tbuckley/cabot-search huggingface dataset:
Physical activity and risk of postmenopausal breast cancer defined by hormone receptor status and histology: A large prospective cohort study with 18 years of follow up
Authors: A. Bardia, A. H. Wang, L. C. Hartmann, J. E. Olson, C. M. Vachon, R. A. Vierkant, J. R. Cerhan
Journal: Journal of Clinical Oncology (2006)

1002 Background: Physical activity is a modifiable breast cancer risk factor, perhaps mediating risk reduction through regulation of estrogen metabolism. Evidence regarding effect of physical activity is conflicting partly because breast cancer is a heterogenous constellation of different tumor subtypes with differing etiologies. No prospective study has examined the relationship between physical activity and breast cancer incidence based on ER/PR status or histological subtype. Objective: Examine effect of physical activity on breast cancer incidence based on ER/PR status and histological subtypes of breast cancer. Methods: The Iowa Women’s Health Study is a prospective cohort study of postmenopausal women (N=41,837). Physical activity was self-reported on baseline questionnaire, and three levels (high, medium and low) were defined. Breast cancer incidence, histologic subtype and ER/PR status, through 18 years of follow-up, were ascertained by linkage with the Iowa SEER Cancer Registry. Cox proportional hazards models were used to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs) of breast cancer, adjusting for other breast cancer risk factors. Results: During 554,819 person-years of follow-up, 2548 incident cases of breast cancer were observed. High physical activity was associated with decreased risk for breast cancer (RR 0.91, 95 % CI 0.81–1.01) compared to low activity. The protective effect was most marked in ER+/PR− (RR 0.66, CI 0.46–0.94), intermediate in ER−/PR− (RR 0.80, CI 0.56–1.15), weakest in ER+/PR+ (RR 0.94, CI 0.81–1.08), and elevated in ER-/PR+ (RR 1.42, CI 0.67–3.01) tumors. Higher physical activity was also associated with a decreased risk of invasive ductal/lobular carcinoma (RR 0.90, CI 0.80–1.02), but not with invasive breast cancer with a favorable histology (RR 1.19, CI 0.78–1.81). Conclusions: Higher physical activity was associated with a 10% decreased risk of breast cancer. Unexpectedly, risk reduction was most marked in PR- tumors, particularly ER+/PR-, and the more aggressive histologic forms. Further studies are needed to confirm these findings, and also evaluate other risk factors based on ER/PR status and histological subtypes. No significant financial relationships to disclose.
Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy.
Authors: A Y Bedikian, G R Weiss, S S Legha, H A Burris, J R Eckardt, J Jenkins, O Eton, A C Buzaid, L Smetzer, D D Von Hoff
Journal: Journal of Clinical Oncology (1995)

PURPOSE A phase II study was undertaken to determine the efficacy of docetaxel in patients with metastatic malignant melanoma. PATIENTS AND METHODS Between June 1992 and March 1994, 40 patients with metastatic malignant melanoma and no prior chemotherapy were treated with docetaxel 100 mg/m2 administered intravenously over 1 hour every 21 days. None of the patients had brain metastasis. Toxicity and follow-up data are provided. RESULTS One patient had a histologically confirmed complete response that lasted for 14+ months. Four patients had partial responses, bringing the overall response rate to 12.5% (95% confidence interval [CI], 6% to 30%). A patient with a partial response had a single chest-wall metastasis and was rendered free of disease surgically after a maximal response to docetaxel and remained free of tumor recurrence after 18+ months. Tumor was stabilized in 22 patients. The overall median survival time was 13 months. The main hematologic toxicity was neutropenia, which was severe but transient. Peripheral neuropathy was the limiting nonhematologic toxicity in three patients. Other important toxicities included cutaneous toxicity, fluid retention, oral mucositis, and hypersensitivity reactions. Preadministration of dexamethasone and diphenhydramine reduced the incidence of hypersensitivity reactions, cutaneous toxicities, and fluid retention. CONCLUSION Docetaxel has definite but low-level activity against malignant melanoma. Further investigation of this drug should be conducted in multidrug combination programs.
Familial clustering and predisposition to HPV-associated malignancy.
Authors: Judith Conroy, Eve Gaughan, Tom Walsh, Bill Boyd, Sean Ennis, David James Gallagher
Journal: Journal of Clinical Oncology (2014)

