tbuckley/cabot-search huggingface dataset:
Natural killer (NK) cells are associated with reduced relapse without increased graft-versus-host disease (GVHD) after allogeneic hematopoetic stem-cell transplantation (HSCT)
Authors: V. Reddy, J. B. Levine, S. S. Mahmood, J. D. Schold, H. Meier-Kriesche, E. M. Dunbar
Journal: Journal of Clinical Oncology (2006)

6542 Background: Natural killer cells have potential for anti-leukemia activity after haplo-identical HSCT. However, the role of reconstituted NK cells in relapse and survival after matched HLA-identical HSCT is unknown. We investigated the correlation between NK reconstitution and death, relapse, and GVHD after HSCT. Methods: We prospectively studied NK reconstitution in 123 patients with predominantly high-risk hematologic malignancies. Peripheral blood absolute NK cell count (ANK) was determined by flow cytometry analysis of lymphocytes co-expressing bright staining CD56+ and CD16+. Cluster analysis distinguished patients at engraftment with high ANK (&gt;12.2/mm3) (n=80) and low ANK (n=43), and at 60 days with high ANK (&gt;20/mm3) (n=64) and low ANK (n=26). Primary study endpoints were death, relapse and acute grade II-IV GVHD with median follow up of 360 days (28–1967). A cox proportional hazard model was adjusted for important covariates, including age, transplant conditioning (myeloablative vs. non-myeloablative), graft source (peripheral blood vs. bone marrow), and donor-type (HLA-matched related vs. unrelated), dendritic cell level and absolute neutrophil count. Results: A low ANK at engraftment was significantly associated with death (p=0.03) after non-myeloablative HSCT. Using a selection model, only NK remained in the model, and a low ANK was associated with a 2.5 hazard ratio for subsequent death (p=0.04). Additionally, for the overall cohort, ANK at 60 days was strongly associated with time to death (92% in high vs 65% in low group; LR p=0.0007), at 310 days after HSCT. ANK level at 60 days was strongly associated with time to relapse (n=82, (LR p=0.0001). In a multivariate model, low ANK at 60 days was associated with a 4.2 fold relative risk (RR) of death (1.9, 9.1) and 8.6 RR for time to relapse (3.1, 24.3). Conclusions: High NK cell reconstitution is associated with reduced relapse and death without increased incidence of GVHD after HLA-identical HSCT. Our study suggests that NK may have both a potential anti-tumor effect, as well as be tolerogenic. Measuring NK after HSCT may have novel prognostic and therapeutic implications. No significant financial relationships to disclose.
Vaccine therapy with tumor specific mutated VHL peptides in adult cancer patients with renal cell carcinoma
Authors: M. S. Achtar, R. A. Ibrahim, V. E. Herrin, B. Gause, S. A. Bernstein, T. B. Brent-Steel, C. M. Maruffi, J. A. Berzofsky, S. N. Khleif
Journal: Journal of Clinical Oncology (2004)

2589 Background: Chemotherapy in metastatic renal cell carcinoma is ineffective. Although Interferon α and IL-2 have been used with some success, there is a long way to go to achieve satisfactory results. Despite the success of local treatment in early disease, the overall survival is around 50%. Therefore, the development of another therapeutic approach is needed. Human cancers are commonly associated with mutations in oncogenes. These mutated genes produce proteins that are unique to cancer cells. The von Hipple-Lindau (VHL) gene was found to be mutated in 57% of sporadic renal cell carcinomas. 40 - 90% of these mutations are frame shift, 90% of the rest of the mutations are mis-sense point mutations, and very few are nonsense or stop mutations. Novel mutant proteins are processed and displayed as short peptides through HLA molecules on the tumor cell surface. Thus, mutant VHL protein can be an attractive vaccine therapy target. Methods: : In previous clinical trials, vaccination with peptide spanning the patient's mutations in Ras and P53 produced specific immunological responses. Specific lymphocytes, whetherCD4+ or CD8+, were generated that specifically recognized the mutant peptide with which the patient was vaccinated. On this trial, we treated 5 patients with advanced renal carcinoma with 1000 μg of the corresponding mutant VHL peptide mixed with Montanide ISA-51 adjuvant subcutaneously (SQ). Vaccine cycles were repeated every 4 weeks for a total of four vaccinations. Results: No grade 3 or grade 4 toxicities occurred. Grade I-II toxicities resolved spontaneously. Three of five patients showed evidence of lack of progression after four vaccinations (2 ms, 4 ms, 5.5 ms, 8.5ms+, 25ms+) and continued to receive additional vaccinations. Two patients started the vaccinations NED (no evidence of disease) and remained NED. For the first time, specific immunological responses for the mutant VHL peptides have been demonstrated by Elispot assay. Conclusions: We believe that this treatment may form a potentially promising approach in combination with other therapeutic modalities in metastatic renal cell carcinoma. No significant financial relationships to disclose.
New Appliances
Authors: R MARCUS, L E MUSSEL, J WATT
Journal: BMJ (1964)

