tbuckley/cabot-search huggingface dataset:
Sox9 regulates self‐renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma
Authors: Chungang Liu, Limei Liu, Xuejiao Chen, Jiamin Cheng, Heng Zhang, Junjie Shen, Juanjuan Shan, Yanmin Xu, Zhi Yang, Maode Lai, Cheng Qian
Journal: Hepatology (2016)

Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs) that participate in tumor propagation, resistance to conventional therapy, and promotion of tumor recurrence, causing poor patient outcomes. The protein SRY (sex determining region Y)-box 9 (Sox9) is a transcription factor expressed in some solid tumors, including HCC. However, the molecular mechanisms underlying Sox9 function in liver CSCs remain unclear. Here, we show that Sox9 is highly expressed in liver CSCs and that high levels of Sox9 predict a decreased probability of survival in HCC patients. We demonstrate that Sox9 is required for maintaining proliferation, self-renewal, and tumorigenicity in liver CSCs. Overexpression of exogenous Sox9 in liver non-CSCs restored self-renewal capacity. Additionally, a reduction in the asymmetrical cell division of spheroid-cultured liver CSCs was observed when compared with differentiated cancer cells or liver CSCs with inhibited Notch signaling. Furthermore, we demonstrate that Sox9 is responsible for the asymmetrical-to-symmetrical cell division switch in liver CSCs. Sox9 also negatively regulates Numb expression, contributing to a feedback circuit that maintains Notch activity and directs symmetrical cell division. Clinical analyses revealed that the Sox9(High) Numb(Low) profile is associated with poor prognosis in human HCC patients.We demonstrate that Sox9 plays a critical role in self-renewal and tumor propagation of liver CSCs and identify the molecular mechanisms regulated by Sox9 that link tumor initiation and cell division. (Hepatology 2016;64:117-129).
Sex hormones and renal nitric oxide synthases.
Authors: J Neugarten, Q Ding, A Friedman, J Lei, S Silbiger
Journal: Journal of the American Society of Nephrology (1997)

The present study was undertaken to determine whether sex hormones influence nitric oxide synthase levels in the kidney. Five groups of rats were studied: males, castrated males, females, oophorectomized females, and oophorectomized females receiving estradiol replacement therapy. Endothelial nitric oxide synthase (eNOS) levels in the kidney were measured by Western blotting. eNOS levels were significantly greater in the renal medulla of female rats compared with male rats (3545 +/- 473 versus 2418 +/- 205 densitometry units (DU), P < 0.05). Oophorectomy reduced renal medullary eNOS levels to that of intact male rats (2566 +/- 304 DU, P = NS). Estrogen replacement therapy significantly increased medullary eNOS levels in oophorectomized animals (3249 +/- 377 versus 2302 +/- 213 DU, P < 0.05). Renal inducible nitric oxide synthase (iNOS) levels were measured after induction with lipopolysaccharide. iNOS levels were significantly greater in the renal medulla of female rats compared with male rats (677 +/- 253 versus 252 +/- 12 DU, P < 0.05). Oophorectomy reduced renal medullary iNOS levels to that of intact male rats (295 +/- 57 DU, P = NS). In contrast, estrogen replacement therapy significantly increased medullary iNOS levels in oophorectomized animals (682 +/- 356 versus 160 +/- 92 DU, P < 0.05). Steady-state levels of mRNA for iNOS were found to be higher in the inner medulla of female rats compared with male rats (1519 +/- 211 versus 899 +/- 105 DU, P < 0.05). In contrast to these findings, sex hormones failed to influence nitric oxide production or iNOS levels in lipopolysaccharide-stimulated mesangial cells in culture. These results suggest that gender may influence renal medullary synthesis of nitric oxide.
Safety and efficacy of neratinib (HKI-272) in combination with vinorelbine in patients with solid tumors
Authors: S. A. Limentani, A. Awada, L. Dirix, J. Beck, V. Dieras, F. Binlich, C. Germa, V. Agrapart, C. Powell, D. Hershman
Journal: Journal of Clinical Oncology (2009)

e14554 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m 2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m 2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m 2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m 2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2. [Table: see text]
ENACCT's pilot education program (PEP): A model to enhance understanding of cancer clinical trials for community providers and community leaders
Authors: M. Michaels, N. Blakeney, L. Schapira, A. Britton, L. Swords, N. Bitow, B. Gibbs, S. Yeun, B. Rytkonen, R. Goodman
Journal: Journal of Clinical Oncology (2009)

e17514 Background: While nearly 20% of adult cancer patients are eligible for cancer clinical trials, less than 3% of cancer patients participate. Rates of participation are lower among communities of color and the medically underserved. Enhanced community engagement and provider training about cancer clinical trials can potentially result in greater awareness, access, and ultimately, patient accrual. Methods: A three-year Pilot Education Program was developed to explore the impact and feasibility of a community-driven outreach and education intervention focusing on community members, community health care providers, and cancer researchers in three medically underserved communities. Using a train-the-trainer model, PEP sought to raise clinical trial awareness among peers and encourage public inquiries about clinical trials. Workshops for clinical trials staff addressed recruitment and retention practices. Additionally, community sites worked to reduce local policy barriers to clinical trials participation.PEP used web-based surveys, interviews, focus groups and field observation to evaluate impact. Results: Seventy-five trainers were recruited. PEP reached 882 community members (63% minority), 374 health care providers (16% minority) and 61 cancer clinical trial staff. Approximately 5,800 individuals were exposed to educational activities through extended community outreach activities and dissemination of educational materials. Among those completing evaluation surveys, 66% of community leader trainees said they spoke to others about cancer clinical trials. Seventy-two percent of health care providers agreed their role is to inform patients about the possibility of receiving treatment through a clinical trial. Among cancer clinical trial staff, 80% indicated intention to work with community groups on cancer clinical trials education. Seventy-seven unique patient profiles were created with a national cancer clinical trials matching service also associated with PEP. Conclusions: Results from ENACCT's Pilot Education Program suggest promise in improving knowledge among community leaders and health care providers, and fostering greater peer-to-peer education about cancer clinical trials. [Table: see text]
Distress in oncology patients: Distress thermometer in a Latin American study
Authors: I. E. Piriz, N. E. Ferro, M. Di Pretoro, R. Cesarco, A. Hannois, G. N. Cuello, D. Berdinelli, A. Romeo, M. Allende
Journal: Journal of Clinical Oncology (2005)

8211 Background: The impact of the psychosocial distress in cancer populations is well known and has been amply studied. In the literature of the last five years many papers have shown that the Distress Thermometer is a valid instrument for the screening and follow up of the psychosocial distress. Research shows that significant levels of distress are found among both hospitalised and ambulatory patients with cancer OBJETIVES: This study is concentrated on: a) The measure of the distress in oncology patients. b) Comparison between diagnosis and levels of distress.Correlation between current state of the illness and level of distress. Methods: We decided to use a Distress Thermometer according to guidelines of the American Society of Psychosocial and Behavioral Oncology/ AIDS, as developed by the Standars of Care and Management of Distress Panel, National Comprehensive Cancer Network, translating it into Spanish. After eight months of work in the Psycho-oncology Commission of the Argentine Association of Clinical Oncology, a more appropriate terminology was agreed for our population. The patients indicates his/her level of distress on the “thermometer”. Scores above five have been shown to indicate significant distress. It is accompanied by a Problem List which people can indicate their major sources of distress: physical, psychological, social, practical or spiritual problems. Results: The simple studied is composed by 400 oncology out patients and inpatients who assisted to four centres that treat different type of population: from high, medium, and low socio-economic and cultural levels. The data has been studied specifying age, educational level, employment, marital status, social level, religion, diagnosis, stage of illness, current and previous treatment modality, for each centre and the hole sample.The analysis of data as well as the psychometrical results will be presented in detail Conclusions: A) More than half the cancer patients of our population have a high degree of emotional distress. B) The high level of distress is correlated positively with the state of the illness and is higher in patients with advanced illness than in those with the disease under control. No significant financial relationships to disclose.
Evaluation of cross-resistance among endocrine therapies and predictive factors for response in recurrent or advanced breast cancer treated with 3rd generation aromatase inhibitors
Authors: K. Kai, R. Nishimura, M. Matsuda, H. Miyayama
Journal: Journal of Clinical Oncology (2004)

790 Background: The 3rd aromatase inhibitors (AI) have been demonstrated to be an effective for hormone-dependent recurrent or advanced breast cancers. And they have been considered as the effective agents for tamoxifen-resistant tumors. However, there were few data about cross-resistance between 3rd generation AI and other hormonal compounds. We assessed the efficacy of 3rd generation AI in relation to clinicopathological findings and cross-resistance between other hormonal compounds in recurrent or advanced breast cancer. Methods: Seventy-six recurrent patients who were treated with 3rd generation AI at our hospital between March 2000 and November 2003 were enrolled in this retrospective study. All patients were postmenopausal with positive ER and/or PgR tumors and most of the cases were treated with Tamoxifen in adjuvant setting. The average of a disease-free interval (DFI) was 56.5 months in recurrent cases. The expressions of MIB-1, p53 and HER2 were evaluated by immunostaining. The 3rd generation AI includes anastrozole and exemestane, and their response rates (RR) were assessed combined or separately. Results: An overall RR of 3rd generation AI was 39.1%. The median time to progression was 8.2 months. In anastrozole-failure patients, RR of exemestane was observed in 11.1%. In patients who had progressed during 2nd generation AI or MPA, 3rd generation AI had a RR of 55.6% or 26.7%, respectively. The RR of MPA was 23.1% in patients having prior exposure to 3rd generation AI. In relation to response of 3rd generation AI, patients with soft tissue lesions had a significantly higher RR than those with viscera. And patients with longer DFI or lower proliferative activity had a higher RR. Conclusions: Cross-resistance is incomplete between 3rd generation AI and other hormonal compounds. The 3rd generation AI might be a key drug in a recurrent or advanced setting, especially for the patients with lower proliferation or soft tissue lesions. No significant financial relationships to disclose.
Quantitative measurement of HER3 total protein (H3T) and association with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab
Authors: L. J. Goodman, J. K. Weston, A. Mukherjee, J. Sperinde, A. Paquet, S. Williams, G. Parry, M. Bates, W. Koestler, A. Lipton
Journal: Journal of Clinical Oncology (2009)

1021 Background: The heterodimerization of HER3, with HER2 and the subsequent activation of the AKT pathway, has been implicated in both regulation of tumor cell growth and in resistance to HER2 targeted therapies such as trastuzumab. Currently available methods of measuring H3T in formalin-fixed, paraffin-embedded (FFPE) samples are insufficiently sensitive or specific; thus the impact of quantitative measurement of H3T expression on clinical response to trastuzumab has not been evaluated. Methods: We have developed a highly quantitative, accurate, precise, sensitive, and reproducible H3T assay in FFPE samples based on the VeraTag technology platform. Consequently, the H3T assay displays ∼5-fold greater sensitivity than conventional IHC measurements. Additionally, the rank order and accuracy of the H3T measurements were preserved over a wide dynamic range in well-characterized cell line panels. Intra- and inter-assay reproducibility measurements demonstrated 7–11 %CV and 8–16 % CV, respectively. Results: Quantitative levels of HER2 total protein (H2T) and H3T expression were determined by the VeraTag technology in 81 tumors from patients with trastuzumab-treated metastatic breast cancer. A previously reported H2T cutoff was used to sub-divide the patients into HER2-normal (N = 26, median TTP = 4.1 mos) and HER2-overexpressing (N = 55, median TTP = 11.1 mos, HR = 0.43, p = 0.0002) groups. In the HER2-overexpressing group, high H3T expression, as defined by a positional scanning cutoff analysis, predicted shorter median time to progression (N = 25, median TTP = 6.1 mos) compared with low H3T expression (N = 30, median TTP = 13.1 mos, HR = 2.7, p = 0.0002). Univariate Cox proportional hazards analyses examining the HER2-overexpressing subgroup identified H3T (high vs. low) as the most significant predictor of TTP (HR = 2.98, p = 0.0004). Conclusions: These results demonstrate that the accurate and sensitive measurement of H3T in a cohort of patients with HER-2 positive breast cancer predicts TTP in response to trastuzumab and could indicate a population of patients with worse outcome requiring additional therapeutic intervention. [Table: see text]
Geographic components of linkage disequilibrium in natural populations of Escherichia coli.
Authors: T S Whittam, H Ochman, R K Selander
Journal: Molecular Biology and Evolution (1984)

Geographic variation in the genetic structure of natural enteric populations of Escherichia coli was assessed at both the single-locus and dilocus levels from allozyme genotypes at 12 enzyme loci in 178 cell lines isolated from human hosts in Sweden, Iowa, and Tonga. Although there was significant heterogeneity in allele frequencies at six of the 12 loci, geographic variation accounted for only 2.0% of the total genetic diversity (HT = 0.518). Ohta's D-statistics were used to partition the total variance of dilocus linkage disequilibrium into within-population and between-population components. The observed total variance in disequilibrium (0.0339), averaged over 66 locus-pairs, was significantly greater than would be expected (0.0103) if alleles were randomly associated in an unstructured total population; and both within-locality and between-locality components made substantial contributions to the total variance. Half the locus-pairs exhibited the specific dual relationship among components expected when random factors are generating disequilibrium, but 20% of the locus-pairs showed the opposite relationship, reflecting systematic allele associations. The magnitude of dilocus disequilibrium apparently is unrelated to the chromosomal distance between loci. This and other evidence indicates that substitutive recombination rates in natural populations are sufficiently low to permit indirect periodic selection to play a prominent role in generating multilocus genetic structure.
P205Adipokines in patients undergoing on-pump and off-pump coronary artery bypass grafting
Authors: A Nemeth, A Cziraki, E Sulyok, S Szabados, I Horvath, A Nasri, M Rauh, W Rascher
Journal: Cardiovascular Research (2014)