1557 Background: Familial clustering of cervical cancer occurs, with a likely heritable component, but the genetic etiology of this disease is poorly understood. Human Papilloma Virus (HPV) is ubiquitous and HPV infection is common. The majority of infected individuals are asymptomatic. A minority of individuals fail to clear HPV infection and a subset of this cohort develop HPV-associated malignancy. We hypothesized the presence of an inherited predisposition to carcinogenesis following HPV infection in an Irish family with a striking number of HPV-related malignancies, and performed a linkage analysis to identify a susceptibility region. Methods: DNA was extracted from blood samples ascertained from an Irish family with multiple individuals affected by HPV-associated malignancies.Twenty-four samples were genotyped using the Illumina HumanCytoSNP-12 microarray (Illumina Inc., San Diego, California). Non-parametric linkage was performed in two phases. The first phase of analysis included only those individuals who had a clinical diagnosis of Cervical or head and neck cancer (n=5) and individuals with no cancer diagnosis, and no abnormal smear tests to date (n=2). The second phase of analysis included an additional 7 female patients who have had positive smear tests. Results: One early onset head and neck cancer, 4 cervical cancer, and 7 cases of cervical dysplasia occurred in this family. For phase 1 analysis, five loci with LOD scores >0.5 were identified on chromosomes 2p11.2-q13, 7q32.3-34, 11q23.3-25, 12p13.33-13.2 and 17q12-23.2 (LOD>0.5). Non-parametric linkage ruled out all but one of the Phase 1 linkage peaks. A single linkage peak of length was identified on chromosome 17q21.31-33 (6Mb, Z score > 2.3, LOD >1.13, p<0.01). Conclusions: We identified an association between 17q21.31-33 and HPV-associated malignancy in an Irish family with multiple affected individuals. Fine mapping of this region is underway and will be reported.
Laterally Transferred Gene Recruited as a Venom in Parasitoid Wasps
Authors: Ellen O. Martinson, Vincent G. Martinson, Rachel Edwards, None Mrinalini, John H. Werren
Journal: Molecular Biology and Evolution (2015)

Parasitoid wasps use venom to manipulate the immunity and metabolism of their host insects in a variety of ways to provide resources for their offspring. Yet, how genes are recruited and evolve to perform venom functions remain open questions. A recently recognized source of eukaryotic genome innovation is lateral gene transfer (LGT). Glycoside hydrolase family 19 (GH19) chitinases are widespread in bacteria, microsporidia, and plants where they are used in nutrient acquisition or defense, but have previously not been known in metazoans. In this study, a GH19 chitinase LGT is described from the unicellular microsporidia/Rozella clade into parasitoid wasps of the superfamily Chalcidoidea, where it has become recruited as a venom protein. The GH19 chitinase is present in 15 species of chalcidoid wasps representing four families, and phylogenetic analysis indicates that it was laterally transferred near or before the origin of Chalcidoidea (∼95 Ma). The GH19 chitinase gene is highly expressed in the venom gland of at least seven species, indicating a role in the complex host manipulations performed by parasitoid wasp venom. RNAi knockdown in the model parasitoid Nasonia vitripennis reveals that-following envenomation-the GH19 chitinase induces fly hosts to upregulate genes involved in an immune response to fungi. A second, independent LGT of GH19 chitinase from microsporidia into mosquitoes was also found, also supported by phylogenetic reconstructions. Besides these two LGT events, GH19 chitinase is not found in any other sequenced animal genome, or in any fungi outside the microsporidia/Rozella clade.
Normal calcium oxalate crystal growth inhibition in severe calcium oxalate nephrolithiasis.
Authors: J L Porile, J R Asplin, J H Parks, Y Nakagawa, F L Coe
Journal: Journal of the American Society of Nephrology (1996)