Tllwl'-7 ~! of witolema four is said to be poorly absorbed because of the presence of large amounts of phytic acid.There have also been rumours that the added iron may likewise be poorly absorbe&The barring of low-extraction flour from the diet and its repla nt by wholemeal would therdore cause a slight increase in the iron intake, which might be counterbalanced by poor absorption.It seems improbable that this minor change in iron intake would bave any noticeable effect on health.If the white flour banned from the diet were to be replaced by ektra sugar or fat, however, the change in iron intake would be in the reverse direction and might be more serious.
Use of the electronic medical record (EMR) to identify women at increased risk for hereditary breast and ovarian cancer (HBOC).
Authors: Hilary B. Kershberg, Monica Alvarado, Jaime L. Natoli, Emily Parkhurst, Hui Zhou, George E. Tiller
Journal: Journal of Clinical Oncology (2013)

236 Background: Diagnosis of breast cancer at a young age is an indication for genetic counseling and possible BRCA testing. However, not all women with this early diagnosis are referred for genetic counseling, especially if they do not have a family history of breast or ovarian cancer. Methods: The genetics department in Kaiser Permanente Southern California (KPSC) provides clinical genetic services in an integrated health care system serving over 3.6 million members. Using data from the KPSC tumor registry, the KPSC EMR system, and a departmental cancer test results database, we identified 454 women diagnosed with early breast cancer (&lt;46 years) between September 2005 and September 2010 who had not received genetic counseling. We contacted these women with a letter and/or phone call offering a genetics consultation, and we offered BRCA testing to all those who came for counseling. Results: 142 women (31%) came in for genetic counseling, and 312 women (69%) declined, did not keep their appointment, or never responded. Hispanics were more likely to schedule and keep an appointment than Caucasians (OR=1.35, 95% CI, 0.79-2.31), although this was not statistically significant. Of those who came in for counseling, African Americans were significantly less likely to accept genetic testing than Caucasians (OR=0.31, 95% CI, 0.10-0.98).Of the 142 patients who were counseled, 122 (86%) accepted testing. We identified 6 patients (5%) who were positive for a deleterious BRCA mutation and 6 patients (5%) who had a variant of uncertain significance. Of the 6 women with deleterious mutations, only 1 had a first-degree relative with breast or ovarian cancer, and 4 had mutation probabilities &lt;10%. Conclusions: This project demonstrates how an integrated care approach and EMR system provide an opportunity to identify and contact women who are at increased risk for inherited cancer susceptibility.
Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1
Authors: Fan Xuan, Mengying Huang, Wen Liu, Hanfei Ding, Liqun Yang, Hongjuan Cui
Journal: Neuro-Oncology (2015)

The transcription factor homeobox C9 (HOXC9) plays a crucial role in developmental regulatory systems, where it determines the specific positional identities of cells along the anteroposterior axis. The expression of HOXC9 has been found to be dysregulated in some cancers such as lung cancer, breast cancer, and neuroblastoma. Here, we report for the first time that HOXC9 is a novel autophagy regulator and reveal its oncogenic role in cell survival and its usefulness as a prognostic marker in glioblastoma patients. Kaplan-Meier analysis was performed to evaluate the possible prognostic value of HOXC9 in glioblastoma. Growth curve assays, subcutaneous, and orthotopic implantations were used to analyze cell viability and tumor formation, respectively. Luciferase and chromatin immunoprecipitation assays were employed to explore the mechanisms involved in the association between HOXC9 and its downstream effector, death-associated protein kinase 1 (DAPK1). High expression of HOXC9 was found to be an indicator of a poor prognosis in glioblastoma. HOXC9 knockdown resulted in a significant reduction of cell viability, migration, invasion, and tumorigenicity and a marked increase in autophagy. During the autophagy process, HOXC9 inhibited DAPK1 transcription by directly binding to its promoter. The downregulation of HOXC9 releases its transcriptional inhibition of DAPK1, resulting in the activation of the DAPK1-Beclin1 pathway, which induces autophagy in glioblastoma cells. Collectively, our data indicate that HOXC9 is an oncogene in glioblastoma. We have revealed its role in the control of autophagy, and we suggest that HOXC9 is a novel and promising therapeutic target.
Abstract P342: Assessing Interaction in GFR-risk Associations in Meta-analyses: An example of Hypertension in the CKD Prognosis Consortium
Authors: Bakhtawar K Mahmoodi, Kunihiro Matsushita, Yingying Sang, Morgan Grams, Brad C Astor, Mark Woodward, Ron T Gansevoort, Josef Coresh
Journal: Circulation (2012)

Background: Meta-analysis methods for evaluating interactions are not well described. Assessing interactions with eGFR is particularly challenging due to its non-linear association with risk. We describe methods to evaluate point-wise and overall interactions using an example of hypertension-eGFR interaction on mortality risk. Methods: The applicability of our methods was evaluated in 28 out of 46 cohorts joining the Chronic Kidney Disease Prognosis Consortium (CKD-PC). In each study, eGFR linear splines (knots at each 15 from 15 to 105 ml/min/1.73m²) and their product terms with hypertension were fitted, providing hazard ratios (HRs) for eGFR (vs. eGFR 95) in both hypertensive and non-hypertensive groups. From this model, the interaction was evaluated as the relative HR (rHR) in hypertension vs. non-hypertension at each 1 ml/min/1.73m² of eGFR between 15 and 120 (point-wise interaction). HRs and rHRs for each eGFR value in each cohort were then pooled using random effects models. The overall interaction was assessed as the inverse-variance average of differences in all spline coefficients for the entire range of eGFR between hypertensive vs. non-hypertensive groups. Results: There were 942,429 participants and 69,072 deaths. Low eGFR was associated with increased mortality in the hypertensive (gray line) and non-hypertensive (black line) groups ( figure ). Significant interactions by hypertension status were observed at eGFR range below 60 ml/min/1.73m² at each eGFR value p-interaction&lt;0.05 is noted by “x” in the figure . In this range, the impact of low eGFR on mortality was weaker in the hypertensive group as compared with the non-hypertensive group. Overall interaction test was also significant (P&lt;0.001). Conclusion: We developed and implemented meta-analytic methods to assess point-wise and overall interactions in non-linear regression models. Interactions can be comprehensively evaluated using both methods and should be interpreted based on biological and clinical relevance.
Key role of MEK/ERK pathway in sustaining tumorigenicity and in vitro radioresistance of embryonal rhabdomyosarcoma stem-like cell population
Authors: Carmela Ciccarelli, Francesca Vulcano, Luisa Milazzo, Giovanni Luca Gravina, Francesco Marampon, Giampiero Macioce, Adele Giampaolo, Vincenzo Tombolini, Virginia Di Paolo, Hamisa Jane Hassan, Bianca Maria Zani
Journal: Molecular Cancer (2016)

