tbuckley/cabot-search huggingface dataset:
Inhibition of ovarian tumor-associated DJ-1 expression and tumor progression.
Authors: Natasha Gupta, Janice M Bahr, Sameer Sharma, Pincas Bitterman, Alfred S Guirguis, Sanjib Basu, Animesh Barua
Journal: Journal of Clinical Oncology (2014)

e16527 Background: DJ-1, an oncogene product, plays a critical role in tumor survival, invasion and progression. Enhanced expression of DJ-1was associated with increased resistance to cisplatin in several cancers. Long-standing inflammation due to frequent ovulation has been suggested as a risk factor for the development of ovarian cancer (OVCA). The goals of this study were to examine: (1) the changes in DJ-1 expression in association with OVCA progression in patients and (2) prevention of DJ-1 expression by dietary supplementation with Ashwagandha (ASH, a natural product) in laying hens, a preclinical model of OVCA. Methods: Two studies were performed. In the first one, specimen from normal (n = 10) and benign (n = 5) ovarian as well as ovarian epithelial cancers (papillary serous) at early (n= 5) and late stages (n = 10) were collected from patients and processed for DJ-1 expression. In the second one, normal hens or hens with early stage OVCA were selected by ultrasound scanning. Hens were assigned into control (basal diet), 1% and 2%-ASH supplemented groups with 20 hens (15 healthy, 5 with early stage OVCA) in each. All hens received feed and water ad libitum for 90 days and euthanized thereafter. Tumor stages were recorded, serum, normal or cancer ovaries were collected and DJ-1 expression was examined. Results: DJ-1 was localized in the nucleus and cytoplasm of normal, benign and malignant tumor cell. Compared with normal and benign tumors, the intensity of DJ-1 expression was significantly (P<0.05) higher in OVCA patients. A band of 20kDa was detected by Western blotting. Compared with normal hens, intensity of DJ-1 expression was higher in hens with early and late OVCA (P<0.05). Compared with untreated and 1% ASH treated, tumor incidence, progression, and DJ-1 expression decreased significantly (P<0.01) in hens treated with 2% dietary ASH. Conclusions: Results of this study suggest that DJ-1expression increases with OVCA progression, and ASH treatment reduces its expression, and OVCA metastasis. Thus, DJ-1 represents a potential target for OVCA prevention, and ASH may be used to enhance cytotoxicity of conventional chemotherapeutics. This study may form the foundation of a clinical study. Support: DOD award # W81XWH-12-1-0460.
Phase 1 study of preoperative radiotherapy combined with S-1 plus cisplatin in clinically resectable type 4 or large type 3 gastric cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG1205).
Authors: Masaki Yokokawa, Motohiro Imano, Hiroshi Furukawa, Yasumasa Nishimura, Yukinori Kurokawa, Taroh Satoh, Daisuke Sakai, Takushi Yasuda, Haruhiko Imamoto, Toshimasa Tsujinaka, Toshio Shimokawa, Hitoshi Shiozaki
Journal: Journal of Clinical Oncology (2015)

