tbuckley/cabot-search huggingface dataset:
Abstract 2048: Pharmacodynamic biomarker studies of TRC105 anti-endoglin (CD105) antibody revealed anti-angiogenic activity associated with CD105 depletion
Authors: Liang Cao, Fatima Karzai, Andrea Apolo, Ravi Madan, Yunkai Yu, James Gulley, William Figg, William Dahut
Journal: Cancer Research (2016)

Abstract Introduction: CD105 is involved in normal vascular development. It is over expressed on the surface of proliferating vascular endothelial cells and is implicated in tumor angiogenesis. In hypoxic conditions, CD105 is upregulated through induction of hypoxia-inducible factor 1-α. TRC105 is a chimeric IgG1 antibody specific for CD105 and the agent for this phase I trial. Methods: 20 patients with metastatic prostate cancer were treated with TRC105 at six dose levels in a phase I trial. Blood samples were analyzed for CD105 antigen depletion, VEGF as a marker for systemic hypoxia, and PSA. Results: Maximum tolerated dose of 20 mg/kg every two weeks was reached. Significant plasma CD105 reduction was observed at high dose levels. The reduction of CD105 was associated with induction of plasma VEGF. Ten patients had stable disease, and the reduction of CD105 is associated with PSA stabilization. Conclusion: A significant induction of VEGF was associated with CD105 reduction at three high dose levels, suggesting the anti-angiogenic activity of TRC105. Exploratory analysis showed a tentative correlation between the reduced CD105 and a decreased PSA velocity, suggestive of potential antitumor activity of TRC105 in metastatic prostate cancer. Citation Format: Liang Cao, Fatima Karzai, Andrea Apolo, Ravi Madan, Yunkai Yu, James Gulley, William Figg, William Dahut. Pharmacodynamic biomarker studies of TRC105 anti-endoglin (CD105) antibody revealed anti-angiogenic activity associated with CD105 depletion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2048.
Are MGMT promoter methylation and EGFR mutations early markers of tumor progression in colorectal cancer?
Authors: T. Wenner, B. Metzger, L. Chambeau, G. Mahon, M. Pauly, J. Kaiser, G. J. Berchem, M. Dicato
Journal: Journal of Clinical Oncology (2010)

3584 Background: The colorectal adenoma-carcinoma sequence summarizes the epigenetic and genetic modifications arising during cancer progression. These modifications notably affect the methylation status of different gene's promoters and mutation in the K-ras gene. In the present study, in order to determine if MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation and EGFR mutation may be an early event in the progression of colorectal cancer, we determine the methylation status of H-cadherin and E-cadherin promoters as early and late markers of the disease in more than 200 patients. Methods: Tumour samples were obtained from CRC patients at the adenocarcinoma stage. After resection, they were rapidly frozen in liquid nitrogen and stored at -80°C. Methylation statuses were analyzed by methylation-specific PCR (MSP) and mutation determined by direct sequencing. Results: We screened 236 clinical tumours to detect mutations in the EGFR gene exons 18 to 21, mainly covering the EGFR TK catalytic domain and found a frequency of mutation of 0.5% to 3.8%, except for a silent point mutation in exon 20 found at a very high frequency of about 83%. 24% of the same tumours showed a mutation in K-ras gene and 78%, 63% and 49% an aberrant methylation of H-cadherin, E-cadherin and MGMT genes promoters respectively. When combining the distribution of these methylation statuses according to the mutation in K-ras using statistical analysis we showed that occurrence of G to A mutations in K-ras may be dependent on the methylation of MGMT and H-cadherin, the E-cadherin gene promoter remaining unmethylated. Conclusions: We showed that MGMT promoter methylation may occur between the methylation of H-cadherin gene promoter and the G to A mutation in K-ras gene. The status of MGMT in CRC with known G to A mutations in several genes is now under investigation. In this disease, if the mutation frequency of EGFR gene is very low, we showed the occurrence of a silent point mutation at very high frequency (83%). As this polymorphism is also present in healthy volunteers, correlation with patient's grade and outcome will be crucial to determine if this polymorphism might be used as a predictive marker of the evolution of the disease. No significant financial relationships to disclose.
Ligands That Mimic the Tissue Microenvironment of Replicating Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) Protect Ex Vivo Patient Cell Samples from the Cytotoxicity of Combined Treatment with Ibrutinib and Venetoclax (ABT-199)
Authors: Kallesh D. Jayappa, Craig A. Portell, Vicki Gordon, Michael E. Williams, Emanuel F. Petricoin, Timothy P. Bender, Michael J. Weber
Journal: Blood (2015)
NHS England unveils mental health plan
Authors: Anne Gulland
Journal: BMJ (2016)

NHS England has laid out plans for how extra funding, rising to £1 billion (€1.19bn; $1.32bn) a year by 2020-21, will be spent on mental health services over the next five years.1

The plans build on the Five Year Forward View for Mental Health, published in February,2 which pledged to end the underfunding of mental health services that had led to “hundreds and thousands of lives put on hold or ruined.”

