tbuckley/cabot-search huggingface dataset:
MicroRNA-23b Targets Ras GTPase-Activating Protein SH3 Domain-Binding Protein 2 to Alleviate Fibrosis and Albuminuria in Diabetic Nephropathy
Authors: Binghai Zhao, Hongzhi Li, Jieting Liu, Pengfei Han, Chunlei Zhang, He Bai, Xiaohuan Yuan, Xiaoli Wang, Li Li, Hongchuang Ma, Xiudong Jin, Yanhui Chu
Journal: Journal of the American Society of Nephrology (2016)

Diabetic nephropathy (DN) is a frequent and severe complication of diabetes that is structurally characterized by glomerular basement membrane thickening, extracellular matrix accumulation, and destabilization of podocyte foot processes. MicroRNAs (miRNAs) are dysregulated in DN, but identification of the specific miRs involved remains incomplete. Here, we confirm that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of miR-23b compared with those of their nondiabetic counterparts. Furthermore, exposure to high glucose downregulated miR-23b in cultured kidney cells. In contrast, renal expression of Ras GTPase-activating protein SH3 domain-binding protein 2 (G3BP2), a putative miR-23b target, increased in DN. In vitro , overexpression of miR-23b decreased, and inhibition of miR-23b increased, G3BP2 expression levels. Bioinformatics analysis also revealed p53 binding sites in the miR-23b promoter; in vitro inhibition of p53 or the upstream p38 mitogen-activated protein kinase (p38MAPK) upregulated miR-23b expression in high-glucose conditions. In turn, inhibition of G3BP2 or overexpression of miR-23b downregulated p53 and p38MAPK expression in high-glucose conditions. In vivo , overexpression of miR-23b or inhibition of p53 in db / db mice reversed hyperalbuminuria and kidney fibrosis, whereas miR-23b antagomir treatment promoted renal fibrosis and increased albuminuria in wild-type mice. These data suggest that hyperglycemia regulates pathogenic processes in DN through an miR-23b /G3BP2 feedback circuit involving p38MAPK and p53. In conclusion, these results reveal a role for miR-23b in DN and indicate a novel potential therapeutic target.
A phase II study of irinotecan (CPT-11) and carboplatin in patients with previously untreated small cell lung cancer (SCLC): Preliminary results
Authors: M. Amenedo, F. Vázquez, M. Lázaro, J. Casal, J. R. Mel, L. M. Antón, J. L. Fírvida, C. Grande, J. Castellanos, M. Balcells
Journal: Journal of Clinical Oncology (2004)

7286 Background: CPT-11 and Carboplatin have shown activity in SCLC. We are currently evaluating a combination of both drugs in a phase II trial. Methods: Elegible patients include those with a histological or cytological diagnosis of SCLC; no previous chemotherapy for metastatic SCLC; measurable disease; performance status OMS 0–2; life expectancy >3 months; adequate bone marrow, liver, and renal function, and written informed consent. Patients receive carboplatin at AUC of 5 over 2 hours followed by 50 mg/m2 of CPT-11, both on day 1. CPT-11 is readministered at the same dose on days 8 and 15. Chemotherapy cycles are repeated every 28 days for a maximum of 6 cycles. Response is assessed every 3 cycles. Primary endpoints are efficacy and toxicity, and secondary endpoints include time to progression and survival. Results: Of a planned 40 patients, 21 patients have been enrolled to date (males 100%). Of these, 7 were evaluable for response and 16 for toxicity. 149 infusions of CPT-11 have been administered (median 10 infusions, range 2–18). 16 infusions were delayed due to toxicity, primarily hematologic toxicity (75% of delays). In addition, 4 infusions required dose reduction, due to hematologic (50%) and non-hematologic toxicity (50%). Responses have been evaluated in 7 patients. 1 patient showed a complete response (14.29%) and 4 patients a partial response (57.14%). Disease was stabilized in 1 patient (14.3%) and 1 patient showed disease progression (14.3%). 50% of patients presented grade 3–4 toxicity, the most frequent grade 3 - 4 adverse events being: leucopenia (14.3%), neutropenia (14.3%), anemia (4.8%), liver transaminase (9.5%), alcaline phosphatase (9.5%), pulmonary toxicity (9.5%), pain (9.5%), infection (9.5%), asthenia (4.8%), and hemorrhage (4.8%). Conclusions: Preliminary results suggest that this treatment schedule is feasible. Efficacy data are promising but more data are required. The study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Prasfarma/Almirall
Abstract P232: Common Variants of the Estrogen Receptor 1 Gene Predict Decreased Blood Pressure Salt-Sensitivity in Men: The GenSalt Study
Authors: Tanika N Kelly, Casey M Rebholz, Dongfeng Gu, James E Hixson, Dabeeru C Rao, Jie Cao, Jichun Chen, Jianxin Li, Fanghong Lu, Jixiang Ma, Jianjun Mu, Paul K Whelton, Jiang He
Journal: Circulation (2012)