Purpose: Obesity increases the development of cardiovascular risk factors: hypertonia, diabetes mellitus, endothel dysfunction. Our aim was to follow the response pattern of plasma adipokine and ghrelin levels to coronary artery bypass graft (CABG) surgery in patients with (on-pump) and without (off-pump) cardiopulmonary bypass (CPB).
Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: a report of Radiation Therapy Oncology Group 83-02.
Authors: W J Curran, C B Scott, A S Weinstein, L A Martin, J S Nelson, T L Phillips, K Murray, A J Fischbach, D Yakar, J G Schwade
Journal: Journal of Clinical Oncology (1993)

PURPOSE The purpose is twofold: (1) to identify the malignant glioma patients treated in a trial of hyperfractionated radiotherapy (RT) and carmustine (BCNU) who may have been eligible for a stereotactic radiosurgery (SRS) boost; and (2) to compare survival of such patients with that of those considered SRS-ineligible. PATIENTS AND METHODS From January 1983 to July 1989, 778 malignant glioma patients were enrolled on Radiation Therapy Oncology Group (RTOG) 83-02, a randomized phase I/II hyperfractionated RT dose-escalation trial with BCNU chemotherapy. The SRS criteria used in a single-institution trial were applied to these patients; they are: Karnofsky performance status (KPS) of greater than 60; well-circumscribed tumor less than 4.0 cm; no subependymal spread; and a location not adjacent to brainstem or optic chiasm. RESULTS Eighty-nine patients (11.9%) were identified as potentially SRS-eligible. The median survival times (MST) and 18-month survival rates of the 89 eligible and 643 ineligible patients were 14.4 versus 11.7 months and 40% versus 27%, respectively (P = .047). The MST and 18-month survival rate of the 544 SRS-ineligible patients with KPS greater than 60 were 12.1 months and 29%, respectively, and were not statistically inferior to the survival of the SRS-eligible group (P = .21). Multivariate analysis revealed age, KPS, and histopathology to be strongly predictive of survival, and SRS eligibility was also significantly predictive (P = .047). CONCLUSION SRS-eligible patients enrolled on RTOG 83-02 had survival superior to that of the SRS-ineligible group, and this advantage is mainly due to the selection of a subgroup with a high minimum KPS.
Effect of human papillomavirus (HPV) 16 E6 and E7 gene silencing on epidermal growth factor receptor (EGFR) phosphorylation status in HPV16<sup>+</sup>oropharyngeal cancer cell lines
Authors: T. Rampias, C. Sasaki, A. Psyrri
Journal: Journal of Clinical Oncology (2009)

e17006 Background: Aberrant activation of EGFR intrinsic tyrosine phosphotransferase activity correlates with poor prognosis in several cancers. In this study, we sought to determine the effect of HPV16 E6 and E7 gene silencing on the status of EGFR phosphorylation in HPV16 + oropharyngeal cancer cell lines. Methods: Short hairpin RNAs targeting HPV type 16 E6 and E7 genes were delivered by retrovirus infection to HPV16 + oropharyngeal cancer cell lines 147T and 090. E6/E7 repression was assessed by quantitative reverse transcription polymerase chain reaction and western blotting for p53 and Rb protein levels 48 hours after retrovirus infection. Phospho-EGFR (Tyr 1068 ), (Tyr 845 ), (Tyr 992 ), (Tyr 1045 ) and total EGFR protein levels before and after silencing were then analyzed by western blotting in 147T and 090 oropharyngeal cancer cell lines. Results: Quantitative RT-PCR analysis showed reduction in E6/E7 mRNA levels up to 85% the level in uninfected or control shRNA infected cell lines. Protein expression revealed substantial downregulation of phospho-EGFR (Tyr 992 ) protein levels, 48 h after the retrovirus infection of 090 and 147T cell lines. A slight reduction of phospho-EGFR (Tyr 845 ) was also observed in both HPV16 + cell lines after silencing. No phosphorylation was detected at sites Y1068 and Y1045 of EGFR. Conclusions: We provide evidence that E6 and E7 are involved in tyrosine phosphorylation of epidermal growth factor receptor at sites Y992 and Y845. Phospho-tyrosine 992 is a direct binding site for the PLCγ SH2 domain and phosphorylation in this site is associated with activation of PLCγ-mediated downstream signaling. Phosphorylation of Tyr845 in the kinase domain is implicated in stabilizing the activation loop maintaining the enzyme in an active state. Since enhanced EGFR activation appears to be a direct consequence of E6/E7 expression, targeting E6/E7 may be effective EGFR blockade in HPV16 + oropharyngeal cancers. No significant financial relationships to disclose.