e15207 Background: A phase 1 trial of preoperative RT combined with S-1 plus cisplatin was conducted for patients with advanced gastric cancer (GC). The aim of this study was to determine the recommended dose (RD) of S-1 and cisplatin combined with RT at a fixed dose. Methods: Patients with clinically advanced but potentially resectable, histologically proven GC (type 4 or large type 3), were enrolled to successive cohorts in the conventional 3+3 design. There must be an absence of peritoneal dissemination or a negative finding from peritoneal washing cytology (CY) confirmed by staging laparoscopy. A total of three dose levels were designed as follows : level 0: S-1 60 mg/m2/day from Day 1 to 14 and cisplatin 60 mg/m2 on Day 1 ; level 1: S-1 80 mg/m2/day from Day 1 to 14 and cisplatin 60 mg/m2 on Day 1; level 2: S-1 80 mg/m2/day from Days 1 to 14 and Days 22 to 35 and cisplatin 60 mg/m2 on Day 1 and Day 22. RT at a total dose of 40 Gy in 20 fractions was delivered for 4 weeks. Results: A total of six patients were enrolled from November, 2012 to November, 2013. Three patients were registered at the dose level 1 and completed without showing dose limiting toxicities (DLTs). All the three patients enrolled in the dose level 2 experienced DLTs. Two patients were not able to continue S-1 from hematological reasons and one patient was unsuitable for the surgery within the planned period from severe fatigue. For all the six patients, total gastrectomy with D2 lymph node dissection could be performed without major surgical complications. R0 resection rate was 83% (5/6), one patient underwent R1 resection because of CY1. A metastasis to the gallbladder was detected on one patient during surgery. Pathological complete response rate was 17% (1/6). Majority of grade 3 toxicities were hematological especially in the level 2. As non-hematologic adverse events, G3 hyperkalemia occurred in one patient and G3 nausea was observed in another patient. Conclusions: As all level 2 patients showed DLTs, RD was determined as the level 1 dose. Phase 2 trial using the RD has been started. Clinical trial information: UMIN000008964.
Erratum: Corrigendum: Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia
Authors: Jing Fang, Lyndsey C Bolanos, Kwangmin Choi, Xiaona Liu, Susanne Christie, Shailaja Akunuru, Rupali Kumar, Dehua Wang, Xiaoting Chen, Kenneth D Greis, Peter Stoilov, Marie-Dominique Filippi, Jaroslaw P Maciejewski, Guillermo Garcia-Manero, Matthew T Weirauch, Nathan Salamonis, Hartmut Geiger, Yi Zheng, Daniel T Starczynowski
Journal: Nature Immunology (2017)
Rapid and selective transcriptional induction of the tumor suppressor RhoB by lipid-based Akt inhibitors
Authors: Chunyu Zhang, Abdel Elkahloun, Koffi Messan, Phillip Dennis
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

1230 

Activation of the PI3K/Akt/mTOR pathway contributes to the formation, maintenance, and therapeutic resistance of cancer. Active phosphatidylinositol ether lipid analogues (PIA5, 6, 23, 24, and 25) are analogues of the products of PI3K that inhibit Akt activation, translocation, and the growth of a broad spectrum of cancer cell types. To gain further insight into the cellular and molecular mechanism of PIAs, we performed transcriptional profiling of active PIAs as well as PI3K/Akt/mTOR pathway inhibitors using high-density oligonucleotide arrays representing 34,542 transcripts in NSCLC cells. The tumor suppressor RhoB was identified as one of the early and commonly induced genes by PIAs, and its rapid induction was selective for lipid-based Akt inhibitors (PIA23, perifosine and miltefosine) among the PI3K/Akt/mTOR pathway inhibitors tested (PI3K inhibitors- LY294002 and wortmannin; PDK-1 inhibitor- [OSU03012][1]; Akt inhibitors- PIA23, perifosine, miltefosine, AMPD, API-2, DZ-50; mTOR inhibitors- rapamycin and RAD001). RhoB induction by lipid-based Akt inhibitors was validated by semi-quantitative RT-PCR and immunoblotting. The translation inhibitor cycloheximide and the transcriptional blocker actinomycin D completely prevented this induction, suggesting the increase in RhoB protein by lipid-based Akt inhibitors was due to an increase of RhoB transcription. Comparative genomics across 4 mammalian species (troglodyte, human, mouse and rat) and RhoB promoter-driven luciferase activity assays revealed that a highly conserved region proximal to the transcription start site was responsible for RhoB induction by lipid-based Akt inhibitors, although the basal level of RhoB transcription was dramatically compromised by deleting the upstream region. Deletion of either CEBPB or inverted NFY binding sites in this region completely abolished both basal and induced activities. The upstream region in the longer RhoB promoter constructs, which includes SP1 and NFY binding sites, partially rescued basal but not induced activity in CEBPB binding site mutant, but failed to restore the basal or induced activity in the inverted NFY binding site mutant. The involvement of CEBPB in RhoB induction was confirmed by CEBPB siRNA knockdown assays. These results indicate that CEBPB and inverted NFY binding sites constitute a minimal and essential promoter region for RhoB basal and inductive activities, with greater regulation exerted by the inverted NFY binding site.

 [1]: /lookup/external-ref?link_type=GENPEPT&access_num=OSU03012&atom=%2Fcanres%2F67%2F9_Supplement%2F1230.atom
A pilot phase II multicenter study of nab-paclitaxel (Nab-P) and gemcitabine (G) as preoperative therapy for potentially resectable pancreatic cancer (PC).
Authors: Shawn MacKenzie, Herbert Zeh, Laurence E. McCahill, Timothy D. Sielaff, Nathan Bahary, Thomas Edward Gribbin, John E. Seng, Joseph W. Leach, Jocelyn Harmon, Michael J. Demeure, Daniel D. Von Hoff, A Jim Moser, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2013)

4038 Background: Nab-P plus G is a new option for advanced PC. This combination was evaluated as a preoperative regimen for potentially resectable PC. Methods: Patients (pts, n=25) with resectable PC (NCCN criteria) were treated with 3 cycles of Nab-P (125mg/m 2 ) &amp; G (1000mg/m 2 ) on day 1, 8, and 15, followed by surgical resection. The chosen endpoint was Grade III/IV histological changes (Arch Surg.127:1335-39:1992) in &gt; 30% of resected tumor specimens. Results: Accrual is complete with 25 pts (median age 65, 10 F:15 M), 14/25 completed 3 cycles of treatment. Early drug discontinuation or drug interruption prior to the completion of 3 cycles occurred in 11 pts due to azotemia, cholangitis, pneumonia, catheter infection and pt decision. One pt had a fatal (grade 5) non-neutropenic aspergillus pneumonia. There was one episode of neutropenic fever (4%), and 3 episodes of cholangitis (12%) due to biliary stent malfunction. Other adverse events (grade 3/4) include neutropenia 64%, anemia 20%, dehydration 12%, nausea 12% and thrombocytopenia 12%. Dose reductions due to AEs were required in 5 pts, (3-neutropenia, 2-rash). Surgical resection was successful in 20/25 pts: 12- Pancreaticoduodenectomy, 8- Distal Pancreatectomy, 19/20 pts underwent an R0 resection. Surgical resection was not done in 5/25 pts due to: pre-operatively identified metastatic disease (2), blood vessel involvement at surgery (1), pt declined (1) and a pre-operative death (1).Post-operative tumor staging identified a complete response (n=1); stage IA (n=1); stage IIA (n=6); and stage IIB (n=12). Radiological partial response (PR) was documented in 4 pts prior to surgery. CA19-9 levels decreased from baseline by &gt; 50% in 60% (n=15) of pts and by &gt; 90% in 16% (n=4). Post-operative &gt; 90% histological tumor response (Grade 3/4) was seen in 6 of 20 (30%) resected specimens. Conclusions: Preoperative therapy with Nab-P plus G is feasible with evidence of activity by radiological (PR in 16%), CA19-9 (decrease &gt; 50% in 60% of pts) and pathological down staging (Grade 3/4 in 30% in resected tumor specimens). A larger study is warranted. Supported by Abraxis/Celgene Pharmaceuticals and the TGen foundation. Clinical trial information: NCT01298011.
Gender disparity in breast cancer: A veteran population-based comparison.
Authors: Anita Aggarwal, Brenna R O'Neill, David Maron, Richard L Amdur, Steven H. Krasnow
Journal: Journal of Clinical Oncology (2014)

1606 Background: Male breast cancer (MBC) is <1% of all cancers in men and continues to rise. Because of rarity, there is paucity in literature. Management of MBC is generalized from female breast cancer (FBC). The Veterans Affairs (VA) Central Cancer Registry (VACCR) provides a unique source for the study of MBC. The objective of this retrospective analysis was to compare and contrast the characteristics and outcome of MBC with FBC in the VA population. Methods: VACCR data from 153 VA medical centers were used to analyze the database of VA patients who had breast cancer diagnosed between 1998 and 2013. Primary site codes were identified for breast cancer (50.0-50.9). Data were entered and analyzed using bio-statistical software (SAS 9.3). Results: In total, 6443 patients' records were reviewed, and 1123 MBC were compared with 5320 FBC patients. The mean age at diagnosis was 70 and 57 years for MBC and FBC, respectively (P < .0001). Higher number of MBC (95%) as compare to FBC ( 72%) were age >50years. 75% patients with breast cancer were white in both genders. More MBC (40% vs 24%) presented with higher disease stage (III and IV) in comparison to FBC (21% had DCIS and 53% stage I). The dominant histology was ductal carcinoma. No difference in laterality was observed. Estrogen and progesterone receptor-positive tumors were more common in MBC compared with FBC. 45% and 36% of MBC and FBC, respectively, received hormonal treatment as first course but fewer MBC received chemotherapy and radiation. The mean follow up time was 754 days. As of Dec 2013, 355 (32%) MBC and 791 (15%) FBC died during the course of the study. Males had higher odds of death compared to females after adjusting for age, race, stage, and grade (OR 1.656, 95% CI 1.347, 2.037). Conclusions: To the authors' knowledge, this is the largest series of MBC and FBC to date in the Veterans population. The results suggested that males were older at presentation and had higher stage of breast cancer as compare to FBC. The higher mortality rate in MBC may be due to higher stage and /or tumor biology.
A proposal for a new classification of T4 breast cancer as stage IIIC.
Authors: Hee Jeong Kim, Hwa Jung Kim, Sae Byul Lee, Hyeong-Gon Moon, Woo Chul Noh, Young Up Cho, Youngbum Yoo, Sei-Hyun Ahn
Journal: Journal of Clinical Oncology (2015)

