tbuckley/cabot-search huggingface dataset:
High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney
Authors: Takeshi Yamamoto, Yoshitsugu Takabatake, Atsushi Takahashi, Tomonori Kimura, Tomoko Namba, Jun Matsuda, Satoshi Minami, Jun-ya Kaimori, Isao Matsui, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Yoshitaka Isaka
Journal: Journal of the American Society of Nephrology (2016)

Excessive fat intake contributes to the progression of metabolic diseases via cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.
Breast cancer molecular subtypes in Omani patients: Correlation with age, histology, stage distribution, and outcome—An anaylsis of 542 cases.
Authors: I. Mehdi, A. a. Abdulmasood, B. J. Al Bahrani
Journal: Journal of Clinical Oncology (2011)

219 Background: Breast cancer is the commonest malignancy and major health issue globally. There is initial evidence and high possibility of molecular differences across the ethnic and geographic groups; responsible for variation in presentation, responses to treatment, and outcome. Methods: Breast cancer data from 2006 to 2010 at National Cancer Center, The Royal Hospital Oman was retrospectively retrieved from electronic record system, and analyzed with respect to ER, PR, and HER2 status. The molecular subtypes were correlated with age, histology, and treatment out come. The results were compared with published international/regional data. Results: Total 542 cases were available for evaluation (535 male and 7 male: 459 Omani and 83 Non-Omani). Right, left, and bilateral tumors were 42.6%, 51.4%, and 6%. IDC were 79.6%. G1 were 7.7%, while other grades were equally distributed. Luminal A, B, basal-like (TNBC), and HER2 positive were 35.9%, 15.8%, 25.5%, and 22.8% respectively. Their age (cut off 50 years) was a significant factor in basal-like (63.8% vs. 36.2%) and HER2 tumors (61% vs. 39%). High-grade tumors were highest (41%) in basal tumors and lowest in Luminal A (19%). Higher stage at presentation (stage 3 and 4) was highest in HER2 tumors (59%). Mortality was recorded higher 22.4% in basal-like/TN tumors. Table shows comparison with selected published data. Conclusions: The molecular classification and subtyping have shown ethnic and geographic variation in taxonomy. These differences may have diagnostic, therapeutic, and prognostic implications. Large scale and multicenter studies may confirm these findings. They can be translated and incorporated to management strategies wherever applicable. [Table: see text]
Results of a comparison between European countries for esophagectomy and gastrectomy: Initiative for a European upper GI audit (EURECCA Upper GI).
Authors: Cornelis J. H. Van De Velde, Johan L. Dikken, Michel W. Wouters, Hein Putter, Valery E. P. Lemmens, Marcel Verheij, Annemieke Cats, Jan Johansson, Lone S. Jensen, William H. Allum, Victoria Coupland, Johanna W. van Sandick
Journal: Journal of Clinical Oncology (2012)

98 Background: In Europe, several countries have implemented national audit programs to reduce variation in outcomes and improve care for esophageal and gastric cancer. These audits provide insight in national variations, but currently no international comparisons can be made. Purposes of the current study were to compare patterns of care and outcomes in several European countries, and to evaluate the effect of hospital volume on outcomes for esophagectomy and gastrectomy. Methods: Data were obtained from national cancer registries or audits in the Netherlands, Sweden, Denmark, and the United Kingdom. Differences in postoperative 30-day mortality and 2-year survival were adjusted for available case-mix variables and separately analyzed for esophagectomy and gastrectomy, using generalized estimated equations and Cox regression. In the current study, high-volume hospitals were defined as hospitals with an annual volume of &gt; 20. Results: From 2004-2009, 10,854 esophagectomies and 9,010 gastrectomies were performed in the participating countries. Availability of case-mix variables varied between countries, and a limited number of variables could be used in the international comparison. On univariate analysis, 30-day mortality and 2 year survival differed significantly between participating countries, but on multivariate analysis, no significant differences were found. The percentage of resections performed in high-volume hospitals varied considerably between countries (esophagectomy: 20% to 94%, gastrectomy: 0% to 59%). Increasing annual hospital volume was associated with lower 30-day mortality after esophagectomy (P &lt; 0.001) and gastrectomy (P = 0.025), and with improved 2-year survival after esophagectomy (P = 0.004), but not after gastrectomy. Conclusions: This study provides an initial step towards a European Upper GI Cancer Audit. However, with the available data only limited case-mix adjustments could be made. Future steps would include synchronization of registered variables and the use of uniform variable definitions. Increasing annual hospital volume is associated with improved short-term outcomes of upper GI cancer surgery.
Effect of PTEN protein expression on benefit to adjuvant trastuzumab in early-stage HER2+ breast cancer in NCCTG adjuvant trial N9831.
Authors: E. A. Perez, A. C. Dueck, M. M. Reinholz, B. Chen, X. Geiger, R. B. Jenkins, W. L. Lingle, C. Andorfer, N. E. Davidson, S. Martino, P. A. Kaufman, L. A. Kutteh, G. W. Sledge, L. Harris, J. Gralow, A. E. McCullough
Journal: Journal of Clinical Oncology (2011)

