tbuckley/cabot-search huggingface dataset:
Long-Term Effects of High-Protein Diets on Renal Function
Authors: Anne-Lise Kamper, Svend Strandgaard
Journal: Annual Review of Nutrition (2017)

Chronic kidney disease (CKD) has a prevalence of approximately 13% and is most frequently caused by diabetes and hypertension. In population studies, CKD etiology is often uncertain. Some experimental and observational human studies have suggested that high-protein intake may increase CKD progression and even cause CKD in healthy people. The protein source may be important. Daily red meat consumption over years may increase CKD risk, whereas white meat and dairy proteins appear to have no such effect, and fruit and vegetable proteins may be renal protective. Few randomized trials exist with an observation time greater than 6 months, and most of these were conducted in patients with preexisting diseases that dispose to CKD. Results conflict and do not allow any conclusion about kidney-damaging effects of long-term, high-protein intake. Until additional data become available, present knowledge seems to substantiate a concern. Screening for CKD should be considered before and during long-term, high-protein intake.
Abstract 1857: Dysregulation of transsulfuration enzymes contribute to malignant transformation in a murine model of colitis-associated carcinogenesis
Authors: Paul Johnson, Ches’Que M. Phillips, Carl Grim, John R. Zatarain, Aakash H. Gajjar, Suimin Qiu, Rui Wang, Celia Chao, Iryna V. Pinchuk, Mark R. Hellmich
Journal: Cancer Research (2016)

Abstract Introduction: Ulcerative colitis (UC) is a highly morbid, chronic inflammatory disease characterized by mucosal ulceration of the colonic mucosa and is associated with the higher risk of colitis-associated cancer (CAC). The exact mechanism(s) causing UC progression to CAC is currently unknown. The balanced activity of transsulfuration pathway enzymes, cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS), and their production of endogenous hydrogen sulfide gas, are critical to maintenance of the colonic homeostasis. CSE activity is suggested to be important for wound healing and mucosal protection. Consistent with this, we have previously showed a decrease CSE expression in human colonic mucosa obtained from patients with chronic UC, compared to normal colonic mucosa by immunocytochemistry. By contrast, increased CBS expression is implicated in the progression of sporadic colorectal carcinoma. However, the role of these enzymes in CAC is unknown. We hypothesize that the dysregulation in CSE/CBS expression and activity is important to the progression from UC to CAC. Methods: CSE null mice and wild type Sv129/B6 (control) mice were used in azoxymethane-dextran sodium sulfate (AOM-DSS) colon cancer model which mimics human CAC. The disease development was followed up to day 80. Confocal microscopy and Western blot was used to assess the gene expression during cancer development. Size, number, and time interval to tumor formation, as well inflammation were assessed. Results: Abrogation of CSE expression using CSE null animals in AOM-DSS model of CAC accelerated the time to tumor development and resulted in an increase in both tumor size (p&amp;lt;0.001) and number (p&amp;lt;0.001) compared to wild-type controls. CBS protein expression was increased within the colonic tumor when compared to the normal margin in AOM-DSS treated animals by Western blot analysis and tissue immunostaining. Interestingly, CAC liver metastases, an exceedingly rare finding in this mouse model, were identified. Conclusion: Taken together, our human and murine data suggest that dysregulation in the transsulfuration pathway enzymes CSE and CBS expression/activity may be critical contributor to the CAC development in UC and may serve as a potential biomarker for disease progression in the future. Citation Format: Paul Johnson, Ches’Que M. Phillips, Carl Grim, John R. Zatarain, Aakash H. Gajjar, Suimin Qiu, Rui Wang, Celia Chao, Iryna V. Pinchuk, Mark R. Hellmich. Dysregulation of transsulfuration enzymes contribute to malignant transformation in a murine model of colitis-associated carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1857.
Safety, pharmacokinetic, and antitumor activity of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors.
Authors: Yongkun Sun, Wei Niu, Yihebali Chi, Chuan Li, Chun-Xia Du, Shuting Li, Jinwan Wang, Li Li, Fengqi Wang
Journal: Journal of Clinical Oncology (2015)