e11585 Background: We compared the survival of patients with Stage IIIB and Stage IIIC tumors and evaluated the prognosis of N3 and T4 to determine the criteria for an update of the classification system. Methods: Using information from two databases, including the nationwide Korean Breast Cancer Registry (KBCR), three cohorts composed of patients from the asan medical center from 1989 to 2002 (cohort I), from 2003 to 2008 (cohort II), and KBCR from 2003 to 2005 (cohort III) were assembled. New classifications were suggested that rearranged Stage IIIB as T1-3N3 disease and Stage IIIC as T4 any N disease. Results: A joint analysis of 9640 invasive breast cancer patients from cohorts I and II showed Stage IIIB had significantly poorer disease-free survival (DFS) and breast cancer-specific survival (CSS) compared with Stage IIIC. These findings were validated by an analysis of 14281 cohort III data. The hazard ratio (HR) of CSS for Stage IIIC cancers was 17.1 (range, 11.9 to 24.6), but 14.1 (range, 11.4 to 17.3) for Stage IIIB cancers. Using our new staging system the new Stage IIIB showed a better DFS (HR 6.5; range, 5.3 to 7.9) and CSS (HR 12.59; range, 9.62 to 16.50) compared with the new Stage IIIC (HR 14.07 for DFS; range, 10. 35 to 19.11; HR 28.95 for CSS; range, 20.22 to 41.44). Conclusions: T4 disease shows a poorer survival outcome than N3T1-3 disease. Reclassification of any T4 disease as Stage IIIC and N3T1-3 disease as Stage IIIB is appropriate
Implementation of a novel primary care-centered clinic for survivorship care.
Authors: Archana Radhakrishnan, Youngjee Choi, Zackary Berger, Craig Evan Pollack, Sydney Morss Dy, Kimberly S. Peairs
Journal: Journal of Clinical Oncology (2017)

41 Background: Patients often face challenges in transitioning to the survivorship stage of cancer care and coordinating with primary care. Prior research has highlighted the uncertainty in who provides survivorship care, leaving patients “lost in transition”. Integrating primary care providers (PCP) into cancer care offers one potential solution. Expanding traditional PCP roles to participating throughout the cancer continuum and familiarizing PCPs with cancer patients’ needs can address this gap. We describe an innovative model of incorporating PCPs to delivering primary care to cancer survivors at a large academic institution. Methods: As one part of a plan to address an identified need for improving survivorship care for cancer patients at Johns Hopkins, PCPs and cancer survivorship care experts developed the Primary Care for Cancer Survivors clinic (PCCS) in 11/2015. The clinic receives referrals from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and patients are seen for either a one-time consultation or can transition their primary care to the clinic. We also are creating a database of internal and external referrals to meet the specific needs identified by patients. We descriptively analyzed the utilization of PCCS from 11/2015 through 9/2016. Results: A total of 35 patients have been seen at PCCS. The average age of patients was 56.8 (SD 12.4) and 32 were female and 3 were male. 24 patients identified as white, 8 black, 1 Asian, and 2 others. Most patients transitioned their PC to the clinic (n = 30). The majority of patients had breast (n = 19) and colorectal cancer (n = 5); 10 patients had metastatic disease (3 have deceased). Commonly, referrals were made to physical therapy, including pelvic rehabilitation and lymphedema management, and nutrition counseling. Conclusions: Patients with a wide variety of cancers and at all stages of disease were seen for survivorship care in the PCCS clinic. Integrating nutrition care, psychosocial support, exercise programs, and palliative care were key early factors in meeting patients’ needs. Continuing to assess and meet survivors’ individual needs and build referral networks are important next steps in the development of the clinic.
Upregulation of the long noncoding RNA UCA1 affects the proliferation, invasion, and survival of hypopharyngeal carcinoma
Authors: Ye Qian, Dayu Liu, Shengda Cao, Ye Tao, Dongmin Wei, Wenming Li, Guojun Li, Xinliang Pan, Dapeng Lei
Journal: Molecular Cancer (2017)

Several long noncoding RNAs (lncRNAs) are involved in oncogenesis. Our microarray analysis showed that numerous lncRNAs are dysregulated in hypopharyngeal squamous cell carcinoma (HSCC) tumor tissues as compared with normal tissues. Among those lncRNAs, urothelial carcinoma-associated 1 (UCA1) has been found to have an oncogenic role in HSCC. We confirmed the upregulation of UCA1 in HSCC by assessing its expression levels in a cohort of 53 patient tumors and paired non-tumor samples. In addition, we found that high UCA1 expression was significantly associated with advanced T category, late clinical stage, greater lymphatic invasion, and worse prognosis. Furthermore, in vitro experiments demonstrated that UCA1 functioned as an oncogene by promoting the proliferation and invasion and preventing the apoptosis of HSCC cells. Taken together, our findings for the first time identify the role of UCA1 as a tumor promoter and a pro-metastatic factor in HSCC, demonstrating that UCA1 is a potential prognostic biomarker and therapeutic target in HSCC.
A good asthma catch by professional fishing
Authors: Peter J. Sterk
Journal: European Respiratory Journal (2017)

How long have we all been circling around asthma in order to capture its driving mechanisms? It is quite confronting that, despite excellent research during the past half century, we are still largely ignorant with regard to the biological pathways that cause and maintain this highly prevalent disease. Fortunately, asthma patients around the world are experiencing, daily, the benefits of solid research, which has led to very effective treatment options, at least for those that have access to good clinical care. Hence – yes – we have learned how to suppress the disease in most (but not all) patients, but it is paradoxical that this has all been achieved without an exact understanding of the fundamental pathogenesis and pathophysiology of the disease. Broad metabolomic profiling of patients with asthma allows discovery of previously unidentified disease mechanisms <http://ow.ly/dHpo309Kf0G>
Evaluation of efficacy of oral administration of pro-drug of triptolide against pancreatic cancer.
Authors: Vikas Dudeja, Nikita Sharma, Shrey Modi, Nipun B. Merchant, Selwyn M. Vickers, Sulagna Banerjee, Ashok Saluja
Journal: Journal of Clinical Oncology (2017)

296 Background: Pancreatic cancer is an aggressive disease. The current chemotherapy only marginally increases the survival of patients with PDAC. Hence there is an urgent need for novel therapies. We have shown that minnelide, a pro-drug of triptolide which is currently in phase I trials, when administered intra-peritoneally is very effective against pancreatic cancer in multiple animal models. In the current study we evaluated the efficacy of oral minnelide against pancreatic cancer, alone or in combination with standard therapy in PDAC. Methods: Xenograft, subcutaneous and orthotopic models were established using S2-VP10 and MIA PaCa-2 cell lines. Minnelide was used in doses ranging from 0.15-0.6 mg/kg/day either oral or i.p. and standard chemotherapy was gemcitabine 250 mg/kg/week + nab-paclitaxel 25 mg/kg/week. The tumor burden was compared between various treatment groups. Results: Minnelide i.p significantly decreased tumor mass in MIA PaCa-2 derived tumors and oral administration had equipotent effects. In the S2-VP10 model, combination of low doses of orally administered minnelide with gemcitabine + nab-paclitaxel was significantly more effective in decreasing the tumor burden leading to an increased survival of tumor bearing mice when compared with either therapy alone (p &lt; 0.05). Combination therapy significantly reduced cancer-related morbidity by decreasing ascites and metastasis. Conclusions: Oral administration of minnelide is effective against pancreatic cancer at doses which have been shown to be safe in phase I clinical trial. Oral minnelide has great potential to emerge as novel therapy for pancreatic cancer.