10504 Background: Preclinical data suggest that PTEN, a regulator of PI3K/AKT signaling, tumor growth and invasion, is involved in tumor sensitivity to trastuzumab. Thus, we sought to investigate the impact of PTEN expression on the benefit of trastuzumab in the prospective phase III HER2+ adjuvant N9831 study (Perez EA, et al. JCO 2010) We evaluated PTEN prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients (pts) randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C). Methods: The % of cells with PTEN staining at 0 (none), 1+ (weak), 2+ (moderate), and 3+ (strong) intensity was determined in TMA sections containing 3 cores per block (N=1286) or in whole tissue sections (WS) (N=515) using immunohistochemistry (rabbit polyclonal PTEN Ab, Cell Signaling; dilution 1:200, overnight incubation). A tumor was considered positive (PTEN+) if any TMA or WS had ≥1+ cytoplasmic staining in >0% invasive cells. Median follow-up was 6.1 yrs. Results: Of 1,801 pts, 1,341 (75%) were PTEN+. PTEN+ was associated with lower % of hormone receptor positivity (45% vs 55%, chi sq p<0.001) and higher nodal positivity (87% vs 83%, chi sq p=0.04) but not associated with age, race, tumor histology, grade or size. PTEN did not impact DFS within arms (not shown). Between Arms A and C, PTEN+ and PTEN- pts had DFS HRs of 0.65 (p=0.004) and 0.47 (p=0.005) respectively (interaction p=0.15). Between Arms A and B, PTEN+ and PTEN- pts had DFS HRs of 0.71 (p=0.001) and 0.85 (p=0.44) respectively (interaction p=0.48). Conclusions: In contrast to preclinical and limited clinical studies that suggest a decrease in trastuzumab sensitivity in PTEN- tumors, our adjuvant data show benefit of adding trastuzumab for both PTEN+ and PTEN- groups (with slightly greater benefit for PTEN- group). Supported by NIH CA129949 and BCRF. PTEN Arm N Events HR 95% CI P value 5yr DFS + AB 424504 119106 0.71 0.54-0.92 0.001 73.981.0 - AB 176146 5338 0.85 0.55-1.30 0.44 72.377.8 + AC 424413 11977 0.65 0.49-0.87 0.004 73.985.1 - AC 176138 5319 0.47 0.28-0.79 0.005 72.386.7 + BC 504413 10677 0.90 0.67-1.21 0.49 81.085.1 - BC 146138 3819 0.56 0.32-0.97 0.04 77.886.7
NOTCH1 Activation Neutralizes the Unfavorable Prognostic Effect of PTEN Mutations in BFM-Treated Children with T-ALL
Authors: Obul R Bandapalli, Corinne Kox, Martin Zimmermann, Martin Stanulla, Martin Schrappe, Wolf-Dieter Ludwig, Rolf Koehler, Martina U. Muckenthaler, Andreas E Kulozik
Journal: Blood (2011)
Does bladder urothelial cancer behave differently in young patients?
Authors: Z. Wang, Y. Li, H. Lu, X. Zeng, Q. Zhuang, H. Zhu, Z. Hu
Journal: Journal of Clinical Oncology (2011)

