tbuckley/cabot-search huggingface dataset:
A human monoclonal antibody drug conjugate against EphA2 inhibits tumor growth in vivo through the induction of apoptosis
Authors: John Gooya, Shenlan Mao, Christine Bachy, Damon Meyer, Peter Senter, Peter Kiener, Laura Richman, Steve Coats, David Tice, Dowdy Jackson
Journal: Cancer Research (2007)

5744  The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many human cancers, including prostate and breast cancers. We have generated a human monoclonal antibody that selectively binds to human and rodent EphA2 receptor. Upon antibody binding to the EphA2 receptor, the receptor is phosphorylated and is subsequently internalized. We now report data from our preclinical evaluation of an ADC that specifically inhibits the growth of EphA2 expressing tumor cells.  We have conjugated the microtubulin inhibitor monomethylauristatin F (MMAF) to a human monoclonal antibody against the EphA2 receptor using the maleimidocaproyl (mc) linker. The EphA2-mcMMAF antibody conjugate is internalized resulting in the intracellular release of MMAF and the inhibition of cell growth through the induction of caspase dependent apoptosis. The EphA2-mcMMAF antibody conjugate inhibits the growth of EphA2 expressing tumors with an IC50 between 1- 90 ng/ml where the IC50 values for cells that do not express the EphA2 receptor are in the 2 - 3 μg/ml range.  In vivo tumor efficacy studies using the EphA2-mcMMAF conjugate antibody resulted in significant inhibition of EphA2 expressing tumor growth when the mice were treated with 1 mg/kg of the antibody. The isotype matched control antibody drug conjugate and the unconjugated EphA2 antibody did not inhibit tumor growth.  Our data support the use of an antibody drug conjugate approach to target and inhibit the growth of EphA2 expressing tumors in vivo.
The Epidemiology of Hypertension.
Journal: Annals of Internal Medicine (1968)

INTRODUCTION Blood pressure (BP) is a quantitative trait with a normal, continuous, bell-shaped (Gaussian) distribution pattern, skewed to the upper end in any general population (Figure 1.1), and hypertension represents a clinical definition of the upper part of the distribution curve. Figure 1.1 shows a distribution curve for diastolic BP plotted using BP measurements in 158,906 individuals aged 30-69 years screened for the Hypertension Detection and Follow-up Program in the United States (1).
Phase II Trial to Evaluate the Efficacy and Safety of the Combination of Obinutuzumab and Bendamustine Treatment in Patients (Pts) with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Authors: Jose Garcia-Marco, Patricia Baltasar Tello, Esther González Garcia, Eduardo Ríos Herranz, Angel Ramirez Payer, María José Terol Castera, Diana Champ, Angeles Medina Perez, Mercedes Gironella, Alicia Rodríguez Fernández, Ana Muntañola Prat, Alexia Suárez Cabrera, Manuel Jurado Chacón, Miguel Fernández Zarzoso, Mercedes Rodríguez, Juana Clavel, Maria Victoria Dourdil Sahun, Christelle M Ferra Coll, Ernesto Pérez Persona, Carmen Milagros Marrero Santos, Rafael Forés, Julio Delgado
Journal: Blood (2017)
NHS declares national emergency over shortage of intravenous feeds
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The NHS has declared a national emergency incident in response to an ongoing shortage of intravenous feed supplies that has affected hundreds of patients across England.

In separate letters sent to clinicians, trusts, and affected patients on 7 August, the NHS national patient safety director Aidan Fowler said the service was considering importing products to ensure sufficient supplies.

The incident has been declared following shortages that arose as a result of manufacturer Calea being ordered by the Medicines Health and Regulatory Agency (MHRA) to take immediate action to change its manufacturing process for parenteral …
Anti-Myeloma Effects of the Selective JAK1 Inhibitor INCB052793 Using a Platform Study Utilizing the Lagκ-1A Multiple Myeloma Xenograft Model
Authors: Eric Sanchez, Mingjie Li, Cathy S Wang, Edward J Tanenbaum, Saurabh Patil, Camilia Soof, Tara Hekmati, Remy E Schlossberg, Moryel A Yashar, Autumn L Porter, George Y Tang, Haiming Chen, James R Berenson
Journal: Blood (2017)
Diverse functional roles of myosin VI in human prostate cancer
Authors: Shuanzeng Wei, Thomas Dunn, Rong Hu, Angelo De Marzo, Jun Luo
Journal: Cancer Research (2007)