e13586 Background: To establish the safety, pharmacokinetics, recommended dose, and antitumor activity of anlotinib, a novel oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. Methods: Anlotinib was given orally once a day for consecutive 4 weeks or 2 weeks on/1 week off. In consecutive dose group, 5mg/d (n = 4) and 10mg/d (n = 4) was explored; in 2 weeks on/1 week off group, 10mg/d (n = 3), 16mg/d (n = 3), and 12mg/d (n = 21) was explored. Human plasma and urine samples were analyzed by liquid chromatography-mass spectrometry. Results: Dose-limiting toxicities (DLT) at the 10mg/d for consecutive 4 weeks group was grade 3 hypertension, and significant accumulation of anlotinib was observed. For 2 weeks on/1 week off group, DLT were grade 3 hypertension and grade 3 fatigue at the dose of 16 mg/d, the maximum-tolerated doses (MTD) was 12mg/d, the plasma concentration of anlotinib was well controlled. Anlotinib reached its maximum plasma concentration with Tmax of 4–11 h after orally administration at 10, 12, or 16 mg/subject. Then it eliminated slowly with t1/2of 64–136 h and MRT of 124–167 h. 20 patients of the 21 patients at the dose of 12mg/d (2 weeks on/1 week off) were assessable for efficacy; 3 patients had a partial response(include renal cancer(n = 2), and soft tissue tumor),14 patients had stable disease(include medullary carcinoma of thyroid, NSCLC, colon cancer, melanoma, thymic carcinoma, and adenoid cystic carcinoma), with 9 patients lasting > 72 weeks. Conclusions: Oral anlotinib was well tolerated and appeared to provide broad-spectrum antitumor activity. Anlotinib at 12mg/d (2 weeks on/1 week off) is recommended for ongoing and future studies. Clinical trial information: NCT01833923.
Abstract 216: The effect of UCP2 upregulation on cellular redox status and mitochondrial respiration
Authors: Annapoorna Sreedhar, Yunfeng Zhao
Journal: Cancer Research (2016)

Abstract Uncoupling protein 2 (UCP2) is a mitochondrial protein present in the inner mitochondrial membrane. They belong to the family of anion mitochondrial carriers. UCP2 are thought to have natural antioxidant effect by attenuating the generation of superoxides. Since cancer cells exhibit elevated oxidative stress, they can effectively adapt to this situation by upregulating UCP2. As a matter of fact, UCP2 is overexpressed in many forms of cancer including prostate, breast, lung and head &amp; neck. Not surprising, our early studies demonstrate that knockout of UCP2 suppresses skin tumor formation in a multistage skin carcinogenesis model. The purpose of this study was to detect the impact of UCP2's upregulation on mitochondrial redox status and mitochondrial respiration, using the well characterized tumor promotion model, JB6p+ cells. Our results have demonstrated that UCP2 overexpression enhanced protein expression and activity levels of manganese superoxide dismutase (MnSOD), a mitochondrial-resident enzyme that governs the egression of superoxides. To assess the impact of MnSOD upregulation on mitochondrial redox status, levels of superoxides and hydrogen peroxides were detected. Our results indicated that MnSOD upregulation maintained steady flow of hydrogen peroxides originating from mitochondria. We further examined the effect of UCP2 upregulation-induced MnSOD expression on mitochondrial respiration and glycolytic rate. In agreement with our data, cells overexpressing UCP2 had significantly higher oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). In conclusion, our data suggests that UCP2 promotes carcinogenesis via decreasing superoxide generation whereas promoting hydrogen peroxide production via elevating MnSOD. Collectively, our results support the hypothesis that enhanced UCP2 expression sustains metabolic switch in cancer cells. Citation Format: Annapoorna Sreedhar, Yunfeng Zhao. The effect of UCP2 upregulation on cellular redox status and mitochondrial respiration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 216.
Abstract 2381: A multiancestral model of colorectal cancer:in vivoevidence that early heterogeneity contributes to cancer progression
Authors: Alyssa A. Leystra, Brook Luers, Junbo Son, Chelsie K. Sievers, Amanda M. Wisinger, Alexander R. Schwartz, Christopher D. Zahm, Kristina A. Matkowskyj, Dawn M. Albrecht, Linda Clipson, Dustin A. Deming, Michael A. Newton, Richard B. Halberg
Journal: Cancer Research (2016)