294 Background: From 2000 to 2008, the incidence of bladder urothelial cancer in the young adults was diagnosed at an increasing trend at the Tongji Hospital, China. To investigate whether bladder urothelial cancer in patients under the age of 40 years behaves significantly differently from the bladder urothelial cancer in elder patients. Methods: From 1994 to 2008, the records of 4,568 patients with pathological diagnosis of bladder urothelial cancer presented to the Tongji Hospital were retrospectively reviewed. 82 patients were younger than 40 at the time of diagnosis. The clinicopathologic parameters were compared between this group and a serial of 164 older patients during the same time period. The Kaplan-Meier and Cox regression analyses were performed for the survival analysis. Results: 2.05% of patients with pathological diagnosis of bladder urothelial cancer presented to the Tongji Hospital were younger than 40 years (median age 32.93). Compared to the older group, young adults group had a lower sex ratio (male-to-female ratio, 3.4:1vs.6.5:1, p&lt;0.05); much less likely with advanced stages (the percentage of invasive tumor, i.e., T1 or above, 28.1% vs. 52.4%, p&lt;0.01); less with a high grade (the percentage of high grade tumor, 14.6% vs. 22.6%, p&lt;0.05); lower recurrence rate (23.2% vs. 39.6%, p&lt;0.05); less with big tumor size (the percent of tumor size greater than 3 cm, 18.3% vs. 22.0%, p&lt;0.05); and less with multifocal (12.2% vs. 50.6%, p&lt;0.01). Kaplan-Meier method and the log-rank test showed a significantly better cancer specific and overall survival for the group of young patients (p&lt;0.01). The multivariate Cox regression analyses showed the following criteria were independent prognostic factors of overall survival: bladder tumor multiplicity, size greater than 3 cm, T2 or above stage, and high grade. Conclusions: Despite an increasing trend of diagnosis, both the pathologic features and clinical outcomes were significantly better in the young patients with bladder urothelial cancer when compared to their elderly counterparts. These findings suggested that more consevertive management approaches may be warranted for this group of patients even under the circumstances of extensive bladder involvement. No significant financial relationships to disclose.
Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study
Authors: A Desjonquères, P Chevallier, X Thomas, F Huguet, T Leguay, M Bernard, J-O Bay, E Tavernier, A Charbonnier, F Isnard, M Hunault, P Turlure, M Renaud, J-N Bastié, C Himberlin, S Lepretre, B Lioure, V Lhéritier, V Asnafi, K Beldjord, M Lafage-Pochitaloff, M C Béné, N Ifrah, H Dombret
Journal: Blood Cancer Journal (2016)

The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ⩾18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients.
Responses rates and outcome to neoadjuvant chemotherapy in triple-negative breast cancers (TNBC).
Authors: S. P. Neciosup, L. Ventura, H. Gomez, J. A. Pinto, M. J. Marcelo, T. Vidaurre, C. Vallejos Sologuren
Journal: Journal of Clinical Oncology (2011)

e11522 Background: TNBC are characterized by the lack of both hormonal receptors expression and overexpression of human epidermal receptor type-2 (HER2), and represents around of 15% of all invasive breast cancers in our population. Our aim was to describe demographic and clinical characteristics, response to neoadjuvant treatment and survival rates. Methods: We realized a retrospective review of 90 patients diagnosed with TNBC and treated with neoadjuvant chemotherapy at the Instituto Nacional de Enfermedades Neoplásicas during 2002-2008. The main clinicopathological and demographic variables were evaluated to determine risk factors for outcome, pathological response rates, progression free survival (PFS) and overall survival (OS). Results: The median age at diagnosis was 39 years, 15% were nulliparous, 66% had overweight or were obese, 44% had early menarche, 77% were premenopausal, 96% had locally advanced clinical stages, and 97% had infiltrating ductal histology. Different neoadjuvant chemotherapy regimens were used. Adriamycin-cyclophosphamide/paclitaxel was the most frequent (58.8%). Thirthy four patients (37.8%) also received additional neoadjuvant radiotherapy. A total of 32 patients (35%) progressed to neoadjuvant treatment. 64 patients undergone surgery, 11 (17.2%) patients achieved pathologic complete response (pCR) and 53 had residual disease (82.8%). We found significant differences between age and response to therapy (mean of 35.1 years to pCR and 41.3 years to residual disease; P=0.001); number of births (nulliparous or 1 birth VS > 2 births, RR = 3.9; P<0.012); age at first pregnancy (< 30 VS ≥ 30 years old; RR= 0.2; P=0.002). 26 patients (28%) had recurrent disease. Median of Follow-up was 3.4 years. The 3 years-OS was 52.4% and 3 years-PFS was 59.0%. The 3 years-OS for patients who achieved pCR was 100% and 63.0% for patients with residual disease (P = 0.034).The 3 years-PFS for patients who achieved pCR was 90.9% and 51.7% for patients with residual disease (P = 0.036). Conclusions: TNBC in our institution showed pCR similar to those found in other international series. Age at diagnostic, number of births and age at first pregnancy were identified as risk factors for response to therapy.
Preclinical evaluation of <sup>99m</sup>technetium-HYNIC(tricine/TPPTS)-aca-bombesin(7–14) as a targeted imaging agent in prostate cancer.
Authors: H. J. Ananias, Z. Yu, P. H. Elsinga, I. J. de Jong
Journal: Journal of Clinical Oncology (2011)

122 Background: The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical 99m Technetium-HYNIC(tricine/TPPTS)-Aca-BN(7–14) ( 99m Tc-HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for human prostate cancer in athymic mice. Methods: 99m Tc- HABN was synthesized and its lipophilicity and stability were investigated. The IC 50 , internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. 99m Tc-HABN biodistribution and microSPECT imaging were performed in PC-3 tumor-bearing athymic mice. Results: 99m Tc-HABN was prepared with high labeling yield (&gt;90%), high radiochemical purity (&gt;95%) and a specific activity of ∼19.8 MBq/nmol. The partition coefficient log P value was −1.60±0.06. 99m Tc-HABN proved to be stable in human serum for 6 hours. The IC 50 of HABN was 12.81±0.14 nM. Incubation of PC-3 cells with 99m Tc-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with 99m Tc-HABN the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24±0.64 %ID/g after 30 minutes, with a steady decrease during the 4 hours study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. 99m Tc-HABN microSPECT imaging resulted in clear delineation of the tumor. Conclusions: 99m Tc-HABN is a novel BN-based radiopharmaceutical that appears to be suitable for targeted imaging of prostate cancer. No significant financial relationships to disclose.
Effect of chronic treatment of combined statins and aspirin on the risk of prostate cancer detection.
Authors: Cristina Suarez, Rafael Morales, Jose Placer, Isaac Nunez, Jacques Planas, Claudia María Valverde, Jordi Ropero, Xavier Maldonado, Juan Morote, Joan Carles
Journal: Journal of Clinical Oncology (2012)

