tbuckley/cabot-search huggingface dataset:
Preoperative infusional 5-FU and sorafenib with external radiation therapy in locally advanced rectal cancer: Results of a phase I study.
Authors: Gopi Kesaria Prithviraj, Kun Jiang, Xiuhua Zhao, Dung-Tsa Chen, Tiffany Campos, Ravi Shridhar, Sarah E. Hoffe, Khaldoun Almhanna, David Shibata, Richard D. Kim
Journal: Journal of Clinical Oncology (2015)

683 Background: The standard of care in locally advanced rectal cancer (T3, T4, or N1) is preoperative treatment with fluoropyrimidine-based chemotherapy. Sorafenib works synergistically with radiation (RT), and inhibits ras/raf, PDFGR and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-FU and RT in patients with locally advanced rectal cancer. Methods: Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD. A 3+3 dose escalation design was used. RT was given in 25 fractions at 1.8Gy (45 Gy) day 1-5 at all dose levels. 6-10 weeks following neoadjuvant therapy, patients underwent surgery. Results: 17 patients were enrolled at Moffitt Cancer Center, including 10 females and 7 maleswith a median age of 54years (range: 31-72).After observing toxicity in the first cohort (2 patients with G2 and G3 skin toxicity and 1 patient with G2 mucositis) requiring dose interruptions, an amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily.Following this, the primary G3 toxicity was hypertension, in 2 patients at 200 mg adjusted DL (day 1-5) and 1 patient at the 400 mg PO BID DL. 1 patient had G3 ALT elevation at the 400 mg PO BID DL, and no grade IV toxicities were observed. G1 and G2 toxicities included diarrhea, mucositis, nausea, fatigue, proctitis, and thrombocytopenia. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery.The pCR rate was 35.7% and downstaging was observed in 85.7% of patients.KRAS status was available for 12 patients. The pCR was 40% in those with KRASmutant tumors (2/5 pts). Median NAR (neoadjuvant rectal cancer) score was 8.4. Conclusions: This regimen was very well tolerated after changing the dosing schedule. The pCR and downstaging rate is encouraging, and supports further clinical investigation of this regimen. Clinical trial information: NCT01376453. [Table: see text]
Induction of Squamous Cell Carcinoma in the Rat Lung by 1,6-Dinitropyrene2
Authors: Toshiharu Maeda, Keisuke Izumi, Hisashi Otsuka, Yoshiki Manabe, Takemi Kinouchi, Yoshinari Ohnishi
Journal: JNCI Journal of the National Cancer Institute (1986)

The carcinogenicity of 1-nitropyrene [(1-NP) CAS: 5522-43-0] and 1,6-dinitropyrene [(1,6-DNP) CAS: 42397-64-8] was examined by their direct injection in a beeswax-tricaprylin vehicle into the lung of male F344/DuCrj rats. Of 28 rats given 0.15 mg of 1,6-DNP, 21 (75%) developed squamous cell carcinomas, 2 (7%) developed undifferentiated carcinomas, and 2 (7%) had squamous metaplasias in the lung by 72 weeks. In 32 rats that received 1.5 mg of 1-NP, neither carcinoma nor squamous metaplasia was induced. In all 19 rats (100%) given 0.5 mg of 3-methylcholanthrene [(MCA) CAS: 56-49-5], squamous cell carcinomas were induced earlier than in rats treated with 1,6-DNP. In 1 of 31 rats (3%) given the beeswax-tricaprylin vehicle only, squamous metaplasia was induced. Distant metastases of induced tumors were observed in 4 rats treated with 1,6-DNP and in 1 rat receiving MCA. Two lung tumors induced by 1,6-DNP were successively transplanted into the same strain of rats for 3 generations.
Lung Cancer Mortality Trends in Canada, 1931-1960
Authors: E W BEST
Journal: JAMA (1963)

Trends in mortality due to lung cancer in Canada since 1931 were reviewed and data for 1960 presented. In 1960, 2223 male deaths were due to lung cancer. In each five-year age group over 45, there has been a distinct increase in male lung cancer death rates since 1931. The greatest increase occurred between the ages of 65 and 79. The age group 70-74, where the lung cancer mortality rates increased from 10.7 in the period 1931-33 to 173.5 in 1958-60, indicates the trend. Between 1931 and 1960, the proportion of male lung cancer deaths to all male cancer deaths increased from 3% to 18.8%. Female deaths due to lung cancer numbered 321 in 1960. Between 1931 and 1960 the proportion of female lung cancer deaths to all female cancer deaths increased only from 1.4% to 3.2%.
Abstract 12037: Alanine Aminotransferase Levels and Incident Cardiovascular Events
Authors: Paulo H Harada, David E Cohen, Lynda Rose, Paul M Ridker
Journal: Circulation (2014)

Introduction: The relationship between hepatic serum markers within the normal range and cardiovascular risk is uncertain. Hypothesis: Alanine aminotransferase (ALT) levels in normal range predicts cardiovascular risk. Methods: 17,515 men and women free of cardiovascular disease participating in a randomized placebo controlled trial of rosuvastatin 20 mg daily had baseline levels of ALT below the lower limits of normal (<40 IU/L) and were followed prospectively for first ever cardiovascular events. Cox proportional hazards models were used to calculate the relative risks of these events according to increasing tertiles and each standard deviation increase in baseline ALT levels. Results: ALT levels at study entry, all within the normal range, were inversely associated with age, smoking status, and inflammation and were positively associated with male gender, alcohol use, and triglycerides. Incident cardiovascular event rates were highest among those in the lowest tertile of baseline ALT; specifically, inc...
Significant Risk of Life Threatening Infections in Elderly Patients With Inflammatory Bowel Disease Receiving Anti-TNF Therapy
Authors: Ahmad Najib Azmi, Way-Seah Lee, Ruey Terng Ng, Sik-Yong Ong, Sanjiv Mahadeva, Khean-Lee Goh, Ida Hilmi
Journal: Clinical Gastroenterology and Hepatology (2015)
H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis
Authors: Woo-Yong Park, Beom-Jin Hong, Jungsul Lee, Chulhee Choi, Mi-Young Kim
Journal: Cancer Research (2016)

Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-κB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C-C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment.
Risk of recurrent stillbirth: systematic review and meta-analysis
Authors: K. Lamont, N. W. Scott, G. T. Jones, S. Bhattacharya
Journal: BMJ (2015)

<b>Objective</b> To determine the risk of recurrent stillbirth. <b>Design</b> Systematic review and meta-analysis of cohort and case-control studies. <b>Data sources</b> Embase, Medline, Cochrane Library, PubMed, CINAHL, and Scopus searched systematically with no restrictions on date, publication, or language to identify relevant studies. Supplementary efforts included searching relevant internet resources as well as hand searching the reference lists of included studies. Where published information was unclear or inadequate, corresponding authors were contacted for more information. <b>Study selection</b> Cohort and case-control studies from high income countries were potentially eligible if they investigated the association between stillbirth in an initial pregnancy and risk of stillbirth in a subsequent pregnancy. Stillbirth was defined as fetal death occurring at more than 20 weeks’ gestation or a birth weight of at least 400 g. Two reviewers independently screened titles to identify eligible studies based on inclusion and exclusion criteria agreed a priori, extracted data, and assessed the methodological quality using scoring criteria from the critical appraisal skills programme. Random effects meta-analyses were used to combine the results of the included studies. Subgroup analysis was performed on studies that examined unexplained stillbirth. <b>Results</b> 13 cohort studies and three case-control studies met the inclusion criteria and were included in the meta-analysis. Data were available on 3 412 079 women with pregnancies beyond 20 weeks duration, of who 3 387 538 (99.3%) had had a previous live birth and 24 541 (0.7%) a stillbirth. A total of 14 283 stillbirths occurred in subsequent pregnancies, 606/24 541 (2.5%) in women with a history of stillbirth and 13 677/3 387 538 (0.4%) among women with no such history (pooled odds ratio 4.83, 95% confidence interval 3.77 to 6.18). 12 studies specifically assessed the risk of stillbirth in second pregnancies. Compared with women who had a live birth in their first pregnancy, those who experienced a stillbirth were almost five times more likely to experience a stillbirth in their second pregnancy (odds ratio 4.77, 95% confidence interval 3.70 to 6.15). The pooled odds ratio using the adjusted effect measures from the primary studies was 3.38 (95% confidence interval 2.61 to 4.38). Four studies examined the risk of recurrent unexplained stillbirth. Methodological differences between these studies precluded pooling the results. <b>Conclusions</b> The risk of stillbirth in subsequent pregnancies is higher in women who experience a stillbirth in their first pregnancy. This increased risk remained after adjusted analysis. Evidence surrounding the recurrence risk of unexplained stillbirth remains controversial.
Risk assessment for percutaneous coronary intervention: our version of the weather report?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Donald E Cutlip, Kalon K.L Ho, Richard E Kuntz, Donald S Baim
Journal: Journal of the American College of Cardiology (2003)
Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection
Authors: Anita Kohli, Sarah Kattakuzhy, Sreetha Sidharthan, Amy Nelson, Mary McLaughlin, Cassie Seamon, Eleanor Wilson, Eric G. Meissner, Zayani Sims, Rachel Silk, Chloe Gross, Elizabeth Akoth, Lydia Tang, Angie Price, Tim A. Jolley, Benjamin Emmanuel, Michael Proschan, Gebeyehu Teferi, Jose Chavez, Stephen Abbott, Anuoluwapo Osinusi, Hongmei Mo, Michael A. Polis, Henry Masur, Shyam Kottilil
Journal: Annals of Internal Medicine (2015)

Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs.
Progression after AKI
Authors: David P. Basile, Joseph V. Bonventre, Ravindra Mehta, Masaomi Nangaku, Robert Unwin, Mitchell H. Rosner, John A. Kellum, Claudio Ronco
Journal: Journal of the American Society of Nephrology (2015)

Recent clinical studies indicate a strong link between AKI and progression of CKD. The increasing prevalence of AKI must compel the nephrology community to consider the long-term ramifications of this syndrome. Considerable gaps in knowledge exist regarding the connection between AKI and CKD. The 13th Acute Dialysis Quality Initiative meeting entitled "Therapeutic Targets of Human Acute Kidney Injury: Harmonizing Human and Experimental Animal Acute Kidney Injury" convened in April of 2014 and assigned a working group to focus on issues related to progression after AKI. This article provides a summary of the key conclusions and recommendations of the group, including an emphasis on terminology related to injury and repair processes for both clinical and preclinical studies, elucidation of pathophysiologic alterations of AKI, identification of potential treatment strategies, identification of patients predisposed to progression, and potential management strategies.
Aging and Defective Healing, Adverse Remodeling, and Blunted Post-Conditioning in the Reperfused Wounded Heart⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Bodh I. Jugdutt, Anwar Jelani
Journal: Journal of the American College of Cardiology (2008)
A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape via cooperation between BAF and p63
Authors: Xiaomin Bao, Adam J. Rubin, Kun Qu, Jiajing Zhang, Paul G. Giresi, Howard Y. Chang, Paul A. Khavari
Journal: Genome biology (2015)

Open chromatin regions are correlated with active regulatory elements in development and are dysregulated in diseases. The BAF (SWI/SNF) complex is essential for development, and has been demonstrated to remodel reconstituted chromatin in vitro and to control the accessibility of a few individual regions in vivo. However, it remains unclear where and how BAF controls the open chromatin landscape to regulate developmental processes, such as human epidermal differentiation. Using a novel "on-plate" ATAC-sequencing approach for profiling open chromatin landscapes with a low number of adherent cells, we demonstrate that the BAF complex is essential for maintaining 11.6 % of open chromatin regions in epidermal differentiation. These BAF-dependent open chromatin regions are highly cell-type-specific and are strongly enriched for binding sites for p63, a master epidermal transcription factor. The DNA sequences of p63 binding sites intrinsically favor nucleosome formation and are inaccessible in other cell types without p63 to prevent ectopic activation. In epidermal cells, BAF and p63 mutually recruit each other to maintain 14,853 open chromatin regions. We further demonstrate that BAF and p63 cooperatively position nucleosomes away from p63 binding sites and recruit transcriptional machinery to control tissue differentiation. BAF displays high specificity in controlling the open chromatin landscape during epidermal differentiation by cooperating with the master transcription factor p63 to maintain lineage-specific open chromatin regions.
Inhibition of the insulin like growth factor 1 receptor by a specific monoclonal antibody in multiple myeloma
Authors: A. Gualberto, M. Alsina, M. Lacy, S. Poutney, A. Birgin, B. Littman, C. Melvin, J. Petersen
Journal: Journal of Clinical Oncology (2005)

3048 Background: The Insulin Like Growth Factor 1 Receptor (IGF-1R) plays a key role in multiple myeloma (MM). IGF-1 is a growth factor for MM cells. It promotes plasma cell survival to chemotherapy and its blood levels correlate with those of paraprotein. CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of the autophosphorylation of IGF-1R. CP-751,871 induces ligand blockade and receptor internalization. Based on its mechanism of action and the relevance of IGF-1 in MM, CP-751,871 constitutes a potential novel therapeutic approach for this disease. In order to monitor the biological activity of CP-751,871 in myeloma patients, a pharmacodynamic assay to quantify the surface expression of IGF-1R on WBC was developed. A clinical methodology study was conducted to determine the performance specifications of imprecision and reportable range, as well as the intra-patient variability of the procedure on circulating tumor plasma cells and granulocytes of MM patients. Methods: Following informed consent, 12 myeloma patients were enrolled. Patients underwent two 5-replicate blood draws on days 1 and 2. D2 samples were spiked with increasing concentrations of CP-751,871. FACS IGF-1R determinations were performed on multiple myeloma cells and granulocytes assessing CD38, CD45 and IGF-1R simultaneously, as well as forward and side light- scatter characteristics. BD-Pharmingen 1H7-PE conjugated R-Phycoerythrin was employed as anti-IGF-1R analytical antibody. FACS data were normalized to MESF units. Results: 113 samples were analysed. MESF ranges were 214–24,001 for multiple myeloma cells and 1691–9582 for granulocytes. No 1H7-PE/CP-751,871 interference was detected. The granulocyte assay was found to be the most precise, with a median within-a-run imprecision and 24 h-variability of 7% and 12%, respectively (significant RCV = 37%). Higher than 50% IGF-1R downregulation was observed at CP-751,871 concentrations ≥ 0.03 microg/mL in both cell types. Conclusions: These results demonstrated that CP-751,871 effectively downregulates IGF-1R expression on MM cells, and that IGF-1R FACS is a reliable pharmacodynamic marker of the biological activity of CP-751,871. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Epidemic Malaria Transmission--Armenia, 1997
Journal: JAMA (1998)