Previous reports have documented increased blood pressure (BP) salt-sensitivity in women compared to men, suggesting that genes encoding sex hormones could influence BP response to sodium. In the current study, we examined the association between 799 single nucleotide polymorphisms (SNPs) in 44 genes involved in sex hormone biosynthesis, bioavailability and metabolism for their association with BP responses to sodium intervention separately in men and women. A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding-study (307.8 mmol sodium/day) was conducted among 1,906 participants from 633 Han Chinese families. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. Additive associations between each SNP and BP responses to low and high-sodium interventions were assessed using a mixed linear regression model to account for familial dependencies. Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453 and rs9383951. For example, men with genotypes C/C, C/T, and T/T of rs9397453 had respective mean DBP responses [95% confidence intervals (CI)] of: -2.67 (-3.13, -2.22), -1.23 (-1.98, -0.48), and 0.08 (-2.31, 2.47) mmHg to low-sodium intervention [p=1×10 -4 ; false discovery rate (FDR)-q=0.04]; and 1.46 (1.03, 1.89), 0.19 (-0.54, 0.91), and -1.10 (-2.82, 0.61) mmHg to high-sodium intervention (p=2×10 -4 ; FDR-q=0.04). In addition, mean SBP responses (95% CI) were: -5.70 (-6.19, -5.20), -4.34 (-5.37, -3.31), and -2.65 (-5.15, -0.16) mmHg, respectively, for low-sodium intervention (p=2×10 -3 ; FDR-q=0.17); and 4.56 (4.12, 4.99), 3.47 (2.63, 4.30), and 1.97 (-0.49, 4.43) mmHg, respectively, for high-sodium intervention (p=3×10 -3 ; FDR-q=0.40). ESR1 variants were not associated with BP responses in women, with highly significant genotype-gender interactions noted. In summary, we identified strong, consistent associations between genetic variants in the ESR1 gene and decreased salt-sensitivity in men. Although replication of these findings is needed, our results support a role for sex-hormones in the etiology of this complex trait. Funding(This research has received full or partial funding support from the American Heart Association, National Center)
Analysis of Human Human Adenovirus Cancer DNA Type&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: J K Mackey, M Green, W S Wold, P Rigden
Journal: JNCI Journal of the National Cancer Institute (1979)

We investigated whether human adenovirus type 4 (Ad4) might cause cancer in humans. Cell culture and animal model studies indicated that Ad4-induced human tumors should contain Ad4 DNA sequences. Thus Ad4 DNA was labeled in vitro (sp act, approximately 10(7) 3H counts/min/microgram) and hybridized in liquid phase with DNA extracted from human tumors. No viral sequences were detected in 31 squamous cell carcinomas of the lung, 5 adenocarcinomas of the lung, 4 oat cell carcinomas of the lung, 4 carcinomas of the stomach, 10 carcinomas of the colon, 3 carcinomas of the kidney, 3 carcinomas of the breast, 2 carcinomas of the ovary, and 6 Hodgkin's lymphomas. Reconstruction experiments with added Ad4 DNA indicated that the probe detected about 1 copy of 5% of the Ad4 genome per tumor cell. Therefore, these data were strong evidence (but did not prove) that none of these particular tumors were induced by Ad4.
Abstract 338: p55γ Suppresses VSMC Proliferation and Neointimal Formation
Authors: Chun-Mei Cao, Ning Xie, Yuan Yao, Yan Zhang, Rui-Ping Xiao
Journal: Circulation Research (2014)