Urine from mammalian kidneys is regularly supersaturated with respect to calcium oxalate monohydrate, the most common solid phase in human nephrolithiasis, and also inhibits the nucleation, growth, and aggregation of calcium oxalate crystals. Nephrolithiasis is often associated with increased supersaturation, and it is assumed that this increase overbalances the inhibition effects, causing stones. However, some patients form stones in the absence of increased supersaturation, and in those patients, one might assume that reduced inhibition is the cause of their stones. This hypothesis was tested in 25 patients who formed at least ten stones each, yet lacked the usual metabolic abnormalities that increase supersaturation. Compared with 25 age- and sex-matched control subjects, urine supersaturation among the patients was not increased; this is an expected result of this study's selection criteria. Compared with the same age- and sex-matched control subjects, urine from the patients showed no evidence for reduced inhibition of calcium oxalate crystal growth, so low inhibition of growth did not contribute to pathogenesis of stones in our highly selected study population, despite their otherwise unexplained and active stone formation. These results do not support the hypothesis that growth inhibition defects are a cause of stone disease.
Prolonged survival after radiofrequency ablation of synchronous colorectal liver metastases
Authors: R. C. Martin, S. Casos, C. Chao, S. L. Wong, K. M. McMasters
Journal: Journal of Clinical Oncology (2004)

3763 Background: Synchronous liver metastasis (SLM), commonly defined as liver metastasis occurring within 12 months of the colon primary, represents 13–25% of the 90,000 newly diagnosed colorectal liver metastases. SLM have historically been found to have a worse overall survival when compared to metachronous lesions. The primary reason for this worse overall survival has been related to a majority of patients having unresectable disease because of multiple bilobar tumors or comorbid conditions. We hypothesized that patients with synchronous liver metastases would benefit from an aggressive ablation and resection to the same degree as patients with metachronous metastases. Methods: Review of our prospective database revealed 64 pts with unresectable colorectal liver metastases treated since 1998. The vast majority of patients underwent RFA as an open procedure. Survival was determined by the Kaplan-Meier. Results: Sixty-four pts underwent treatment for 200 liver metastases (38 resected, 162 RFA; mean 3.1 tumors/pt). Median age was 63 years (range 17–88). Median follow-up was 22 mo. The median size of the largest metastasis was 3 cm (range 1–10 cm). RFA was performed for 9 pts known to have minimal extrahepatic (EH) disease preoperatively, and 6 who were found to have EH disease at operation. Synchronous metastases were present in 38 pts. Eighteen pts (28%) experienced postoperative complications, usually minor and self-limited. Thirty-day mortality was 1.6%. Repeat RFA was performed in 11 pts for liver recurrence. Median disease-free and overall survival rates for the entire group were 12 and 31 mo, respectively. Median overall survival rates were 26 and 36 mo, respectively, for pts with or without EH metastasis (P=0.14). There were no differences in survival for pts with synchronous vs. metachronous liver metastases, or for pts who underwent RFA alone vs. RFA + resection. Conclusions: RFA is as effective for patients with synchronous metastases as it is for those with metachronous metastases. Patients without EH disease appear to benefit the most, although further study is necessary to determine the potential benefit for patients with limited EH disease. No significant financial relationships to disclose.
Prospective neurocognitive effects and quality of life (QOL) in patients with multiple brain metastases receiving whole brain radiation (WBRT) ± thalidomide on radiation therapy oncology group (RTOG) trial 0118
Authors: S. Fox, B. Berkey, J. Knisely, A. Chakravarti, W. A. Yung, W. Curran, H. Robins, D. Brachmen, R. Henderson, M. Mehta, B. Movas
Journal: Journal of Clinical Oncology (2006)