In 1994 the Ministry of Health of Armenia detected the first locally acquired case of malaria since the 1940s.  While no locally acquired cases were reported in 1995 the number of imported cases increased to 502 compared to the 15 total imported cases reported during 1986-89.  In 1996 and 1997 the total number of reported cases of malaria were 347 and 841 respectively.  This report summarizes surveillance for malaria in Armenia during 1996-97.  Cases initially identified based upon clinical suspicion were subsequently confirmed through the microscopic examination of blood samples at the national laboratory.  All cases were caused by Plasmodium vivax.  From 1996 to 1997 the incidence rate for all reported cases of malaria increased from 9 to 22 per 100000 population.  Locally acquired cases accounted for 567 (67%) of the 841 cases reported in 1997.  While 30 (37%) of 81 districts recorded malaria cases only 7 (9%) reported locally acquired infections with the seasonal peak for these latter cases occurring in September.  Anopheles maculipennis was the vector species captured 98% of the time using standard trapping procedures.
A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation
Authors: Sally Arai, Joseph Pidala, Iskra Pusic, Xiaoyu Chai, Samantha Jaglowski, Nandita Khera, Jeanne Palmer, George L. Chen, Madan H. Jagasia, Sebastian A. Mayer, William A. Wood, Michael Green, Teresa S. Hyun, Yoshihiro Inamoto, Barry E. Storer, David B. Miklos, Howard M. Shulman, Paul J. Martin, Stefanie Sarantopoulos, Stephanie J. Lee, Mary E.D. Flowers
Journal: Clinical Cancer Research (2015)

Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.
Dasatinib sensitizes chronic lymphocytic leukemia lymphocytes to chemotherapeutic agents
Authors: Anne-Christine Goulet, Lilian Amrein, Michael Dunn, Raquel Aloyz, Lawrence Panasci
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4753 

B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. CLL is characterized by the accumulation in the blood of affected patients of mature quiescent B-lymphocytes. At an early stage of the disease, B-lymphocyte accumulation occurs likely as a consequence of an undefined defect in the apoptotic machinery rather than an increased proliferation of leukemic cells. While the patients often initially respond to conventional treatment with chlorambucil or fludarabine they eventually become resistant to the drugs. De novo and acquired resistance to chemotherapy in CLL have been associated with alterations in apoptosis mediated by the presence of p53 mutations, alterations in the expression of anti-apoptotic factors and/or pro-apoptotic factors and altered DNA repair (alterations in the Rad51-related homologous recombinational pathway and the non homologous endjoining DNA repair pathway).

Recently we have shown that inhibition of DNA repair sensitize CLL lymphocytes from treated and untreated patients to chlorambucil and fludarabine, using these drugs in combination with the c-abl inhibitor, Gleevec (Imatinib). Here we report that in vitro the c-abl/src kinase inhibitor Dasatinib: (1) is toxic to CLL lymphocytes and (2) when used at sublethal concentrations sensitizes CLL lymphocytes to chlorambucil and fludarabine. We assess the effect of the drugs alone or in combination using the MTT assay 72 hours after treatment in purified lymphocytes from 30 treated and untreated CLL patients. Dasatinib IC50 ranged from 0.03 to 80 μM. In all cases, when used at sublethal concentrations, Dasatinib sensitized CLL-lymphocytes to chlorambucil and fludarabine irrespectively of the clinical status of the patients. Our results using western blot and flow cytometry analysis with specific antibodies against phospho-Lyn and phospho-c-abl suggest that the effect of Dasatinib on CLL-lymphocytes survival, when used alone or in combination with chlorambucil or fludarabine, is mediated through the inhibition of those kinases. Moreover, Dasatinib specifically inhibits the repair of chlorambucil-induced DNA damage through the inhibition of c-abl kinase.