Yoji Hakamata, Keiichi Fukuda, Takanori Kanai
Journal: Circulation Research (2019)

Background: Indigo naturalis is a Chinese herbal medicine, whose dramatical effects for treatment of ulcerative colitis have been reported. However, some patients who took indigo naturalis developed pulmonary arterial hypertension (PAH), which is a poor prognostic disease with right ventricular (RV) failure and progressive remodeling of pulmonary vessels. Aims: We examined the reproducibility in experimental animals and elucidate the mechanisms for indigo naturalis to induce PAH. Methods and Results: Rats with 12-week intake of low-dose indigo naturalis (60 mg/kg body weight; corresponding to therapeutic dose for patients) did not induce PAH. However, RV and pulmonary vessel remodeling were identified in rats fed with high-dose indigo naturalis (600 mg/kg body weight) for 12 weeks. Significantly elevated RV systolic pressure was identified in rats administered with vascular endothelial growth factor-2 receptor blocker (Sugen 5416) and fed with indigo naturalis for 8 weeks compared to that of rats fed with normal diet (38.6 [38.2, 40.0] mmHg) vs. 31.9 [31.4, 34.6] mmHg, p &lt; 0.001). Indigo, a major compound of indigo naturalis, also induced mild PAH. Indigo works as a ligand of aryl hydrocarbon receptor (AhR), and the mRNA levels of CYP1A1, downstream of AhR signal, were elevated in lungs. Rats with indigo naturalis and AhR antagonist gavage developed less pulmonary vessel remodeling than rats without AhR antagonist. Conclusions: The combination of Sugen 5416 and indigo naturalis can be a novel unique approach to generate rat PAH model without a hypoxic chamber. The effects of indigo naturalis to PAH might be mediated at least in part through activation of AhR-CYP1A1 pathway.
Identifying the gap in goals of care communication across care settings in a flagship cancer research and treatment facility.
Authors: Mamta Bhatnagar, Ellen Ormond, Swati Bhosale, Rebecca Felice, Edward Chu
Journal: Journal of Clinical Oncology (2019)

180 Background: There is widespread recognition of the importance of having and documenting timely Goals of Care (GOC) conversations with seriously ill patients. Inpatient oncology teams at UPMC have noted the limited availability in the Electronic Medical Record (EMR) of documentation of patient preferences about end of life care. This project aims to identify the gaps in GOC communication across care settings for cancer patients at UPMC. Methods: We identified sources of information regarding goals of care available to inpatient oncology providers. Using the EMR we accessed the following for each patient of interest: CPR status, GOC documentation, scanned Advance Directives and/or POLST and last two available outpatient notes. Patients of interests were older than 65 years with metastatic cancer and 2 hospital admissions in the past year, or any cancer patient &gt; 90 years. We reviewed outpatient notes for words suggesting that GOC conversations had occurred, and for a subset (50%), we did a detailed review identifying documentation of prognosis, treatment options, treatment decisions and patient values. Results: Of a total 114 high risk patients admitted over a 6-month period, 73 (64%) died within 6 months, with 52 (46%) dying within one month of their last hospitalization. Thirty nine (34%) patients had at least 5 admissions. Only 35% patients had GOC documented using the EMR template, and only 38% had a completed POLST. Rates of CPR status completion were high (95%). However, when tracking CPR status across multiple admissions, 73% of patients were full code on their first admission, with 31% of patients with five admissions remaining full code. The qualitative analysis of outpatient notes revealed that most documentation (87%) reflected continued treatment with minimal discussion of hospice or patient values. Conclusions: In a cohort of patients with advanced cancer, documentation of GOC discussions is limited in both inpatient and outpatient settings. Available documentation suggests minimal discussion of the limited benefits of medical interventions to prolong life. Future efforts will be designed to improve the quality and frequency of documentation of GOC conversations.
Abstract 13115: Nitric Oxide Differentially Regulates White and Brown Adipogenesis Through Effects on Thermogenesis and Mitochondrial Biogenesis <i>(Best of Basic Science Abstract)</i>
Authors: Paul Huang, Sylvia Lee-Huang
Journal: Circulation (2015)

Introduction: In addition to its roles as a vascular signaling molecule, nitric oxide (NO) plays roles in metabolism. Mice deficient in eNOS are overweight and develop insulin resistance. It is not known whether the metabolic effects are due to primary roles of NO, or to increased visceral adiposity, leading to secondary metabolic changes. Hypothesis: We hypothesized that NO plays distinct and separable primary roles in white and brown adipogenesis, which underlie the effects on adiposity, energy metabolism, and expression of thermogenic genes. Methods: We exposed wild-type and mice carrying specific gain of function and loss of function eNOS mutations to cold at 4C for 48 hours and assessed expression of thermogenic gene programs in white and brown adipose tissue. To study cell autonomous effects, we differentiated adipocyte precursors from brown and white fat in the presence of NOS inhibitors and NO donors, as well as with siRNA to knockdown eNOS expression. Results: Cold exposure resulted in upregulation of the thermogenic gene program in brown adipose tissue. Animals carrying a gain of function mutation in eNOS showed increased UCP1 expression even without cold exposure. Induction of thermogenic genes was more pronounced in the animals with gain of function eNOS mutation. Differentiation of adipocyte precursors showed effects of eNOS on adipogenesis. Cells treated with the pharmacologic blockade (L-NAME and L-NA) as well as genetic knockdown (siRNA) showed dose-dependent inhibition of adipocyte differentiation. MitoTracker Red CMXRos staining showed that treatment with the NO donor SNAP increases mitochondrial biogenesis, while L-NAME decreases mitochondrial biogenesis. Conclusions: We show that eNOS-derived NO plays distinct and separable roles in white and brown adipogenesis. In brown adipocytes, eNOS regulates the expression of the thermogenic gene program, with upregulation of expression even without cold exposure, and greater increase in response to cold. In white adipocytes, eNOS-derived NO is required for adipocyte differentiation and mitochondrial biogenesis.
Oncology multidisciplinary clinic development.
Authors: Sheila Jacobs, Kathy Mashanic
Journal: Journal of Clinical Oncology (2019)