The identification of signaling pathways that affect the cancer stem-like phenotype may provide insights into therapeutic targets for combating embryonal rhabdomyosarcoma. The aim of this study was to investigate the role of the MEK/ERK pathway in controlling the cancer stem-like phenotype using a model of rhabdospheres derived from the embryonal rhabdomyosarcoma cell line (RD). Rhabdospheres enriched in cancer stem like cells were obtained growing RD cells in non adherent condition in stem cell medium. Stem cell markers were evaluated by FACS analysis and immunoblotting. ERK1/2, myogenic markers, proteins of DNA repair and bone marrow X-linked kinase (BMX) expression were evaluated by immunoblotting analysis. Radiation was delivered using an x-6 MV photon linear accelerator. Xenografts were obtained in NOD/SCID mice by subcutaneously injection of rhabdosphere cells or cells pretreated with U0126 in stem cell medium. MEK/ERK inhibitor U0126 dramatically prevented rhabdosphere formation and down-regulated stem cell markers CD133, CXCR4 and Nanog expression, but enhanced ALDH, MAPK phospho-active p38 and differentiative myogenic markers. By contrast, MAPK p38 inhibition accelerated rhabdosphere formation and enhanced phospho-active ERK1/2 and Nanog expression. RD cells, chronically treated with U0126 and then xeno-transplanted in NOD/SCID mice, delayed tumor development and reduced tumor mass when compared with tumor induced by rhabdosphere cells. U0126 intraperitoneal administration to mice bearing rhabdosphere-derived tumors inhibited tumor growth . The MEK/ERK pathway role in rhabdosphere radiosensitivity was investigated in vitro. Disassembly of rhabdospheres was induced by both radiation or U0126, and further enhanced by combined treatment. In U0126-treated rhabdospheres, the expression of the stem cell markers CD133 and CXCR4 decreased and dropped even more markedly following combined treatment. The expression of BMX, a negative regulator of apoptosis, also decreased following combined treatment, which suggests an increase in radiosensitivity of rhabdosphere cells. Our results indicate that the MEK/ERK pathway plays a prominent role in maintaining the stem-like phenotype of RD cells, their survival and their innate radioresistance. Thus, therapeutic strategies that target cancer stem cells, which are resistant to traditional cancer therapies, may benefit from MEK/ERK inhibition combined with traditional radiotherapy, thereby providing a promising therapy for embryonal rhabdomyosarcoma.
A phase I study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma (MM) or renal cell carcinoma (RCC)
Authors: J. F. Spicer, M. B. Jameson, P. Savage, D. Jodrell, S. M. Rudman, F. Erlandsson, G. Acton, M. McKeage
Journal: Journal of Clinical Oncology (2009)

3024 Background: AS1409 (huBC1-huIL-12) is a fusion protein combining a humanized antibody specific for the ED-B splice variant of fibronectin with human IL-12. ED-B-fibronectin is expressed in tumor vasculature. IL-12 stimulates T and NK cell activity. Responses to IL12 occur in MM and RCC, but with high systemic toxicity. AS1409 is designed to target IL-12 to tumor vasculature. Methods: Patients with MM or RCC were treated in a dose-escalating trial of weekly i.v. AS1409 for 6 weeks with a starting dose of 15mcg/kg. Patients without unacceptable toxicity or disease progression could continue therapy. IFN-gamma and IP-10 were measured as biomarkers of activation of cellular immunity. Results: 13 patients (9 males; median age 53 years; 11 MM, 2 RCC) were treated (7 at 15mcg/kg, 6 at 25mcg/kg). DLTs observed at 25 mcg/kg were transaminase elevation and fatigue. Other toxicities included flu-like syndrome, fever, myalgia, and mucositis. Three patients continued to receive AS1409 beyond 6 weeks and 1 patient remained on treatment beyond 30 weeks. All patients showed elevation of IFN-gamma and IP10 following the first dose, although subsequently attenuated; prominent anti-drug antibody (ADA) responses were seen. A partial response was seen in a patient with MM metastatic to lymph nodes treated at 15mcg/kg, and a best response of stable disease was seen in 4 patients. Mean AS1409 half-life was 19.3 ±5.3h, mean distribution volume was 0.25 ± 0.098L/kg and clearance was 9.8 ± 6.5mL/hr/kg. Conclusions: At 15mcg/kg AS1409 was well tolerated. Biomarker activation and objective radiological evidence of anticancer activity was observed at this dose. Further study of AS1409 is focussed on optimizing dosing and scheduling, characterizing the ADA response, and antibody biodistribution. [Table: see text]
Expression III: Final results of an international survey in eight European countries with 1,830 patients—What are the differences in expectations from their doctors and therapy management of patients with primary and recurrent ovarian cancer? (NOGGO/ENGOT-ov4 study).
Authors: Gülten Oskay-Özcelik, Maren Keller, Domenica Lorusso, Sandro Pignata, Florence Joly, Dominique Berton-Rigaud, Michal Maciejewski, Marcin Jedryka, Ignace Vergote, Sandrina Lambrechts, Antonio Casado, Cesar Mendiola, Patrick Achimas, Daniel Uwe Reimer, Alain G Zeimet, Hans-Joachim Hindenburg, Rolf Richter, Jalid Sehouli
Journal: Journal of Clinical Oncology (2014)