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to various vascular diseases, but the factors that maintain VSMCs in a quiescent state remain poor understood. Phosphatidylinositol 3 kinases (PI3Ks) are important protein kinases that regulate vascular cell proliferation, but the biological and pathological functions of p55γ, a regulatory subunit of PI3K, and its regulation in the cardiovascular system are completely unknown. We aimed to determine the relationship between p55γ and vascular proliferation and neointimal formation. In the present study, we have demonstrated that p55γ expression is markedly downregulated in primary cultured VSMCs in response to mitogenic stimulation and in carotid arteries after balloon injury, and that overexpression p55γ profoundly inhibits mitogenic stimuli and injury induced VSMC proliferation as well as neointimal formation. p55γ overexpression inhibited, whereas knockdown of p55γ promoted PDGF-BB- and serum-induced VSMC proliferation. Importantly, in vivo adenoviral gene transfer of p55γ into carotid arteries attenuated, while knockdown of p55γenhanced balloon injury-induced neointimal formation. Furthermore, p55γ sequentially upregulated p53 and p21, resulting in cell-cycle arrest in S phase; knockdown of either p53 or p21 blocked p55γ-induced VSMC growth arrest. Mechanistically, p55γ interacted with and stabilized p53 protein by blocking MDM2-mediated p53 ubiquitination and degradation, subsequently activating its target gene p21. Concurrently, p55γ upregulated Bcl-xl expression, which counterbalanced p53-mediated apoptosis. These findings mark p55γ as a novel upstream regulator of the p53-p21 signaling pathway which negatively regulates VSMC proliferation, suggesting that malfunction of p55γ may trigger vascular proliferative disorders. * Correspondence to Chun-Mei Cao (caochunmei@pku.edu.cn) or Rui-Ping Xiao (xiaor@pku.edu.cn).
Refinement of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) via cognitive interviewing.
Authors: J. Hay, T. M. Atkinson, T. R. Mendoza, B. B. Reeve, G. Willis, J. J. Gagne, A. P. Abernethy, C. S. Cleeland, D. Schrag, E. M. Basch
Journal: Journal of Clinical Oncology (2010)

9060 Background: A patient-reported outcomes (PRO) version of the NCI's Common Terminology Criteria for Adverse Events (CTCAE), is in development under a contract from the NCI (N02-PC-85002-29; PI: Basch). An essential step in refining these PRO items involves cognitive interviews to examine cancer patient comprehension and the extent to which items correspond to concepts of interest. Methods: Using prior research and investigator consensus, we developed item question verbiage, response options, and response scales for 77 adverse events in the CTCAE which have a subjective component amenable to patient self-reporting. Cognitive interviewing probes included comprehension (level of understanding), clarity (level of straightforward meaning), knowledge and memory (ease of recall of information needed to respond), and judgment (ease of fitting personal responses to response options) relating to the following aspects for each of the PROs: question introduction, symptom terms, response scales, verbal anchors, and recall period. Sixty audio-taped and transcribed cognitive interviews were conducted at four study sites with patients undergoing chemotherapy or radiation for advanced cancer. Patients were varied in terms of education (33% ≤ high school); disease site (10 colorectal; 10 ovarian; 6 prostate; 5 breast; 5 lung; 5 bladder, 9 other); were 25% non-Caucasian; and 60% female. Results: Qualitative analysis was done via structural coding. Major comprehension issues were stratified by education level. Major findings were that: 1) patients felt they could recall their “worst” symptom experience over the recall period; 2) patients often did not adhere to the 7-day reference period when answering; 3) some key terms lacked clarity (ex: wheezing); and 4) subjects were confused concerning whether “daily activities” included a full 24-hour time period. Conclusions: Cognitive interviewing represents an important step in refining the PRO-CTCAE so that it will be understood by broad segments of the general population. Cognitive interviews have identified a need for item clarification and have contributed to the content validity of the PRO-CTCAE assessment system. No significant financial relationships to disclose.
French drug trial protocol fails to answer key questions
Authors: Nigel Hawkes
Journal: BMJ (2016)

Details of the drug trial in France in which one man died and others were left with severe health problems have emerged, but there is still no clear evidence of what went wrong.

After Le Figaro published the trial protocol,1 the French national agency for the safety of medicines and health products formally released it. The report revealed the chemical structure of the drug BIA 10-2474, developed by the Portuguese company Bial, and the trial procedure—single administrations of the drug at increasingly higher doses, followed by multiple administrations given on successive days.