8589 Background: RTOG 0118 was a randomized trial of WBRT (37.5 Gy/15 fractions) ± thalidomide in patients (pts) with brain metastases, which showed no effect on survival (Knisely et al, ASCO, 2005). This analysis examined the relationship between neurocognitive progression (NCP) and QOL in patients on both arms. Methods: NCP was assessed with the Folstein Mini-Mental Status Exam (MMSE) and QOL with the Spitzer QOL Index (SQLI). Pts with MMSE scores below age/education adjusted cutoff levels were considered to have NCP. T-test and Chi-Square statistics were used to determine significant differences in NCP and QOL between the two treatment arms over time. Results: Of 176 pts, 88 and 92% had SQLI and MMSE scores at baseline (43% were below the MMSE cutoff). Baseline SQLI (but not MMSE) was a significant predictor for OS (p=0.034). From baseline, SQLI and MMSE compliance rates were 74 and 60% at 1–2 months (mo), 37 and 29% at 4 mo, and 21 and 19% at 6 months, respectively. While QOL was stable, those who failed to meet MMSE cutoffs increased by 60% by 6 mo, on both study arms. Although a weak correlation (r=.23) existed at baseline between QOL and MMSE for both the WBRT (0.04) and WBRT/thalidomide (0.058) arms, there was no correlation beyond baseline. Conclusions: Baseline QOL is a significant predictor of OS. While QOL remained essentially stable, the degree of neurocognitive decline (60%) over time is concerning. These findings suggest the importance of these outcome measures in pts with brain metastases and the need for interventions to conserve cognitive status. RTOG is developing a trial to study the role of preventive strategies for NCP in brain metastases. No significant financial relationships to disclose.
Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector
Authors: Wei Huang, Travis McMurphy, Xianglan Liu, Chuansong Wang, Lei Cao
Journal: Molecular Therapy (2016)

Recombinant adeno-associated virus (rAAV) vectors are attractive vehicles for gene therapy. Gene delivery to the adipose tissue using naturally occurring AAV serotypes is less successful compared to liver and muscle. Here, we demonstrate that oral administration of an engineered serotype Rec2 led to preferential transduction of brown fat with absence of transduction in the gastrointestinal track. Among the six natural and engineered serotypes being compared, Rec2 was the most efficient serotype achieving high level transduction at a dose 1~2 orders lower than reported doses for systemic administration. Overexpressing vascular endothelial growth factor (VEGF) in brown fat via oral administration of Rec2-VEGF vector increased the brown fat mass and enhanced thermogenesis. In contrast, knockdown VEGF in brown fat of VEGF (loxP) mice via Rec2-Cre vector hampered cold response and decreased brown fat mass. Oral administration of Rec2 vector provides a novel tool to genetically manipulate brown fat for research and therapeutic applications.
Enzymatic activity and clinical parameters in non-cystic fibrosis bronchiectasis: A cohort analysis
Authors: Pieter Goeminne, Jennifer Vandooren, Ans Pauwels, Ann Decraene, Ghislain Opdenakker, Lieven Dupont
Journal: European Respiratory Journal (2012)

Introduction: Non-cystic fibrosis bronchiectasis (NCFB) is characterized by a vicious cycle of infection, inflammation and enzymatic actions, reinforcing each other and leading to progressive lung damage. We aimed to investigate the enzymatic activity in a NCFB population, to compare with controls and to correlate with clinical parameters.  Methods: 63 patients (27male, 59 ± 18y) with NCFB were recruited and 16 controls (7male, 56 ± 18y), perfectly matched. Each patient was evaluated by spirometry, Leicester Cough Questionnaire (LCQ) and Sputum Colour Chart (SCC). Sputum was induced with hypertonic saline inhalation and succeeded in 49 NCFB patients and 12 controls. Total/differential cell count in sputum was assessed and total gelatinolytic activity (TGA), neutrophil elastase (NSE) and MMP-9 were measured.  Results: TGA and NSE were higher in patients vs controls (p=0.04 and p=0.0003) and both correlated with neutrophil count (NSE: p=0.009; r=0.38 and TGA: p  Conclusion: TGA is significantly higher in NCFB and correlates with indices of inflammation and infection (neutrophils and SCC). The majority of TGA was exercised by NSE (82%) in NCFB. No correlation was seen with radiologic score or LCQ.
Representation of Epitopes on Colon-Specific Antigen-p Defined by Monoclonal Antibodies&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M A Nocera, D Shochat, F J Primus, J Krupey, D L Jespersen, D M Goldenberg
Journal: JNCI Journal of the National Cancer Institute (1987)