5579 Background: The primary aim of this study was to investigate information needs and preferences among patients with ovarian cancer, in different European countries, focusing on patients with primary and recurrent ovarian cancer. Methods: A questionnaire was developed based on the experiences of “German-Expression II”, and then provided to ovarian cancer patients via internet or print-version in 8 European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain). Basic data and questions concerning the expectations and needs regarding their therapy management and doctor-patient communication were requested from the patient. Results: From December 2009 to October 2012, a total of 1,830 patients with ovarian cancer from 8 European countries participated in the survey, 902 patients with primary ovarian cancer and 731 with recurrent ovarian cancer. The median age was 58 years. Concerning the completeness and understandability of the explanations about the therapies from their doctors there was no significant difference in both groups. In contrast to patients with primary disease the recurrent patients measure the success of the therapy on the development of their CA 125. Recurrent patients attach more importance to know how long they must stay in the hospital and how many patients with their sickness are being treated for by their doctor. The three most important aspects for recurrent ovarian cancer patients to improve the therapy were:
Prognostic influence of revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease, submitted to low dose dobutamine echocardiography
Authors: R Rossini, G Mengozzi, C Palagi, G Musumeci, C Nardi, As Petronio, L Papi, L Frediani, Di Bello, M Mariani
Journal: Circulation (2001)
Alcoholism and forcible rape
Authors: R T Rada
Journal: American Journal of Psychiatry (1975)

Data collected from detailed autobiographies of 77 convicted rapists revealed that 50 percent of them were drinking at the time of the rape and that 35 percent were alcoholics. This strong association between alcoholism and forcible rape highlights the importance of follow-up treatment programs for the alcoholic sex offender; such programs should focus on adequate control of his drinking behavior as well as on his sexual adjustment.
A systematic review on the efficacy of repeat hepatectomy for recurrent liver metastases from colorectal carcinoma
Authors: J. Sim, T. D. Yan, D. Black, D. L. Morris
Journal: Journal of Clinical Oncology (2007)

14506 Background: Liver recurrence after hepatectomy for colorectal liver metastases (CRLM) is common and associated with a reduced survival if not treated aggressively. The objectives of this systematic were to critically appraise the quantity and quality of current clinical evidence and demonstrate the efficacy of repeat hepatectomy for CRLM. Methods: Electronic searches for relevant studies published in peer-reviewed medical journals on repeat hepatectomy for recurrent CRLM prior to September 2006 were performed on six databases. The reference lists of all retrieved articles were manually searched for further identification of potentially relevant studies. All relevant articles identified were assessed with application of selection criteria. The quality of each included study was assessed. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies. Results: Seventeen studies with more than 20 patients were included for quality appraisal and data extraction. These 17 studies consisted of two multi- institutional, one bi-institutional and 14 single-center observational studies. The overall perioperative morbidity rate ranged from 7–30% and mortality rate varied from 0–5%. The rates of intra-abdominal abscess, wound infection, bile leak, hepatic failure and pleural effusion ranged from 2.4–23%, 2.4–11%, 0.8–10%, 0–4.5% and 2.4–9.5%, respectively. The overall median survival since initial hepatectomy was 26 to 73 months. The overall median survival since the repeat hepatectomy ranged from 23 to 56 months, with 3- and 5-year survival of 24–68% and 21–49%, respectively. The median disease-free survival ranged from 9 to 52 months, with 3- and 5-year disease-free survival of 16–68% and 16–48%, respectively. After repeat hepatectomy the rates of disease recurrence in the liver and at an extra-hepatic site were 15–67% and 27–64%, respectively. Conclusions: The current literature suggests that repeat hepatectomy is associated with a prolonged survival for recurrent CRLM. Although all studies were observational case series, repeat hepatectomy is justified in selected patients, as there is a lack of evidence for alternative treatment. No significant financial relationships to disclose.