185 Background: The role of chronic treatment (ChT) with statins and aspirin on prostate cancer (PC) carcinogenesis is controversial. Both drugs are frequently used in adult men who are at risk of PC, and many of them receive both drugs simultaneously. The impact of the combined treatment (CT) with statins and aspirin on PC risk has never been reported. We proposed to explore the influence of ChT with statins and aspirin in the PC risk detection and their aggressiveness. Methods: 2408 men were consecutively biopsied for cause: PSA &gt; 4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). ChT with statins and aspirin (&gt;1 year) was controlled. Median age was 68 years (46–86) and median PSA 7.0 ng/mL (0.7-1279). At least 10 cores, plus 1 to 8 additional cores, were obtained. The PC detection rate was 35.2% and the Gleason score was &lt; 7 in 20.8%, 7 in 50.9% and &gt; 7 (HGPC) in 28.3%. Multivariate and univariate analysis were done and OR calculated to analyze the strength of the relationships. Results: 440 men (18.3%) were receiving statins alone (SA), 160 (6.6%) aspirin alone (AA), and 304 (12.6%) both drugs simultaneously. Multivariate analysis showed that CT was the only independent predictor of a reduced risk of PC detection, p=0.025, (OR 0.589, 95%CI 0.370-0-936). PC was detected in 552 of 1502 men (36.7%) not receiving statins or aspirin, 34.5% (152/440) receiving SA, 40% (64/160) receiving AA, and in 26.3% (80/304) receiving statins and aspirin simultaneously. Related to cancer aggressiveness, multivariate analysis showed that combined treatment predicted significantly an increased risk of HGPC, p=0.013, (OR 2.672, 95%CI 1.226-5.825). HGPC was detected in 136 of 552 (24.6%) PCs detected in men not receiving statins or aspirin, in 40 of 152 (26.3%) PCs detected in men receiving SA, in 24 of 64 (37.7%) PCs detected in men receiving AA, and in 40 of 80 (50%) PCs detected in men receiving statins and aspirin simultaneously. Conclusions: This study suggests that ChT with the combination of statins and aspirin reduce significantly the risk of PC detection in men subjected to prostate biopsy for cause. However, this reduction of PC detection is accompanied by a significant increase of PC aggressiveness.
Comparison of Outcomes for Myeloablative Conditioning Regimens Combining Busulfan with Either Cyclophosphamide or Fludarabine in Children
Authors: Andrew C. Harris, Jaap Jan Boelens, Kwang Woo Ahn, Mingwei Fei, Allistair Abraham, Andrew Artz, Christopher C. Dvorak, Haydar Frangoul, Cesar O Freytes, Robert Peter Gale, Sanghee Hong, Hillard M. Lazarus, Shin Mineishi, Taiga Nishihori, Tracey O'Brien, Kirsten M. Williams, Marcelo C. Pasquini, John E Levine
Journal: Blood (2016)
Early Molecular Response in Chronic Myeloid Leukemia Patients Predicts Future Response Status
Authors: Irina Martynkevich, Vasily Shuvaev, Ekaterina Petrova, Lyubov Polushkina, Lyudmila Martynenko, Marina Ivanova, Natalya Cybakova, Elizaveta Kleina, Elena Shabanova, Mikhail Fominykh, Kudrat Abdulkadyrov
Journal: Blood (2014)
Usefulness of an original self-completed questionnaire for screening of cancer-related mental disorder in patients with newly diagnosed early breast cancer.
Authors: K. Kawaguchi, S. Tuyuki, E. Y. Yoshitoshi, M. Honda, M. Takase, Y. Yoshida, Y. Kono
Journal: Journal of Clinical Oncology (2011)

267 Background: Cancer-related mental disorder reduces (e.g., depression and anxiety disorder) not only treatment compliance but also compromises the quality of life of the patient. However, psychiatric intervention at the cancer notification has been barely performed in Japan because Japanese people traditionally tend to have a prejudice against psychiatric consultation and about sexual activity. In order to provide more effective treatment for breast cancer patients, it is necessary to treat cancer-related mental disorder in Japan. Methods: Based on Self-rating Depression Scale, Hamilton's Rating Scale for Depression and Beck Depression Inventory, the questionnaires were modified for Japanese patients by psychiatrists and clinical psychologists of our hospital. We asked newly diagnosed breast cancer patients an original self-completed questionnaire regarding the depression and anxiety disorder between January 2010 and March 2011. This questionnaire consists of 14 questions about depression and anxiety disorder without questions of sexual activity, which has two points each question (maximum total points were 28). We recommended the psychiatric interference by a psychiatrist and the clinical psychologist to all patients with more than 14 points in this questionnaire. Results: We obtained data from 116 patients. No patient refused to answer the questionnaire. 23 patients had higher than 14 points in this questionnaire. Of 23 patients, 9 patients received psychiatric intervention without medication, and four patients received psychotropic medications. Based on the results, we avoided the administration of anticancer agent by intravenous infusion in three patients who had higher than 14 points in the questionnaire. Multivariate analysis revealed that unmarried status is associated with a significantly higher score (OR 16.1; p = 0.013). Conclusions: Our data suggest that our original self-completed questionnaire is useful for the screening of the cancer-related mental disorder in order to provide appropriate therapy to newly diagnosed breast cancer patients.