Colon-specific antigen-p (CSAp) is a large molecular-sized protein restricted to normal and neoplastic gastrointestinal tissues and to some mucinous ovarian tumors. Murine monoclonal antibodies (MAbs) were raised against CSAp that was affinity purified with goat polyclonal antibodies from GW-39 human colonic carcinoma xenografts or against the CSAp-producing colon cancer cell line SW-948. Two of the MAbs, designated Mu-2 and Mu-4, recognized a CSAp determinant containing sialic acid, and this epitope was also expressed on bovine submaxillary mucin (BSM). Blocking experiments demonstrated that the Mu-2 and Mu-4 MAbs recognized different determinants. A third MAb, Mu-3, did not cross-react with BSM, but unlike Mu-2 and Mu-4, it did react with human saliva. Reactivity of Mu-3 with saliva did not correlate with major blood group and Lewis-related secretory blood group substances in saliva. This reactivity was not related to sialylated Lewis activity. The fourth antibody, Mu-1, appeared to react with a conformational determinant since its epitope was destroyed by heat treatment or thiol reduction. Enzyme immunoassays have demonstrated that all four epitopes may be expressed on one molecular species.
Enhancing collaboration between China and African countries for schistosomiasis control
Authors: Jing Xu, Qing Yu, Louis-Albert Tchuem Tchuenté, Robert Bergquist, Moussa Sacko, Jürg Utzinger, Dan-Dan Lin, Kun Yang, Li-Juan Zhang, Qiang Wang, Shi-Zhu Li, Jia-Gang Guo, Xiao-Nong Zhou
Journal: The Lancet Infectious Diseases (2016)
A phase I trial of spirohydantoin mustard (NSC 172112) in patients with advanced cancer.
Authors: T D Brown, D S Ettinger, R C Donehower
Journal: Journal of Clinical Oncology (1986)

Spirohydantoin mustard (spiromustine, NSC 172112) is a classical bifunctional alkylating agent synthesized in an effort to develop antitumor agents effective against CNS tumors. The rationale was to combine the reactive moiety of an active antitumor agent with the hydantoin part of the molecule, which might serve as a carrier to cross the blood brain barrier. Thirty-eight patients with refractory solid tumors received spiromustine as part of a phase I trial at the Johns Hopkins Oncology Center. Three schedules were investigated: intravenously (IV) daily for three consecutive days, IV every other day for 3 days, and IV on a weekly basis for three doses, all cycled every 28 days. Hematologic toxicity was infrequently seen. Mild to moderate nausea and vomiting occurred on all schedules. The dose limiting toxicity was CNS toxicity characterized by mydriasis, xerostomia, lethargy, confusion, and hallucinations. This CNS toxicity was dose related, cumulative, and reversible. IV physostigmine appeared to diminish the neurotoxicity if administered before spiromustine and at frequent intervals following the drug. The maximum tolerated dose of spiromustine (without concomitant physostigmine) on the three times a week schedule is 6 mg/m2. With physostigmine pretreatment, 8 mg/m2 can be administered. The three times daily and every other day for three days schedules are not recommended for further study due to the severity of neurotoxicity. It is recommended that 6 mg/m2 be used as the starting dose for any phase II studies using the three times weekly schedule, and that physostigmine be used as needed to minimize neurotoxicity. Dose escalation above this level can be considered when individual tolerance has been established. Phase II trials to investigate the activity of this agent against primary and metastatic CNS malignancies appear indicated on the basis of three transient radiographic responses in refractory malignancies metastatic to the CNS.
STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion
Authors: Dagmar Gotthardt, Eva M. Putz, Eva Grundschober, Michaela Prchal-Murphy, Elisabeth Straka, Petra Kudweis, Gerwin Heller, Zsuzsanna Bago-Horvath, Agnieszka Witalisz-Siepracka, Abbarna A. Cumaraswamy, Patrick T. Gunning, Birgit Strobl, Mathias Müller, Richard Moriggl, Christian Stockmann, Veronika Sexl
Journal: Cancer Discovery (2016)

Natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-deficient NK cells can be rescued by overexpression of BCL2. Our experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-deficient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verified by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These findings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis.The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis.