tbuckley/cabot-search huggingface dataset:
Reducing the Global Burden of Cardiovascular Disease, Part 1
Authors: Philip Joseph, Darryl Leong, Martin McKee, Sonia S. Anand, Jon-David Schwalm, Koon Teo, Andrew Mente, Salim Yusuf
Journal: Circulation Research (2017)

Current global health policy goals include a 25% reduction in premature mortality from noncommunicable diseases by 2025. In this 2-part review, we provide an overview of the current epidemiological data on cardiovascular diseases (CVD), its risk factors, and describe strategies aimed at reducing its burden. In part 1, we examine the global epidemiology of cardiac conditions that have the greatest impact on CVD mortality; the predominant risk factors; and the impact of upstream, societal health determinants (eg, environmental factors, health policy, and health systems) on CVD. Although age-standardized mortality from CVD has decreased in many regions of the world, the absolute number of deaths continues to increase, with the majority now occurring in middle- and low-income countries. It is evident that multiple factors are causally related to CVD, including traditional individual level risk factors (mainly tobacco use, lipids, and elevated blood pressure) and societal level health determinants (eg, health systems, health policies, and barriers to CVD prevention and care). Both individual and societal risk factors vary considerably between different regions of the world and economic settings. However, reliable data to estimate CVD burden are lacking in many regions of the world, which hampers the establishment of nationwide prevention and management strategies. A 25% reduction in premature CVD mortality globally is feasible but will require better implementation of evidence-based policies (particularly tobacco control) and integrated health systems strategies that improve CVD prevention and management. In addition, there is a need for better health information to monitor progress and guide health policy decisions.
Online biomarker validation of survival-associated biomarkers in breast and ovarian cancer using microarray data of 3,862 patients.
Authors: Balazs Gyorffy, Andras Lanczky, Zoltan Szallasi
Journal: Journal of Clinical Oncology (2012)

10571 Background: The pre-clinical validation of prognostic gene candidates in large independent patient cohorts is a pre-requisite for the development of robust biomarkers. Today, curated microarray cohorts combined with appropriate clinical data offer a cost effective tool to prescreen potential new biomarkers. In present study we expanded our online Kaplan-Meier plotter tool to assess the effect of genes on ovarian cancer prognosis. Methods: Gene expression data and survival information of breast and ovarian cancer patients were downloaded from GEO and TCGA. To analyze the prognostic value of the selected gene in the various cohorts the patients are divided into two groups according to the quantile expression of the gene. Filtering is implemented for stage, grade, and histology subtypes. Follow-up threshold is implemented to exclude long-term effects. A Kaplan-Meier survival plot is generated and significance is computed in the R statistical environment using Bioconductor packages. The combination of several probe sets can be employed to assess the mean of their expression as a multigene predictor of survival. Results: All together 1,390 ovarian cancer patients and 2,472 breast cancer patients were entered into the database. These groups can be compared using relapse free survival (n=2,324 in breast cancer and 1,090 in ovarian cancer) or overall survival (n=464 and n=1,287). We used this integrative data analysis tool to validate the prognostic power of 37 ovarian cancer associated biomarkers identified in the literature. Of these, CA125 (p=3.7e-5, HR=1.4), CDKN1B (p=5.4e-5, HR=1.4), KLK6 (p=0.002, HR=0.79), IFNG (p=0.004, HR=0.81), P16 (p=0.02, HR=0.66) and BIRC5 (p=0.00017, HR=0.75) were associated with survival. Conclusions: We set up a global online biomarker validation platform to mine all available microarray data to assess the prognostic power of 22,277 genes in 2,472 breast and 1,390 ovarian cancer patients. Registration-free online access at: http://www.kmplot.com/.
In vitro and in vivo efficacy and toxicity comparison between ApoGossypol and Gossypol, Bcl-2 antagonists
Authors: Shinichi Kitada, Jun Wei, Christina Kress, Dayong Zhai, Maryla Krajewska, Lee Jia, Maurizio Pellecchia, John Reed
Journal: Cancer Research (2008)

4387   Altered expression of Bcl-2-family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product (+)Gossypol and its semi-synthetic derivative (+)ApoGossypol and the purified (+) and (-) enantiomers of this compound, All of these compounds were shown to bind anti-apoptotic Bcl-2-family proteins with similar affinities, based on competitive BH3 peptide displacement assays and NMR-based chemical shift mapping experiments. Comparisons of growth inhibitory and cytotoxic activity of (+)Gossypol and (+)ApoGossypol using the NCI panel of 60 tumor cell lines, as well as cultured lymphoma cell lines and primary leukemia cells suggested that Gossypol and ApoGossypol have overlapping but non-identical cytotoxic mechanisms. Daily oral dosing studies showed that mice tolerate doses of ApoGossypol 2-4-times higher than Gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of Gossypol, with ApoGossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is over-expressed in B-cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2-expressing B-cells from transgenic mice were more sensitive to cytotoxicity induced by ApoGossypol than Gossypol, with LD50 values of 3-5 µM and 7.5-10 µM, respectively. In vivo, using the maximum tolerated dose of Gossypol (60 µmoles/kg) for sequential daily dosing (daily x 5 days x 3 weeks), ApoGossypol displayed superior activity to Gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2 transgenic mice. At higher doses (120 µmole/kg), at which ApoGossypol but not Gossypol is tolerated, ApoGossypol showed even greater in vivo activity, reducing spleen weight by 40 ± 14% (p
Airway Mucins in Chronic Obstructive Pulmonary Disease
Authors: Jadwiga A. Wedzicha
Journal: New England Journal of Medicine (2017)

Chronic bronchitis, also known as chronic mucus hypersecretion, is common in cigarette smokers and is a key component of chronic obstructive pulmonary disease (COPD). After the publication of the seminal study by Fletcher and Peto in the 1970s,1 chronic bronchitis was recognized as being associated with cigarette smoking and conferring a predisposition to lower respiratory infections, but was reported as not influencing the progressive airway obstruction that is characteristic of COPD.2 However, a number of later studies showed that chronic bronchitis was indeed not a benign feature of COPD and was clearly linked to disease progression, hospital admission, and mortality.3 . . .
in vitroおよびin vivoでの評価を用いた3次元(3D)印刷を用いた軟部組織再建のための絹に基づくbioinks【Powered by NICT】
Authors: J Rodriguez Maria, Brown Joseph, Giordano Jodie, J Lin Samuel, G Omenetto Fiorenzo, L Kaplan David
Journal: Biomaterials (2017)
STARTRK-1: Phase 1/2a study of entrectinib, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.
Authors: Manish R. Patel, Todd Michael Bauer, Stephen V. Liu, Alexander E. Drilon, Jennifer J. Wheler, Alice Tsang Shaw, Anna F. Farago, Sai-Hong Ignatius Ou, David Luo, Litain Yeh, Zachary Hornby, Adrian Mario Senderowicz, Jonathan Lim
Journal: Journal of Clinical Oncology (2015)

2596 Background: Entrectinib (formerly RXDX-101), a potent and selective small molecule inhibitor of TrkA/B/C, ROS1, and ALK kinases, has demonstrated early clinical activity when orally administered intermittently under fasting conditions (ASCO 2014). In this abstract, we report a companion Phase 1/2a trial of entrectinib administered daily in the fed state. Methods: Pts with advanced solid tumors with molecular alterations in NTRK1/2/3, ROS1 or ALK were treated daily with entrectinib in the fed state. Pts with asymptomatic untreated brain metastases were allowed; pts may have received prior TKI therapy. Endpoints include safety, RP2D, PK, and tumor response Results: Entrectinib was well tolerated across all dose levels. No DLTs or significant safety issues were reported from any cohort. Of 15 pts treated, the majority reported only G1 or G2 AEs. 3 pts reported > G3 AEs (each unrelated to entrectinib). 1 SAE (unrelated) has been reported. Entrectinib was readily absorbed with median Tmax of 4 hr at steady state. Steady state was reached within 7 days of dosing and the estimated t1/2 was approximately 17 hrs. There were dose proportional exposure increases with moderate accumulation (~2x or less) at steady state. 15 pts with various molecular alterations identified by local lab testing were treated in the following dose cohorts (mg/m2): 100 (N = 5), 200 (N = 5), 400 (N = 5). Summary of alterations of enrolled pts: NTRK (point mutation = 5; amplification = 1; rearrangement = 1); ROS1 (SNP = 1); ALK (SNP = 2; ampl = 1; rearr = 4). 3 pts with ALK-rearranged NSCLC failed at least 2 prior ALK inhibitors. No pts with ROS1 rearrangements have been treated. No objective responses observed to date. Conclusions: Entrectinib, administered daily in fed condition, is well tolerated. In STARTRK-1, there have been no responses at doses ≤ 200 mg/m2 (400 mg/m2 cohort recently opened). Doses ≥ 400 mg/m2 were associated with responses in the ALKA-372-001 Phase 1 study. Dose escalation will continue until the RP2D is identified. Thereafter, Phase 2a cohort expansion will begin enrolling pts with NTRK1/2/3, ROS1, or ALK molecular alterations to assess antitumor activity. Clinical trial information: NCT02097810.
JAVELIN head and neck 100: A phase 3 trial of avelumab in combination with chemoradiotherapy (CRT) vs CRT for 1st-line treatment of locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Nancy Y. Lee, Robert L. Ferris, J. Thaddeus Beck, Kevin Harrington, Robert I. Haddad, Jean Bourhis, Makoto Tahara, Margarida Geraldes, Dimitry S. A. Nuyten, Zelanna Goldberg, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2017)

TPS6093 Background: Cisplatin + radiotherapy is a standard-of-care treatment for patients (pts) with LA SCCHN. Combining avelumab (fully human IgG1 anti–PD-L1 antibody) and CRT may synergistically activate multiple immune-mediated mechanisms to effect a robust and durable antitumor response and improve long-term disease control. Methods: JAVELIN Head and Neck 100 (NCT02952586) is a global, multicenter, randomized, double-blind, phase 3 trial of avelumab + cisplatin-based CRT vs placebo + CRT as 1st-line treatment for pts with LA SCCHN. The primary objective is to demonstrate superiority of avelumab + CRT in prolonging progression-free survival (PFS) vs CRT alone. Eligible pts have LA SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx; HPV− or non-oropharyngeal HPV+ disease of stage III, IVa, or IVb; or HPV+ oropharyngeal disease T4, N2c, or N3. Pts must be candidates for cisplatin-based CRT. Other eligibility criteria include ECOG PS ≤1 and no prior systemic treatment for advanced disease. Approximately 640 pts will be randomized 1:1 to receive avelumab 10 mg/kg (1-hour IV) + CRT (intensity-modulated RT [70 Gy/35 fractions] + cisplatin 100 mg/m 2 [x3]) or placebo + CRT. There will be 3 treatment phases: lead-in (single dose of avelumab or placebo), CRT (concurrent avelumab or placebo + CRT for 7 weeks), and maintenance (avelumab or placebo Q2W for 12 months). The rationale for this design is to induce an immune response during lead-in and CRT phases, followed by maintenance treatment to prolong and support immune memory development. The primary endpoint is PFS per modified RECIST v1.1. Secondary efficacy endpoints include overall survival, objective response, locoregional failure, distant metastatic failure, and duration of response. Other endpoints include safety, pharmacokinetics, immunogenicity, pt-reported outcomes, and biomarker assessments. Treatment will continue for 12 months following initiation of the maintenance phase or until progressive disease, unacceptable toxicity, or any other protocol-defined criterion for withdrawal occurs. Enrollment in this phase 3 trial began in November 2016. Clinical trial information: NCT02952586.
Diagnostic Challenge of Staging Metastatic Bone Disease in the Morbidly Obese Patients
Authors: Sharjeel Usmani, Fahad Marafi, Najeeb Ahmed, Abdulredha Esmail, Fareeda Al Kandari, Tim Van den Wyngaert
Journal: Clinical Nuclear Medicine (2017)

Purpose Optimizing diagnostic imaging may be challenging in obese patients. The quality of conventional bone scintigraphy can be poor in the morbidly obese due to a combination of factors including high background soft tissue activity. In comparison, sodium fluoride ( 18 F-NaF PET-CT) has a better target-to-background ratio attributed to rapid single-pass extraction and fast clearance from the soft tissues. The aim of the present study is to assess the diagnostic efficacy of 18 F-NaF PET-CT in the evaluation of bone metastases in obese cancer patients. Patients and Methods Two hundred twelve morbidly obese patients (body mass index, 45 ± 5.1 kg/m 2 ; mean age, 57 years; range, 32–81 years) with body mass index greater than 40 kg/m 2 referred for NaF PET-CT for osseous staging of malignancy were retrospectively analyzed. All patients underwent PET-CT scan by injecting 2.2 MBq/kg (0.06 mCi/kg) of 18 F-NaF. Results 18 F-NaF PET-CT was definitely benign in 145, possibly benign in 3, equivocal in 4, possibly malignant in 13, and definitely malignant in 47 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18 F-NaF PET-CT were 93.1%, 96.1%, 90%, 97.3%, and 95.2%, respectively (95% confidence interval). Conclusions The results of the present study indicate that 18 F-NaF PET-CT retains its high diagnostic accuracy in morbidly obese patients and, by inference, can be a preferred functional modality in these patients.
Identification of GSK461364, a novel small molecule polo-like kinase 1 inhibitor for the treatment of cancer
Authors: Kevin Kuntz, James Salovich, Robert Mook, Kyle Emmitte, Stanley Chamberlain, Tara Rheault, Keith Hornberger, Holly Emerson, Stephon Smith, Brian Wilson, Ronda Davis-Ward, Kelly Donaldson, George Adjabeng, Kristen Nailor, Daniel Hassler, Gary Smith, Timothy Lansing, Derek Duckett, Victoria Knick, Randy McConnell, Jeffrey Jackson, Mui Cheung
Journal: Cancer Research (2007)

4171   Polo-like kinase 1 (Plk1) plays an important role in the entry to, progression through, and exit from mitosis. The multiple roles Plk1 plays in mitosis make it an intriguing target to inhibit to disrupt the cell cycle and treat cancer. This presentation will highlight the lead optimization studies and elucidation of the structure-activity relationship leading to the identification of a novel thiophene amide Plk1 inhibitor. It will include the synthesis of a Plk-selective inhibitor, in addition to optimization of potency and developability characteristics through several iterations of structural changes, culminating in the identification of the clinical candidate. These efforts led to the development of GSK461364, an extremely potent Plk1 inhibitor (IC 50  ~3 nM) with greater than 100-fold selectivity across a panel of 47 other kinases. It also potently inhibits the proliferation of many tumor cell lines  in vitro , shows  in vivo  activity in tumor xenograft mouse models, and has appropriate physical and pharmacokinetic characteristics to support further evaluation as an anticancer agent.
Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections
Authors: Roy W. Beck, Tonya D. Riddlesworth, Katrina Ruedy, Andrew Ahmann, Stacie Haller, Davida Kruger, Janet B. McGill, William Polonsky, David Price, Stephen Aronoff, Ronnie Aronson, Elena Toschi, Craig Kollman, Richard Bergenstal
Journal: Annals of Internal Medicine (2017)

Background: Continuous glucose monitoring (CGM), which studies have shown is beneficial for adults with type 1 diabetes, has not been well-evaluated in those with type 2 diabetes receiving insulin. Objective: To determine the effectiveness of CGM in adults with type 2 diabetes receiving multiple daily injections of insulin. Design: Randomized clinical trial. (The protocol also included a type 1 diabetes cohort in a parallel trial and subsequent second trial.) (ClinicalTrials.gov: NCT02282397) Setting: 25 endocrinology practices in North America. Patients: 158 adults who had had type 2 diabetes for a median of 17 years (interquartile range, 11 to 23 years). Participants were aged 35 to 79 years (mean, 60 years [SD, 10]), were receiving multiple daily injections of insulin, and had hemoglobin A1c (HbA1c) levels of 7.5% to 9.9% (mean, 8.5%). Intervention: Random assignment to CGM (n = 79) or usual care (control group, n = 79). Measurements: The primary outcome was HbA1c reduction at 24 weeks. Results: Mean HbA1c levels decreased to 7.7% in the CGM group and 8.0% in the control group at 24 weeks (adjusted difference in mean change, −0.3% [95% CI, −0.5% to 0.0%]; P = 0.022). The groups did not differ meaningfully in CGM-measured hypoglycemia or quality-of-life outcomes. The CGM group averaged 6.7 days (SD, 0.9) of CGM use per week. Limitation: 6-month follow-up. Conclusion: A high percentage of adults who received multiple daily insulin injections for type 2 diabetes used CGM on a daily or near-daily basis for 24 weeks and had improved glycemic control. Because few insulin-treated patients with type 2 diabetes currently use CGM, these results support an additional management method that may benefit these patients. Primary Funding Source: Dexcom.
チクングニヤウイルスエンベロープを持つ偽型レンチウイルスベクターによる星状細胞とニューロンのCNS亜集団の選択的伝達【Powered by NICT】
Authors: Eleftheriadou Ioanna, Dieringer Michael, Poh Xuan Ying, Sanchez-Garrido Julia, Gao Yunan, Sgourou Argyro, E Simmons Laura, D Mazarakis Nicholas
Journal: Biomaterials (2017)
Effect of BL-8040, high-affinity CXCR4 antagonist, on T-cell infiltration, tumor growth, and synergy with immunomodulatory agents.
Authors: Michal Abraham, Inbal Mishalian, Yaniv Harel, Shiri Klein, Yaron Pereg, Galia Oberkovitz, Hanna Wald, Orly Eizenberg, Baruch Bulvik, Abi Vainstein Haras, Arnon Aharon, Amnon Peled
Journal: Journal of Clinical Oncology (2017)

e14544 Background: Cancer cells affect their micro-environment by recruiting immune cells that support tumor growth, metastasis and inhibition of anti-tumor effector T and NK cell recruitment. In this study, we investigated the role of BL-8040, a CXCR4 antagonist in cancer immunotherapy and its ability to modulate the immunosuppressive tumor micro-environment. Methods: The effect of BL8040 on tumor micro-environment was tested in 3 different cancer mouse models: lung cancer, pancreatic cancer and melanoma. The mobilization of immune cells to the periphery in response to BL8040 was tested, as well as the accumulation of immune cells both within and surrounding the tumor in the pancreatic cancer mouse model. Results: BL8040 was found to be a potent and robust mobilizer of immune cells. Immunophenotyping of the mobilized cells revealed that the mobilization of CD4 and CD8 T lymphocytes, as well as of dendritic cells (DC), was significantly increased in the cancer-bearing mice compared to their naïve counterparts. Importantly, a significant mobilization of effector CD8 T cells and activated CD8 T cells in the cancer-bearing mice was also detected following BL8040 treatment. Concomitantly, in the pancreatic cancer mouse model, treatment with BL8040 increased CD8 T cell accumulation within the tumor and inhibited tumor growth. Conclusions: The immune cell population that is mobilized in response to BL8040 treatment is different in cancer mouse models and naïve mice. The ability of BL8040 to induce mobilization of leukocytes, cytotoxic and activated CD8 T cells and DCs is affected by the presence of a tumor. In our models of pancreatic cancer, mobilization of immune cells from the bone marrow into the circulation and their accumulation within the tumor and tumor microenvironment resulted in inhibition of tumor growth. These results indicate that BL8040 may affect the tumor microenvironment and therefore can potentially synergize with immunomodulatory agents. In vivo pre-clinical studies as well as clinical studies are currently ongoing for testing the combination of BL8040 with immunomodulatory agents in different cancer models.
The Methylcytosine Dioxygenase TET3 Is Aberrantly Expressed in Acute Myeloid Leukemia and Promotes AML Growth
Authors: Alex Pulikkottil Jose, Fabian Mohr, Shiva Bamezai, Holzmann Karlheinz, Ursula Kohlhofer, Leticia Quintanilla-Martinez Fend, Tadafumi Iino, Koichi Akashi, Konstanze Döhner, Hartmut Döhner, Michaela Feuring-Buske, Christian Buske, Vijay P.S. Rawat
Journal: Blood (2016)
The roles of mammalian target of rapamycin (mTOR) and p21 in the autophagy pathway after DNA mismatch repair processing of 6-thioguanine
Authors: Xuehuo Zeng, Tao Yan, Timothy Kinsella
Journal: Cancer Research (2007)

2761  DNA mismatch repair (MMR) proteins play an important role in repairing mismatches caused by DNA polymerase errors during DNA replication. The MMR system also provokes both checkpoint and apoptotic responses following certain types of DNA damage. Our previous studies have shown that MMR also initiates an autophagic response to 6-thioguanine (6-TG), a DNA modifying chemical, in a p53 dependent manner. p21 is a known transcription target gene of p53 while mammalian target of rapamycin (mTOR) has been reported to regulate p21 translation in response to some types of DNA damage including intrastrand crosslinking agents such as cisplatin. In this study, we further explore the potential roles of mTOR and p21 in the autophagic signaling pathway downstream of MMR and p53 after exposure to 6-TG. We treated human colon cancer HCT116 cells stably transfected with MLH1 expression vectors (MLH1+, MMR+) with both 6-TG and rapamycin. Without affecting 6-TG-induced p53 activation, rapamycin cotreatment very dramatically inhibits mTOR activity as measured by immunoblotting with an antibody against Thr-389-phosphorylatedp70 S6 kinase (p70S6K), the main active phosphoform of the mTOReffector p70S6K. This chemical inhibition of mTOR activity completely abrogates the up-regulation of p21 protein levels following exposure to 6-TG. These results indicate that mTOR is involved in regulating p21 translation following MMR processing of 6-TG since p53 activation, a positive regulator of p21 transcription, is not affected by the chemical inhibition of mTOR with rapamycin. Furthermore, using immunoblotting with an antibody against LC3 to measure processing of LC3-I to LC3-II, a specific marker for autophagy, we show that the increase in autophagic activity following MMR processing of 6-TG is also inhibited by rapamycin cotreatment, following the same pattern of expression as p21. Since p21 has been shown to function in cell cycle arrest and apoptosis, we speculate that p21 also plays an essential role in the autophagy pathway following MMR processing of 6-TG. Thus, suppression of p21 translation resulting from inhibition of mTOR by rapamycin results in abrogation of induction of autophagy following MMR processing of 6-TG. Experiments using siRNA-mediated silencing of mTOR and p21 are still in progress to further examine the roles of mTOR and p21 in the autophagic signaling pathway. In conclusion, our results suggest that mTOR may regulate p21 translation after p53 activates transcription of p21 and p21 plays an essential role in the autophagy pathway following MMR processing of 6-TG. Supported by NIH grants CA050595 and CA112963 to TJK.