The implementation plan, published on 19 July, detailed how the extra money would be spent.

Around £72m would be spent in 2016-17 …
South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study
Authors: Hao Chung The, Maia A. Rabaa, Duy Pham Thanh, Niall De Lappe, Martin Cormican, Mary Valcanis, Benjamin P. Howden, Sonam Wangchuk, Ladaporn Bodhidatta, Carl J. Mason, To Nguyen Thi Nguyen, Duong Vu Thuy, Corinne N. Thompson, Nguyen Phu Huong Lan, Phat Voong Vinh, Tuyen Ha Thanh, Paul Turner, Poda Sar, Guy Thwaites, Nicholas R. Thomson, Kathryn E. Holt, Stephen Baker
Journal: PLoS Medicine (2016)

Background Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei. Methods and Findings We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei. Conclusions This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally.
Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice
Authors: Nina Kristofik, Nicole E. Calabro, Weiming Tian, Aaron Meng, Susan MacLauchlan, Yinong Wang, Christopher K. Breuer, George Tellides, Laura E. Niklason, Themis R. Kyriakides
Journal: Blood (2016)
Abstract 5166: Gene expression microarray analysis identifies association of genes in the integrin/fak signaling pathway with claudin-7 in human colon cancer tissue
Authors: Lu Kong, Lei Ding
Journal: Cancer Research (2016)

Abstract The role and mechanism of the integrin/focal adhesion kinase (FAK)/ERK signaling pathway in the progression of many malignant tumor types, including colon cancer, have been widely reported. The claudin family of proteins is integral to the structure and function of tight junctions. The role of claudin-7 (Cldn-7, CLDN7) in the regulation of the integrin/FAK/ERK signaling pathway remains poorly understood. Therefore, we investigated differences in gene expression, primarily focusing on CLDN7 and integrin/FAK/ERK signaling pathway genes, in colon cancer and adjacent normal tissues. Quantitative real-time RT-PCR verified the results for mRNA expression, and immunohistochemistry verified the results for protein expression. In silico analysis was used to predict co-regulation between Cldn-7 and integrin/FAK/ERK signaling pathway members. Our results showed marked cancer stage-specific decreases in the protein expression of Cldn-7, Gelsolin, MAPK1 and MAPK3 in colon cancer samples. The observed changes in the expression of all proteins except Cldn-7 were in agreement with the changes in the corresponding mRNA levels. Cldn-7 was predicted not to directly regulate any genes in the integrin/FAK/ERK signaling pathway, but these factors may participate in a common network that regulates cancer progression, in which the MAPK pathway is the central node. Citation Format: Lu Kong, Lei Ding. Gene expression microarray analysis identifies association of genes in the integrin/fak signaling pathway with claudin-7 in human colon cancer tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5166.
Efficacy of vemurafenib (V), a selective <sup>V600E</sup>BRAF inhibitor, as monotherapy or in combination with erlotinib (Erl) or erbitux (Erb) and irinotecan (Iri) doublets and triplets in a colorectal cancer (CRC) xenograft model.
Authors: Brian Higgins, Kenneth Daniel Kolinsky, Kathleen Schostack, Gideon Bollag, Richard J. Lee, Fei Su, Kathryn Packman
Journal: Journal of Clinical Oncology (2012)

494 Background: B-Raf mutations, particularly at V600 occur in 10% of CRCs resulting in constitutive activation of the MAPK pathway. V (RG7204, PLX4032) is a first-in-class, V600 B-Raf-selective small molecule inhibitor previously shown to potentiate anti-tumor effects in the V600E CRC xenograft model HT29 in combination (combo) with capecitabine ± bevacizumab (ASCO GI, 2008). V600E CRC respond poorly to EGFR inhibition (EGFRi) both preclinically and clinically. We aimed to determine whether antitumor activity could be potentiated by combining V with EGFRi. Methods: The monotherapy (mono) activities of V, Erl, Erb and Iri were compared to combo of these agents in the HT29 model. V was tested as a mono at its optimal dose (OD), Erl was tested at its MTD or 2/3 MTD, and a combo of V OD + 2/3 MTD Erl were tested. V was subsequently tested as mono or combo at the OD and suboptimal-OD with OD Erb. A final study included Iri as mono, doublets of Iri + V or Erb, and triplet combo of Iri, V, and Erb. Results: Tumor growth inhibition (TGI) and increase in life span (ILS) for combo of OD V + 2/3 MTD Erl was superior to all mono arms. TGI in mono arms was equivalent for V, Erb and Iri. ILS was better for V vs Iri and Erb mono, while Iri vs Erb ILS were equivalent. TGI and ILS for Iri + Erb doublet was equivalent to V mono. Otherwise, TGI and ILS in all other doublets and triplets were superior to mono groups. TGI in V + Erb and V + Iri were equivalent, but ILS was better for V + Iri. TGI and ILS for V + Iri was better than Iri + Erb. TGI in V + Erb was better than Iri + Erb, but ILS was equivalent. TGI in the triplet was superior to all doublets except V + Erb, however ILS was superior to all doublets tested. Conclusions: V potentiates anti-tumor activity in a V600E CRC model when used in combo with Erl, Erb and Iri. Although a V + Erb doublet provided impressive TGI equivalent to a triplet with Iri, the triplet yielded sustained antitumor activity as demonstrated by a significant increase in survival as compared to the doublet. Combo with V may afford V600E CRC patients a differential response to what is seen traditionally with single agent EGFi and is worthy of clinical exploration.
MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression
Authors: Agustí Toll, Rocío Salgado, Blanca Espinet, Angel Díaz-Lagares, Eugenia Hernández-Ruiz, Evelyn Andrades, Juan Sandoval, Manel Esteller, Ramón M Pujol, Inmaculada Hernández-Muñoz
Journal: Molecular Cancer (2016)

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and frequently progresses from an actinic keratosis (AK), a sun-induced keratinocyte intraepithelial neoplasia (KIN). Epigenetic mechanisms involved in the phenomenon of progression from AK to cSCC remain to be elicited. Expression of microRNAs in sun-exposed skin, AK and cSCC was analysed by Agilent microarrays. DNA methylation of miR-204 promoter was determined by bisulphite treatment and pyrosequencing. Identification of miR-204 targets and pathways was accomplished in HaCat cells. Immunofluorescence and immunohistochemistry were used to analyze STAT3 activation and PTPN11 expression in human biopsies. cSCCs display a marked downregulation of miR-204 expression when compared to AK. DNA methylation of miR-204 promoter was identified as one of the repressive mechanisms that accounts for miR-204 silencing in cSCC. In HaCaT cells miR-204 inhibits STAT3 and favours the MAPK signaling pathway, likely acting through PTPN11, a nuclear tyrosine phosphatase that is a direct miR-204 target. In non-peritumoral AK lesions, activated STAT3, as detected by pY705-STAT3 immunofluorescence, is retained in the membrane and cytoplasm compartments, whereas AK lesions adjacent to cSCCs display activated STAT3 in the nuclei. Our data suggest that miR-204 may act as a "rheostat" that controls the signalling towards the MAPK pathway or the STAT3 pathway in the progression from AK to cSCC.
Poor adherence to antihypertensive drugs
Authors: Mohammed Awais Hameed, Indranil Dasgupta, Paramjit Gill
Journal: BMJ (2016)

#### What you need to know

A 56 year old man has had persistently raised blood pressure readings at home and in clinic since his diagnosis of hypertension three years ago. He was diagnosed after ambulatory blood pressure monitoring, and is prescribed four antihypertensives. At a routine blood pressure review he says not to bother with another prescription because he doesn’t take the drugs.

As many as half of patients with apparent resistant hypertension do not take their prescribed drugs.1 Consider non-adherence in those taking antihypertensives with elevated blood pressure readings particularly in those with apparent resistant hypertension, where blood pressure is persistently ≥140/90 mm Hg despite taking ≥3 titrated antihypertensive drugs including a diuretic. Biological resistant hypertension affects around 10% of those treated for hypertension in the United Kingdom, and such patients need specialist management. Attempt to identify and manage poor adherence before referring the patient to a specialist.

To find out about adherence to drugs ask patients questions such as: “I know many people have difficulty taking their medicines, how do you manage yours?” or “Take me through your medications.”

The rate that patients are prescribed or collect their drugs can also provide information on adherence. In patients whose blood pressure remains uncontrolled despite multiple (≥3) antihypertensive drugs consider referral to a specialist hypertension clinic for directly observed therapy, …
Targeted case finding for chronic obstructive pulmonary disease versus routine practice in primary care (TargetCOPD): a cluster-randomised controlled trial
Authors: Rachel E Jordan, Peymané Adab, Alice Sitch, Alexandra Enocson, Deirdre Blissett, Sue Jowett, Jen Marsh, Richard D Riley, Martin R Miller, Brendan G Cooper, Alice M Turner, Kate Jolly, Jon G Ayres, Shamil Haroon, Robert Stockley, Sheila Greenfield, Stanley Siebert, Amanda J Daley, K K Cheng, David Fitzmaurice
Journal: The Lancet Respiratory Medicine (2016)
Palliative Care and Cardiovascular Disease and Stroke: A Policy Statement From the American Heart Association/American Stroke Association
Authors: Lynne T. Braun, Kathleen L. Grady, Jean S. Kutner, Eric Adler, Nancy Berlinger, Renee Boss, Javed Butler, Susan Enguidanos, Sarah Friebert, Timothy J. Gardner, Phil Higgins, Robert Holloway, Madeleine Konig, Diane Meier, Mary Beth Morrissey, Tammie E. Quest, Debra L. Wiegand, Barbara Coombs-Lee, George Fitchett, Charu Gupta, William H. Roach
Journal: Circulation (2016)

The mission of the American Heart Association/American Stroke Association includes increasing access to high-quality, evidence-based care that improves patient outcomes such as health-related quality of life and is consistent with the patients’ values, preferences, and goals. Awareness of and access to palliative care interventions align with the American Heart Association/American Stroke Association mission. The purposes of this policy statement are to provide background on the importance of palliative care as it pertains to patients with advanced cardiovascular disease and stroke and their families and to make recommendations for policy decisions. Palliative care, defined as patient- and family-centered care that optimizes health-related quality of life by anticipating, preventing, and treating suffering, should be integrated into the care of all patients with advanced cardiovascular disease and stroke early in the disease trajectory. Palliative care focuses on communication, shared decision making about treatment options, advance care planning, and attention to physical, emotional, spiritual, and psychological distress with inclusion of the patient’s family and care system. Our policy recommendations address the following: reimbursement for comprehensive delivery of palliative care services for patients with advanced cardiovascular disease and stroke; strong payer-provider relationships that involve data sharing to identify patients in need of palliative care, identification of better care and payment models, and establishment of quality standards and outcome measurements; healthcare system policies for the provision of comprehensive palliative care services during hospitalization, including goals of care, treatment decisions, needs of family caregivers, and transition to other care settings; and health professional education in palliative care as part of licensure requirements.
Abstract 3783: Co-treatment of metastasis-derived colon cancer cells with bromoethyl indole (BEI) enhances camptothecin or TNF alpha-induced cell death
Authors: Rupak Chowdhury, Sonni A. Miller, Dominique Gales, Jason White, Upender Manne, Temesgen Samuel
Journal: Cancer Research (2016)

Abstract Colorectal cancer is still the third most deadly cancer in the United States. Currently, there are limited choices of targeted anticancer agents that are durably effective against colorectal cancer. Therefore, chemotherapeutic regimens containing the drugs Camptothecin (CPT), 5-FU and Oxaliplatin remain the mainstays for the treatment of advanced colorectal cancer. We recently found that the indole-derivative small compound Bromoethyl Indole (BEI) potently inhibits the proliferation of colon cancer cells and also suppresses NF-kB activation. In this study, we investigated if the combination of BEI with either CPT or TNFα would enhance cell death in vitro. Metastasis-derived parental or engineered NF-kB-reporter colon cancer cells were used to examine 1) the activation of NF-kB signaling by clinically used drugs, 2) the potential for BEI to inhibit drug-induced NF-kB activation, and 3) the potential for combination treatment to enhance cell death in vitro. Cells were treated with either the drugs alone or in combination with BEI at varying concentrations. NF-kB-inducing concentration of CPT (0.6 to 2.5 μM), TNFα (25 to 50 ng/ml), and BEI concentrations of 1 to 50 μM range were tested. Cell cycle profiles and cell death markers were assessed to determine the effects of single or co-treatments. The expressions of Bcl-xL and cIAP2 (BIRC3) proteins were examined to monitor the targets of NF-kB activation. Our results show that 1) both TNFα and CPT induce NF-kB signaling in metastasis-derived colon cancer cells, 2) combination of BEI and TNFα or CPT inhibits such a drug-induced NF-kB activation and reduces the expression of NF-kB responsive genes, 3) sequential treatment of the cells with CPT and BEI delivers the best outcome, increasing cell death by up to 3-fold compared to either CPT or BEI alone, and 4) co-treatment of the cells with TNFα and BEI increases cell death by up to 2-fold compared to either TNFα or BEI alone, 5) BEI is most effective in inducing cell death at concentrations between 2 and 10 μM. We anticipate that BEI will improve the therapeutic index of some chemotherapeutic drugs. Therefore, the potential benefit for combination of BEI with NF-kB activating drugs needs to be evaluated in vivo. Citation Format: Rupak Chowdhury, Sonni A. Miller, Dominique Gales, Jason White, Upender Manne, Temesgen Samuel. Co-treatment of metastasis-derived colon cancer cells with bromoethyl indole (BEI) enhances camptothecin or TNF alpha-induced cell death. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3783.