62 Background: In 2014 it was decided that a multidisciplinary approach would be beneficial for our breast cancer patients. A pre-conference for a multidisciplinary discussion on the treatment plan for the patients and their ability to see medical oncology, surgical oncology, and radiation oncology in one visit was the goal. Methods: A multidisciplinary planning committee was established to discuss operational issues. Location of the pre-conference and exam rooms were assigned along with the development of the MDC schedule templates for the physicians. The staffing resources were identified along with any additional equipment or supplies. Key staff were engaged to determine a new scheduling workflow including how patient referrals would be handled between departments, phone numbers the patient/family or physician would call for an appointment, and scripted messages to educate all on this model of care. Physicians developed triage questions to direct the caller to appropriate clinic and schedule an MDC appointment. A single phone number was created to ensure adequate access. Physician leadership and the managers of the affected areas worked with marketing on developing a variety of communication strategies to introduce the multidisciplinary initiative to providers, staff, referral networks, and patients. Results: Since the pilot in 2014, additional breast, thyroid/endocrine, thoracic, genitourinary, and gastrointestinal/colorectal MDC clinics have been launched as the outcomes have been very positive. Total MDC’s visits have increased by 200% from 132 in 2017 to 399 projected in 2019. Market share in the MDC programs has increased an average of 3.6 points. There has been a 44% increase in diagnosis at an earlier stage and both patient and provider satisfaction have trended upwards. Conclusions: The MDC’s have been a positive addition to our cancer program. The comprehensive approach to care has resulted in quality experience for all touched by cancer.
Overriding Adaptive Resistance to Sorafenib Through Combination Therapy With Src Homology 2 Domain–Containing Phosphatase 2 Blockade in Hepatocellular Carcinoma
Authors: Carmen Oi Ning Leung, Man Tong, Katherine Po Sin Chung, Lena Zhou, Noélia Che, Kwan Ho Tang, Jin Ding, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Stephanie Ma, Terence Kin Wah Lee
Journal: Hepatology (2019)

Background and Aims The survival benefit of sorafenib for patients with hepatocellular carcinoma (HCC) is unsatisfactory due to the development of adaptive resistance. Increasing evidence has demonstrated that drug resistance can be acquired by cancer cells by activating a number of signaling pathways through receptor tyrosine kinases (RTKs); nevertheless, the detailed mechanism for the activation of these alternative pathways is not fully understood. Approach and Results Given the physiological role of Src homology 2 domain–containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation of various signaling cascades, we first found that SHP2 was markedly up‐regulated in our established sorafenib‐resistant cell lines as well as patient‐derived xenografts. Upon sorafenib treatment, adaptive resistance was acquired in HCC cells through activation of RTKs including AXL, epidermal growth factor receptor, EPH receptor A2, and insulin‐like growth factor 1 receptor, leading to RAS/mitogen‐activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK), and AKT reactivation. We found that the SHP2 inhibitor SHP099 abrogated sorafenib resistance in HCC cell lines and organoid culture in vitro by blocking this negative feedback mechanism. Interestingly, this sensitization effect was also mediated by induction of cellular senescence. SHP099 in combination with sorafenib was highly efficacious in the treatment of xenografts and genetically engineered models of HCC. Conclusions SHP2 blockade by SHP099 in combination with sorafenib attenuated the adaptive resistance to sorafenib by impeding RTK‐induced reactivation of the MEK/ERK and AKT signaling pathways. SHP099 in combination with sorafenib may be a safe therapeutic strategy against HCC.
Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis
Authors: Maureen McHugo, Pratik Talati, Kristan Armstrong, Simon N. Vandekar, Jennifer Urbano Blackford, Neil D. Woodward, Stephan Heckers
Journal: American Journal of Psychiatry (2019)

In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. The authors tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing.Functional MRI data from 45 early-psychosis patients and 35 demographically matched healthy control subjects were analyzed using a block-design 1-back scene-processing task. Hippocampal activation in response to scenes and faces compared with scrambled images was measured. In a subset of 20 early-psychosis patients and 31 healthy control subjects, baseline hippocampal activity using cerebral blood volume (CBV) mapping was measured. Correlation analyses were used to examine the association between baseline hippocampal activity and task-related hippocampal activation.Activation of the anterior hippocampus was significantly reduced and CBV in the anterior hippocampus was significantly increased in the early stages of psychosis. Increased CBV in early-psychosis patients was inversely correlated with task-related activation during scene processing in the anterior hippocampus.Anterior hippocampal hyperactivity in early-psychosis patients appears to limit effective recruitment of this region during task performance. These findings provide novel support for the anterior hippocampus as a therapeutic target in the treatment of cognitive deficits in psychosis.