Of the six people who …
Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience.
Authors: L W Kwak, M Wilson, L M Weiss, R Doggett, R F Dorfman, R A Warnke, S J Horning
Journal: Journal of Clinical Oncology (1991)

Although previous studies have suggested a relatively poor prognosis for some patients with peripheral T-cell lymphoma, the clinical significance of immunologic phenotype in diffuse large-cell lymphoma (DLCL) remains controversial. One hundred one patients with a uniform morphologic diagnosis of DLCL treated at Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were studied with regard to immunologic phenotype. Immunologic analysis, performed on frozen or paraffin-embedded tissue, identified 77 cases of B-cell origin, 21 cases of T-cell origin, and three cases that lacked B-cell or T-cell markers. Analysis of complete remission (CR) rates (84% v 95%), 5-year actuarial freedom from disease progression (38% v 53%), and 5-year actuarial overall survival (52% v 79%) showed no statistically significant differences in prognosis between B- and T-cell patients, respectively. The 5-year actuarial survival of patients with stage IV T-cell DLCL (56%) also did not differ in a statistically significant way from stage IV B-cell patients (36%). We conclude that treatment selection for DLCL should not be based on immunologic phenotype alone.
Natural history of patients with myelodysplastic syndromes (MDS) with interstitial deletions of chromosome 5q detected on G-banded karyotyping
Authors: S. G. Holtan, R. Santana-Davila, G. Dewald, R. Ketterling, A. Tefferi, D. P. Steensma
Journal: Journal of Clinical Oncology (2007)

7077 Background: MDS includes a heterogenous group of hematopoietic stem cell malignancies characterized by ineffective hematopoiesis and recurring clonal cytogenetic abnormalities with poorly understood functional consequences. Interstitial deletion of chromosome 5 including band q31 is of special interest currently because of the striking effectiveness of lenalidomide therapy in patients with this lesion. Methods: We reviewed the clinical and pathological features of 175 consecutive patients with 5q31 deletions whose final diagnosis was MDS from 1996 to 2006. Patients not meeting the definition of a clonal chromosomal anomaly (i.e., only 1 abnormal metaphase) and those with &gt;20% marrow blasts (now defined as AML) were excluded. Results: The median age at diagnosis was 73 years old (range 8–91). The 5 most common MDS subtypes (WHO classification) were RAEB2 (38 cases), 5q- syndrome (33 cases), MDS NOS (26 cases), RCMD (22 cases), and RAEB1 (20 cases). Chromosomal breakpoints encountered most frequently were q13q33 (86 cases), q15q33 (38 cases), and q22q33 (14 cases). The 5q deletion was present as a sole cytogenetic anomaly in 31%, was present along with one other anomaly in 10%, and was part of complex karyotype in 59%. Median time to death from confirmation of diagnosis at our institution was only 7.2 months (range 1 month –1.8 years). Survival was greatest in those diagnosed with 5q- syndrome, but the median survival time of 1.8 years (p=0.001) was lower than reported in other series. Survival was also superior in women (7.9 months, versus 6.6 months for men, p=0.05) and those with non-complex cytogenetics (1.44 versus 0.41 years, p&lt;0.001). Poorer survival was noted in those with prior chemotherapy (median 6.6 months versus 7.6 months, p=0.01). Differences in breakpoint (p=0.55) and number of metaphases involved with the 5q abnormality (p=0.08) did not have a statistically significant impact on survival. Conclusion: Classic 5q- syndrome as defined by the WHO represents only a minority of MDS patients with interstitial 5q deletions. Although the short survival in our series compared with previous reports may be due in part to referral bias, it is also possible that deletions of chromosome 5q are less benign than previously suspected. No significant financial relationships to disclose.
Differences in Cytotoxic Effects of Activated Murine Peritoneal Macrophages and J774 Monocytic Cells on Metastatic Variants of B16 Melanoma&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: K M Miner, J Klostergaard, G A Granger, G L Nicolson
Journal: JNCI Journal of the National Cancer Institute (1983)

The cytotoxic effects of activated peritoneal macrophages and the J774 reticulum cell sarcoma cell line on B16 melanoma cells of differing metastatic potential were investigated in vitro. The melanoma target cells were sublines of low (B16-F1) or high (B16-F10) lung colonization potential as well as a subline of high (B16-B14b) brain colonization ability. Thioglycolate-elicited peritoneal macrophages from syngeneic C57BL/6 mice and J774 cells were activated in vitro with polyinosinic-polycytidylic acid (poly I:C) and used as effector cells. Macrophage-mediated cytolysis was determined by means of 24- to 72-hour radioactivity release assays with [125I]5-iodo-2'-deoxyuridine-labeled melanoma cells; the results indicated that the more metastatic sublines B16-F10 and B16-B14b were less susceptible to cytolysis by activated macrophages and J774 cells than was the poorly metastatic B16-F1 subline. The poly I:C-activated effector cells also released soluble cytotoxin(s), which resulted in melanoma cell lysis and growth inhibition. Cytotoxin-mediated melanoma cell cytolysis was determined by counting the number of viable mitomycin-treated target cells remaining after a 40-hour incubation period in the absence or presence of various concentrations of cell-released factors, and cytotoxin-mediated cytostasis was performed with the use of the same procedures without mitomycin pretreatment of targets. The factors released from both activated macrophages and J774 cells were more effective against the poorly metastatic B16-F1 cells than against the highly metastatic B16-F10 or B16-F14b cells. In addition, the activity of the factors from both activated effector cells was inhibited by fetal bovine serum. The J774 cells and the activated peritoneal macrophages demonstrated similar activities against B16 melanoma variants, indicating that the J774 cell line may be suitable as a model for the study of macrophage cytotoxicity. The results suggested that the potential of the highly metastatic melanoma cells to implant, survive, and grow at secondary sites may be due, in part, to their ability to circumvent host antitumor mechanisms.
춘계학술대회 : 구연 ; B형간염 : 만성 B형간염환자에서 바이러스 활성도와 간내 cccDNA
Authors: 정우진, 홍윤석, 이현웅, 이정민, 이석근, 이승현, 장병국, 박경식, 조광범, 황재석, 안성훈, 임기조, 서성일
Journal: Clinical and Molecular Hepatology (2007)
A phase II study of Epothilone B analog BMS-247550 (NSC 710428) in patients with relapsed aggressive non-Hodgkin’s lymphomas
Authors: S. M. Smith, B. Pro, K. van Besien, K. Conner, T. Karrison, S. Wong, P. Stiff, E. Vokes
Journal: Journal of Clinical Oncology (2005)

6625 The epothilone B analogs are non-taxane tubulin stabilizing compounds that are active in taxane-resistant and -sensitive preclinical models. BMS-247550 is a semi-synthetic epothilone B analog that has shown activity in phase I trials against the non-Hodgkin's lymphomas (NHL). We report a phase II trial of BMS-247550 in relapsed aggressive NHL. Objectives were overall response rate, toxicity, and overall survival. Eligible pts had relapsed aggressive lymphomas, no baseline neuropathy ≥ grade 1, normal organ and bone marrow function, no active CNS disease, HIV negative status, and WHO performance status 0–2. The treatment regimen consisted of BMS-247550 20 mg/m2 given intravenously over 1 hour on Days 1, 8, and 15 of a 28 day cycle on an outpatient basis. Results: To date, 18 pts have been enrolled at 4 institutions. One pt had rapidly progressive disease and died before completing cycle 1. Of 12 pts with a confirmed histologic subtype, 7 had diffuse large B cell lymphoma, 4 had mantle cell lymphoma, 1 pt had follicular grade 3 lymphoma. The median age was 66 years (range, 46–77 years). All pts were heavily pretreated and at least 3 pts had failed a prior autologous stem cell transplant. 15 pts have received a median of 2 cycles (range, 1–4) of BMS-247550. Of 14 evaluable pts, 2 patients have achieved a PR, 6 have stable disease (SD), and 6 pts have progressed. However, of the pts with radiologic SD, at least one pt has become PET negative and has successfully gone on to receive a matched sibling allogeneic transplant. The median time to progression and the progression-free survival are 108 days, and the overall survival is 399 days. 4 pts have died, and 14 pts remain alive. The main toxicities were hematologic (6 pts with grade 3 or 4 neutropenia) and neurologic (5 pts with grade 3 neuropathy), but all toxicity except for a grade 3 unilateral hearing loss resolved to baseline with cessation of drug. 6 pts had either grade 3 (2 pts) or 4 (4 pts) fatigue. In summary, BMS-247550 shows promising activity in a group of heavily pretreated and elderly pts with relapsed aggressive lymphomas, and warrants ongoing study. No significant financial relationships to disclose.