Abstract Background: Intratumoral heterogeneity has been linked to tumor progression and chemotherapy resistance in the clinic. Recent models of colorectal tumor evolution indicate that heterogeneity likely arises early during the first few cell divisions and is maintained in a non-Darwinian fashion with discrete clones coevolving. However, how this heterogeneity arises is not fully understood. We propose that some cancers are derived from multiple unique ancestors, and that discrete clones enhance establishment, growth, progression, and resistance to therapy. Methods: Mice carrying the Min allele of Apc and expressing a constitutively active form of PI3K in a subset of colonic epithelial cells develop multiple adenomas and adenocarcinomas in the colon. Cell lineage tracing and fluorescent endoscopy were used to follow the progeny of individual founding cells through establishment, growth, progression, and response to targeted therapy. Cell sorting and 3D tumor spheroid co-culture were used to further examine the growth behavior and treatment response in vitro. Results: Nearly half (44%; 30/68) of the tumors were derived from at least two ancestral clones. The presence of multiple clones was associated with an increased likelihood of a tumor becoming invasive (p = 0.006). Moreover, each clone was more invasive within multi-ancestral tumors than within their homotypic counterparts, indicating that the increased invasion is shared among clones rather than owing to a single dominant clone (p = 0.05). Additionally, the presence of both clones appeared to protect susceptible clones from targeted therapy. In vitro experiments demonstrated that co-evolved clones adopted similar growth patterns, whereas independently evolved clones did not. Conclusions: Taken together, these data strongly indicate that distinct tumor founding cells and their coevolving progeny can contribute to tumor establishment and moreover can enhance growth and survival during tumor progression and response to therapy. Citation Format: Alyssa A. Leystra, Brook Luers, Junbo Son, Chelsie K. Sievers, Amanda M. Wisinger, Alexander R. Schwartz, Christopher D. Zahm, Kristina A. Matkowskyj, Dawn M. Albrecht, Linda Clipson, Dustin A. Deming, Michael A. Newton, Richard B. Halberg. A multiancestral model of colorectal cancer: in vivo evidence that early heterogeneity contributes to cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2381.
Abstract 3174: Colon cancer molecular subtypes: Concordance, effect on survival and selection of most representative preclinical models
Authors: Zsófia Sztupinszki, Balázs Győrffy
Journal: Cancer Research (2016)

Abstract Introduction: Colon cancer is a genetically heterogeneous disease and there is an increasing need for more detailed classification of stage II and III patients. The NCCN guideline currently lists three FDA approved gene-expression based multi-gene prognostic tests for stage II-III colorectal cancer. However, it is undecided how many molecular subtype would most accurately describe these tumours. Here, we cross-validated known molecular subtypes for their concordance and capability to predict prognosis free survival. We utilized gene expression signatures to identify the most representative cell line model for each subtype. Materials and methods: Using publicly available datasets from the GEO repository we established a database containing clinical and microarray data for 2,166 colon cancer patients. Gene expression measured on Affymetrix HG-U133A and HG-U133 Plus2.0 arrays was processed according to authors’ description for each classifier in R. We conducted a systematic review of the literature in order to identify gene-expression based classifiers. We assigned each sample for these classificators and then compared their potential to predict recurrence free survival. Results: All together 22 different molecular subtypes were re-classified including the CCHS, CIN25, CMS, ColoGuideEx, ColoGuidePro, CRCassigner, MDA114, Meta163, ODXcolon, Oncodefender, TCA19, V7RHS classifiers as well as subtypes established by Budinska, Chang, DeSousa, Marisa, Merlos, Popovici, Schetter, Yuen, and Watanabe (first authors). When comparing the methods the most concordant classifiers were MDA114 and DeSousa (Cramer's V = 0.711). The highest efficacy to predict progression free survival in stage II-III patients was achieved by Yuen (p = 3.9e-05, HR = 2.9), Marisa (p = 2.6e-05, HR = 2.6) and Chang (p = 9e-09, HR = 2.35). We also assigned 61 colon cancer cell lines from four independent studies to the closest molecular subtype. Conclusion: In summary, here we present a comprehensive analysis of human colon cancer molecular subtypes by cross-validation using independent transcriptomic datasets. Citation Format: Zsófia Sztupinszki, Balázs Győrffy. Colon cancer molecular subtypes: Concordance, effect on survival and selection of most representative preclinical models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3174.
Bendamustine and rituximab act synergistically in vitro and are effective in the treatment of relapsed or refractory indolent and mantle cell lymphomas
Authors: M. J. Rummel, S. Al-Bartran, M. Welslau, D. Kofahl-Krause, H. Duerk, D. Hoelzer, P. S. Mitrou
Journal: Journal of Clinical Oncology (2005)

6565 Bendamustine combines a purine-like benzimidazol and bifunctionally alkylating nitrogen mustard group. The drug is active in a variety of lymphoproliferative disorders without crossresistance to cyclophosphamide. We investigated simultaneous combination of rituximab with bendamustine and found synergistic effects of apoptosis in vitro on lymphoma cell lines (DOHH-2, WSU-NHL) as well as on ex vivo cells of pat. with CLL. Apoptosis was determined by Annexin V and JC-1. The synergistic effects of rituximab in combination with bendamustine were evenly strong when rituximab was applied at a dose, at which half of the CD20 molecules per cell were saturated. Based on our in vitro results we initiated a phase-II study to examine efficacy and toxicity of bendamustine combined with rituximab (BR) as therapy of 1st, 2nd or 3rd relapse. Treatment schedule: 6 x Rituximab 375 mg/qm day 1 combined with 4 x Bendamustine 90 mg/qm day 2+3, every 4 weeks. Included entities: 17 immunocytomas, 16 mantle cell (MCL), 24 follicular, 6 marginal zone lymphomas. 63 pat. entered the study. Results: 57 pat. responded to therapy yielding to an ORR of 90% with a CR-rate of 60%. In MCL an ORR of 75% was achieved with an CR-rate of 50%. All pat. with immunocytome achieved a remission with a CR-rate of 53%. The median duration of remission was 25 months. BR induced considerable low hematological toxicity with only 16% granulocytopenias grade 3 and 4. We conclude that BR seems to be very effective in the treatment of relapsed indolent and mantle cell lymphomas reaching an overall response rate of 90% and a CR rate of 60%. Based upon the encouraging results obtained with BR in this study we initiated two Phase III trials that compare BR to established chemo-immunotherapy regimens. One trial compares BR versus R-CHOP in pat. with previously indolent lymphomas to demonstrate a non-inferiority of BR in comparison to R-CHOP with respect to efficacy but to show a more favorable toxicity profile. The second trial compares BR to fludarabine/rituximab in pat. with relapsed indolent lymphomas. These studies should provide considerable guidance for the appropriate role of bendamustine in the treatment of indolent lymphomas. No significant financial relationships to disclose.
Abstract 1552: Nucleotide excision repair gene expression in childhood acute lymphocytic leukemia is a predictor of early relapse
Authors: Omar Ibrahim, Homood As Sobeai, Stephen G. Grant, Jean J. Latimer
Journal: Cancer Research (2016)

Abstract Double strand break repair and its relationship with genomic instability have been well studied in Acute Lymphocytic Leukemia (ALL). In contrast, base repair mechanisms, such as Nucleotide Excision Repair (NER) have not been well characterized in ALL. The NER pathway addresses base damage resulting in helix distortion and replication stalling, making it important for all types of cancer. Since increased NER is a known mechanism of chemotherapeutic drug resistance, we hypothesize that there will be an increase in the expression of the NER genes at the time of relapse in ALL patients. We have studied the role of NER in ALL by secondary analysis of 2 independent gene expression microarray studies performed by Staal et al. (Set A, GSE18497) and Hogan et al. (Set B, GSE28460). Both studies analyzed matched samples of ALL patients at diagnosis and relapse (41 and 49 pairs, respectively). In Set A we found that 17/20 NER genes have higher expression at the time of relapse, than at the time of diagnosis. 4 of these genes were individually significant. However, in a subset analysis of these data sets, based on the time to relapse, patients who have early (&amp;lt;3 years) vs. late (&amp;gt;3 years) relapse gave distinct results. In Set A, 18/20 NER genes were upregulated at the time of diagnosis in the early relapse group vs. the late relapse group. 4 genes were individually significantly increased. In set B, NER gene expression at the time of diagnosis of patients in the early relapse group was increased in all 20 NER genes when compared to the late relapse group. 7 genes showed individually significant increases in expression. In addition patients in the late relapse group showed an increase in expression of many of the NER genes at time of relapse when compared to time of diagnosis. In conclusion, there are two types of ALL. Early relapsing ALL manifests high NER gene expression at diagnosis with little change at relapse. Late relapsing ALL manifests low NER gene expression at diagnosis with substantial increase at the time of relapse. NER gene expression at the time of diagnosis may allow us to predict which patients are at greatest risk for earlier relapse. This will allow pharmacogenomic targeting of each type of ALL. Citation Format: Omar Ibrahim, Homood As Sobeai, Stephen G. Grant, Jean J. Latimer. Nucleotide excision repair gene expression in childhood acute lymphocytic leukemia is a predictor of early relapse. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1552.
MPC-3100, a fully synthetic, orally bioavailable Hsp90 inhibitor, in cancer patients.
Authors: M. K. Yu, W. E. Samlowski, V. Baichwal, B. Brown, B. A. Evans, D. Woodland, G. Mather, A. Patnaik, A. W. Tolcher, K. Papadopoulos
Journal: Journal of Clinical Oncology (2010)

e13112 Background: MPC-3100 is a fully synthetic, orally bioavailable, Hsp90 inhibitor developed by Myriad Pharmaceuticals, Inc. This study is designed to determine the safety and tolerability of daily oral administration of MPC-3100. Secondary objectives include characterizing pharmacokinetics and assessing anti-tumor activity. Methods: Patients with recurrent cancer refractory to available systemic therapy are enrolled into this modified Fibonacci dose-escalation study. MPC-3100 is administered by mouth in tablet form for 21 consecutive days in a 28-day cycle. Patients are observed for dose-limiting toxicities (DLTs) during the first cycle of treatment. Single-patient cohorts are planned until a grade 2 or greater toxicity occurs during the first cycle. After the occurrence of a grade 2 or greater toxicity, 2 more patients are studied at the same dose level. Subsequent 3-subject cohorts will be studied in the traditional "3 + 3" design. Plasma and peripheral blood mononuclear cells (PBMCs) are obtained before and after MPC-3100 administration to evaluate drug concentration and Hsp70 levels. Patients are treated until disease progression or toxicity. Results: Six patients (median age, 62 years; range, 50-84 years; 4 male; ECOG of 0 or 1; median number of prior therapies, 3; range 2-12) with metastatic cancer [prostate (n=1), melanoma (n=1), leiomyosarcoma (n=2), colon (n=1), adenocarcinoma of unknown primary (n=1)] have been enrolled to 4 dose levels. The mean duration of therapy as of December 7, 2009, was 2.8 months (range 1-7); three patients are actively receiving therapy. Single-patient cohorts were studied for the first three dose levels (50, 100, and 165 mg/m2). The first patient treated at the 245 mg/m2 dose level developed a grade 2 pre-renal azotemia requiring intravenous fluids during the first 8 days of treatment. As a result, 2 more patients were enrolled to this dose level. One of these 2 additional patients experienced a DLT of supraventricular tachycardia and respiratory failure 24 hours after the day 21 dose. Conclusions: MPC-3100 at dose levels up to 165 mg/m2 in cancer patients is safe and well-tolerated. The 245 mg/m2 cohort has been expanded to 6 patients with the development of the first DLT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Pharmaceuticals, Inc. Myriad Pharmaceuticals, Inc.