1350  Myosin VI is a unique actin motor that moves to the minus end of the polarized actin filament, a direction opposite to all other characterized myosins. Our previous expression microarray analysis in clinical cancer specimens demonstrated consistent cancer-specific overexpression of myosin VI most prominently in human breast and prostate cancers. In addition, expression levels of myosin VI in a panel of human prostate cancer cell lines positively correlated with the presence of androgen receptor. In light of the diverse biological functions of myosin VI implicated in other model systems, our current study focused on potentially distinctive roles of myosin VI in relation to varying levels of androgen sensitivity in prostate cancer cells. First, through immunohistochemical analysis, we observed well-defined perinuclear staining pattern that is consistently with Golgi localization and suggestive of a secretory function of myosin VI. This Golgi staining pattern is universal and independent of intra-tumor heterogeneity in a subset of cancer specimens but completely absent in other specimens, which demonstrated characteristic diffuse cytoplasmic staining. Next, we conducted immunofluorescent analysis in cell lines with varying levels of androgen receptor. Nearly all the androgen receptor negative PC-3 cells have one or two myosin VI positive foci co-localized with the Golgi apparatus. The androgen receptor positive CWR22Rv1 cells expressed more myosin VI when compared with PC-3 cells and were characterized by intensive staining at the leading edge of the cytoplasm which suggested a role in cell migration. The LNCaP and VCaP cells demonstrated the most abundant androgen receptor expression and concomitantly the most intense diffuse myosin VI staining. Last, we observed a dramatically decreased expression of prostate specific antigen in LNCaP cells following stable knock-down of myosin VI using small hairpin RNA. However, preliminarily, the expression and nuclear localization of androgen receptor did not appear to be perturbed in the absence of myosin VI. These results, while mostly observational, suggest that myosin VI may engage different cellular components in different stages of prostate cancer progression, and that its role in androgen signaling warrants further study.
Incidence, Risk, and Markers of Thrombosis in AML Patients - Single Institution Experience
Authors: Sayeef Mirza, Seongseok Yun, Najla Al Ali, Hannah Shin, Joseph Luke O'Neill, Daniel Schwartz, Amra Kuc, Sammy Abusrur, Jose Jesurajan, Jameson Kuang, Shreyans Patel, Sabrina Khalil, Sonya Bhaskar, Alexander Beard, Toaa Abuelenen, Ethan Nowell, Kevin Ratnasamy, Nathan Visweshwar, Rami S. Komrokji, Michael Jaglal
Journal: Blood (2018)
Correlates of HIV infection in adolescent girls and young women in Lesotho: results from a population-based survey
Authors: Andrea Low, Kyaw Thin, Stefania Davia, Joanne Mantell, Masebeo Koto, Stephen McCracken, Puleng Ramphalla, Limpho Maile, Nahima Ahmed, Hetal Patel, Bharat Parekh, Neway Fida, Amee Schwitters, Koen Frederix
Journal: The Lancet HIV (2019)
Lung Innate Lymphoid Cell Composition Is Altered in Primary Graft Dysfunction
Authors: Laurel A. Monticelli, Joshua M. Diamond, Steven A. Saenz, Elia D. Tait Wojno, Mary K. Porteous, Edward Cantu, David Artis, Jason D. Christie
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.
Induction of cell cycle arrest and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in human ovarian cancer cells
Authors: Sara Vignati, Veronica Albertini, Giuseppina M. Carbone, Carlo V. Catapano
Journal: Cancer Research (2004)

3892  Epithelial ovarian cancer is often diagnosed in advanced stages of disease. Despite the use of potent anticancer drugs the survival rate for patients with ovarian cancer remains poor, making it one of the most common causes of cancer-related death in women. Since current therapy for advanced disease is clearly inadequate, new molecular-targeted agents need to be evaluated for prevention and treatment of this disease. The peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear receptor family of ligand-activated transcription factors. PPAR gamma agonists, such as the antidiabetic thiazolidinedione drugs, inhibit growth and induce apoptosis of different types of cancer cells both in vitro and in vivo and are seen as potentially useful therapeutic and chemopreventive agents in oncology. This study was designed to evaluate expression of this nuclear receptor and the effects of its activation in a panel of human ovarian cancer cell lines. RT-PCR and Western blotting showed that all cell lines tested expressed PPAR gamma RNA and protein. PPAR gamma was functional in these cells as demonstrated by luciferase assays with a PPAR responsive reporter and the selective PPAR gamma ligand ciglitazone. Treatment of ovarian cancer cells with ciglitazone induced dose-dependent inhibition of growth of all cell lines with IC50 ranging from 25 to 100 μM. The antiproliferative effect required continuous exposure to ciglitazone since removal of the drug after 24 hours completely abolished it. Colony-forming assays also showed potent inhibition of proliferation of ovarian cancer cells following continuous exposure to ciglitazone. Cell cycle analysis by flow cytometry indicated that ciglitazone induced G1/S growth arrest after 24 hours of treatment. This was followed by the appearance of a sub-G1 peak at 48 hours in ciglitazone-treated cultures. Induction of apoptosis was confirmed by DAPI staining and fluorescence microscopy. Changes in nuclear morphology characteristic of apoptosis were observed in a dose- and time-dependent manner after incubation of cells with ciglitazone for 24, 48 and 72 hours. In conclusion, our data show that ciglitazone induces growth arrest and apoptosis in human ovarian cancer cells. The mechanisms underlying these effects are currently being investigated. These results suggest that PPAR gamma selective agonists could be useful for treatment of ovarian cancer.
Association of Daytime and Nighttime Blood Pressure With Cardiovascular Disease Events Among African American Individuals
Authors: Yuichiro Yano, Rikki M. Tanner, Swati Sakhuja, Byron C. Jaeger, John N. Booth, Marwah Abdalla, Daniel Pugliese, Samantha R. Seals, Gbenga Ogedegbe, Daniel W. Jones, Paul Muntner, Daichi Shimbo
Journal: JAMA Cardiology (2019)

Little is known regarding health outcomes associated with higher blood pressure (BP) levels measured outside the clinic among African American individuals.To examine whether daytime and nighttime BP levels measured outside the clinic among African American individuals are associated with cardiovascular disease (CVD) and all-cause mortality independent of BP levels measured inside the clinic.This prospective cohort study analyzed data from 1034 African American participants in the Jackson Heart Study who completed ambulatory BP monitoring at baseline (September 26, 2000, to March 31, 2004). Mean daytime and nighttime BPs were calculated based on measurements taken while participants were awake and asleep, respectively. Data were analyzed from July 1, 2017, to April 30, 2019.Cardiovascular disease events, including coronary heart disease and stroke, experienced through December 31, 2014, and all-cause mortality experienced through December 31, 2016, were adjudicated. The associations of daytime BP and nighttime BP, separately, with CVD events and all-cause mortality were determined using Cox proportional hazards regression models.A total of 1034 participants (mean [SD] age, 58.9 [10.9] years; 337 [32.6%] male; and 583 [56.4%] taking antihypertensive medication) were included in the study. The mean daytime systolic BP (SBP)/diastolic BP (DBP) was 129.4/77.6 mm Hg, and the mean nighttime SBP/DBP was 121.3/68.4 mm Hg. During follow-up (median [interquartile range], 12.5 [11.1-13.6] years for CVD and 14.8 [13.7-15.6] years for all-cause mortality), 113 CVD events and 194 deaths occurred. After multivariable adjustment, including in-clinic SBP and DBP, the hazard ratios (HRs) for CVD events for each SD higher level were 1.53 (95% CI, 1.24-1.88) for daytime SBP (per 13.5 mm Hg), 1.48 (95% CI, 1.22-1.80) for nighttime SBP (per 15.5 mm Hg), 1.25 (95% CI, 1.02-1.51) for daytime DBP (per 9.3 mm Hg), and 1.30 (95% CI, 1.06-1.59) for nighttime DBP (per 9.5 mm Hg). Nighttime SBP was associated with all-cause mortality (HR per 1-SD higher level, 1.24; 95% CI, 1.06-1.45), but no association was present for daytime SBP (HR, 1.13; 95% CI, 0.97-1.33) and daytime (HR, 0.95; 95% CI, 0.81-1.10) and nighttime (HR, 1.06; 95% CI, 0.90-1.24) DBP.Among African American individuals, higher daytime and nighttime SBPs were associated with an increased risk for CVD events and all-cause mortality independent of BP levels measured in the clinic. Measurement of daytime and nighttime BP using ambulatory monitoring during a 24-hour period may help identify African American individuals who have an increased cardiovascular disease risk.
Lower respiratory tract amyloidosis: Presentation, survival and prognostic factors. A multicenter consecutive case series
Authors: Jean‐Simon Rech, Bertrand Arnulf, Constance de Margerie‐Mellon, Alexis Talbot, Marion Malphettes, Marguerite Vignon, Bruno Royer, David Lavergne, Marianne Kambouchner, Véronique Meignin, Anne Bergeron, Grégoire Prevot, Pierre‐Yves Brillet, Emmanuel Martinod, Franck Bridoux, Hilario Nunes, Arnaud Jaccard, Dominique Valeyre, Yurdagül Uzunhan
Journal: American Journal of Hematology (2019)

Lower-respiratory-tract (LRT) amyloidosis has rarely been investigated. Our study presents characteristics, outcomes and survival of LRT amyloidosis. This multicenter retrospective study, from 1995 to 2017, included 73 patients with amyloidosis and LRT involvement. Respiratory patterns were: tracheobronchial (n = 17), nodular (n = 10), interstitial (n = 14) or composite (several respiratory involvements, n = 32). Interstitial and composite patterns were associated with multi-organ amyloidosis (n = 37, 80%) while tracheobronchial and nodular patterns were associated with organ-limited amyloidosis (n = 21, 78%). Amyloid light chain (AL) amyloidosis was diagnosed in 43 patients (59%), mainly of lambda type (n = 33, 77%). Smokers' proportion was higher in tracheobronchial (71%) and nodular (90%) patterns than in interstitial (14%) and composite (34%) patterns. The B-cell neoplasms involved 15 patients (21%), solid neoplasms 8 (11%), connective tissue diseases 8 (11%) and multiple myeloma 6 (8%). The B-cell and solid neoplasms were most prevalent in nodular pattern. Median follow-up was 4.4 years (2.2-8.9). Twenty-four patients died, mostly from respiratory infection. Survival at 1, 5, 10 years was respectively 88%, 70% and 54% for multi-organ amyloidosis, 96%, 89% and 69% for organ-limited amyloidosis (P = .125). Tracheobronchial and nodular patterns survival was better than in other respiratory patterns (P = .039). Death risk factors (multivariate analysis) were: cardiac localization (hazard-ratio [HR] 4.3 [95% confidence interval 1.6-11.5]; P = .004), age (HR 2.1 [1.2-3.7]; P = .008) and dyspnea at diagnosis (HR 4.0 [1.3-12.3]; P = .014). Various LRT amyloidosis patterns depend on smoking habits, organ-limited or multi-organ extension and comorbidities. They are associated with a different survival, which is also predicted by age, cardiac localization and dyspnea at presentation.
Abstract #5325: PIK3CA alterations in Middle Eastern ovarian cancers and its clinicopathological significance
Authors: Jehad Abubaker, Prashant Bavi, Wael Al-Haqawi, Zeenath Jehan, Sayer Al-Harbi, Adnan Munkarah, Shahab Uddin, Khawla Al-Kuraya
Journal: Cancer Research (2009)

PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer. Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs. Fluorescence insitu hybridization (FISH) technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA 110 alpha subunit protein expression (p110 \#945;), PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 \#945; overexpression was associated with overexpression of p-AKT-Ser 473 (P = 0.0260) and with the proliferation marker Ki-67 (P = 0.0639). PTEN inactivation was seen in 33 of 144 (22.9 %) EOC\#8217;s analyzed and was associated with histology subtype of clear cell and undifferentiated carcinomas (P = 0.0491); overexpression of p53 protein (P = 0.0413) and a trend was seen with older age (P = 0.0936). Our data showed alternation between PIK3CA amplification, PTEN protein loss, and mutations inthe PIK3CA, KRAS, and BRAF genes. This suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. In conclusion, high prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5325.
JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4
Authors: Chuntang Fu, Qingtian Li, Jia Zou, Changsheng Xing, Mei Luo, Bingnan Yin, Junjun Chu, Jiaming Yu, Xin Liu, Helen Y. Wang, Rong-Fu Wang
Journal: Journal of Clinical Investigation (2019)

Histone H3K27 demethylase, JMJD3 plays a critical role in gene expression and T-cell differentiation. However, the role and mechanisms of JMJD3 in T cell trafficking remain poorly understood. Here we show that JMJD3 deficiency in CD4+ T cells resulted in an accumulation of T cells in the thymus, and reduction of T cell number in the secondary lymphoid organs. We identified PDLIM4 as a significantly down-regulated target gene in JMJD3-deficient CD4+ T cells by gene profiling and ChIP-seq analyses. We further showed that PDLIM4 functioned as an adaptor protein to interact with S1P1 and filamentous actin (F-actin), thus serving as a key regulator of T cell trafficking. Mechanistically, JMJD3 bound to the promoter and gene body regions of Pdlim4 gene and regulated its expression by interacting with zinc finger transcription factor KLF2. Our findings have identified Pdlim4 as a JMJD3 target gene that affects T-cell trafficking by cooperating with S1P1, and provided insights into the molecular mechanisms by which JMJD3 regulates genes involved in T cell trafficking.
Hes1 and Deltex1: yin and yang controlling invasiveness and metastasis in osteosarcoma
Authors: Pingyu Zhang, Yanwen Yang, Kenneth Lee, Patrick Zweidler-McKay, Dennis Hughes
Journal: Cancer Research (2007)

3943  Osteosarcoma, the most common malignant tumor of bone in teenagers, has high potential of pulmonary metastasis. Although primary osteosarcoma is effectively treated by surgery and chemotherapy, pulmonary metastasis is more difficult to control and causes the majority of patient death. Elimination of metastatic disease is essential to cure osteosarcoma patients. However, the molecular mechanisms controlling invasiveness and metastasis are not fully understood. We have identified an essential role of Notch driven Hes1 expression in osteosarcoma invasiveness and metastasis. The Notch pathway is involved in pathogenesis of several cancer types, and pharmacological blockade of Notch signaling is in the clinical trails for human T-cell leukemia. We found that γ-secretase inhibitor-mediated blockade of Notch reduced matrigel invasion in parallel with Hes1 reduction in osteosarcoma cell lines OS187 and LM7, but had no effect on proliferation, survival or anchorage-independent growth. Furthermore, overexpression of constitutively active Notch1 (ICN1, intercellular domain of Notch1), Hes1 or dominant negative Mastermind (dnMAM, an inhibitor of Notch signaling) confirmed the essential role of Notch-induced Hes1 expression in promoting invasion of osteosarcoma cells. Here, we identify the interaction of Hes1 and Deltex1. In one osteosarcoma cell line COL, which high endogenous Deltex1, γ-secretase inhibitor-mediated blockade of Notch did not reduce matrigel invasion, and did not suppress Hes1 expression. Genetic blockade of Notch signaling with dnMAM decreased Deltex1 expression, and increased Hes1 expression, promoting invasiveness of COL cells. This suggested that Deltex1 is a negative regulator of Hes1 expression. The inhibition of Hes1 expression by Deltex1 is also observed in other osteosarcoma cells. Meanwhile, overexpression of Hes1 in COL cells decreased Deltex1 expression, suggesting Hes1 acts as a direct inhibitor of Deltex1 expression. Other Notch downstream target genes, including Hes5 and Herp2, did not consistently alter their expression with transduction of either Hes1 or Deltex1, suggesting Hes5 and Herp2 are not regulated by Hes1 or Deltex1 in osteosarcoma. Our data demonstrate that Hes1 and Deltex1 can inhibit each other and control invasiveness in osteosarcoma. These studies also identify a novel mechanism for regulation of Notch signaling in osteosarcoma. Since Notch pathway inhibitors are under evaluation in clinical trails for human cancer, our work may have important implications for prediction of which patients are at increased risk for metastasis and might benefit from γ-secretase inhibitor treatment.