tbuckley/cabot-search huggingface dataset:
Pituitary adenylate cyclase‐activating polypeptide promotes eccrine gland sweat secretion
Authors: S. Sasaki, J. Watanabe, H. Ohtaki, M. Matsumoto, N. Murai, T. Nakamachi, J. Hannibal, J. Fahrenkrug, H. Hashimoto, H. Watanabe, H. Sueki, K. Honda, A. Miyazaki, S. Shioda
Journal: British Journal of Dermatology (2016)

Sweat secretion is the major function of eccrine sweat glands; when this process is disturbed (paridrosis), serious skin problems can arise. To elucidate the causes of paridrosis, an improved understanding of the regulation, mechanisms and factors underlying sweat production is required. Pituitary adenylate cyclase-activating polypeptide (PACAP) exhibits pleiotropic functions that are mediated via its receptors [PACAP-specific receptor (PAC1R), vasoactive intestinal peptide (VIP) receptor type 1 (VPAC1R) and VPAC2R]. Although some studies have suggested a role for PACAP in the skin and several exocrine glands, the effects of PACAP on the process of eccrine sweat secretion have not been examined.To investigate the effect of PACAP on eccrine sweat secretion.Reverse transcriptase-polymerase chain reaction and immunostaining were used to determine the expression and localization of PACAP and its receptors in mouse and human eccrine sweat glands. We injected PACAP subcutaneously into the footpads of mice and used the starch-iodine test to visualize sweat-secreting glands.Immunostaining showed PACAP and PAC1R expression by secretory cells from mouse and human sweat glands. PACAP immunoreactivity was also localized in nerve fibres around eccrine sweat glands. PACAP significantly promoted sweat secretion at the injection site, and this could be blocked by the PAC1R-antagonist PACAP6-38. VIP, an agonist of VPAC1R and VPAC2R, failed to induce sweat secretion.This is the first report demonstrating that PACAP may play a crucial role in sweat secretion via its action on PAC1R located in eccrine sweat glands. The mechanisms underlying the role of PACAP in sweat secretion may provide new therapeutic options to combat sweating disorders.
Abstract 2007: Transcriptional regulatory program controlled by the oncogenic transcription factor LMO1 in neuroblastoma
Authors: Takaomi Sanda, Koshi Akahanse, Brian J. Abraham, Nina Weichert, Adam Durbin, Lars Anders, Shi Hao Tan, Alice Wei Yee Yam, Lee N. Lawton, Richard A. Young, John M. Maris, A Thomas Look
Journal: Cancer Research (2016)

Abstract Neuroblastoma is an embryonal tumor of the peripheral sympathetic nervous system, accounting for 15% of all childhood cancer deaths. Both overexpression of the transcription factor LMO1 and the polymorphisms within this gene locus are associated with the susceptibility to neuroblastoma, but the oncogenic roles of LMO1 in neuroblastoma pathogenesis have not been elucidated. The roles of LMO1 in T-cell acute lymphoblastic leukemia (T-ALL) are better understood, and these suggest that some of its effects may be similar between the two malignancies. Here we identify the transcriptional regulatory program controlled by LMO1 in neuroblastoma and T-ALL cells. Knockdown of LMO1 induces apoptotic cell death in both tumor types. ChIP-seq and microarray analyses demonstrate that LMO1 frequently co-occupies its target genes with GATA3 and regulates gene expression in a tissue-specific manner. LMO1 positively regulates genes involved in neuronal development, tumor invasion and metastasis in neuroblastoma cells, whereas it regulates genes involved in lymphopoiesis and immune function in T-ALL cells. Gene set enrichment analysis reveals that many genes bound by LMO1 and GATA3 are significantly downregulated upon MYCN knockdown in the MYCN-amplified neuroblastoma cells. Importantly, LMO1 binds at the CDK6 gene locus, which is associated with a super-enhancer both in neuroblastoma and T-ALL cells. The mRNA expression of CDK6 is positively correlated with LMO1 expression in primary neuroblastoma samples. Knockdown of LMO1 downregulates CDK6 protein expression, whereas overexpression of LMO1 upregulates CDK6 expression. CDK6 knockdown induces apoptosis both in neuroblastoma and T-ALL cells. Our results indicate that CDK6 is a critical downstream target that is directly activated by LMO1 and is required for cell survival in neuroblastoma and T-ALL cells. Citation Format: Takaomi Sanda, Koshi Akahanse, Brian J. Abraham, Nina Weichert, Adam Durbin, Lars Anders, Shi Hao Tan, Alice Wei Yee Yam, Lee N. Lawton, Richard A. Young, John M. Maris, A Thomas Look. Transcriptional regulatory program controlled by the oncogenic transcription factor LMO1 in neuroblastoma. [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 2007.
Chemotherapy (CT) versus tamoxifen (T) versus chemoterapy plus tamoxifen (CTT) in patients with node-positive (N+), estrogen receptor-positive (ER+) breast cancer (bca): Very late results of an Italian multicentric trial.
Authors: F. Boccardo, P. Guglielmini, A. Marasco, A. Rubagotti
Journal: Journal of Clinical Oncology (2010)

575 Background: CTT is the gold standard for all N+ ER+ early bca pts. However the use of modern genomic platforms suggests that selected groups of these pts might be safely managed by endocrine therapies alone. The GROCTA01 trial was designed to assess whether: 1) T might represent a safe alternative to CT in ER+ pts; 2) CTT would achieve better results than either modality alone. Details and results of this trial have been previously reported (JCO 1990;EJC 1992). Here we present mature data relative also to S, which was a secondary endpoint. Methods: 504 eligible pts were randomly allocated to either 8 q21 CMF(500, 40, 600) cycles followed by 4 q21epirubicin (75) cycles (CT) or Tam, 30 mg daily for 5 years (T) or the combination of the two (CTT). Results: Groups were well balanced in respect to age, menopausal status, median ER concentration, T size and grade, number of involved nodes, and local treatment. At the time of the present analysis (median follow-up:19.6 y, range: 0.5-23 y) 290 pts relapsed and 303 died. The relapse- free survival (RFS) and S outcomes by treatment arm adjusted for menopausal status, T size and grade, and number of involved nodes are provided below (Table). Conclusions: T appears to achieve comparable RFS but significantly better S than CT in ER+, N+ pts, irrespective of their age or menopausal status. The addition of CT to T improves the results in a marginal way mainly at local level, but no benefit on overall and bca specific S has emerged so far. Results of subgroup analysis will be presented. RFS: HR (95%CI) S: HR (95%CI) All sites Distant Local Overall Bca specific Bca nonspecific CT 1.0 0.03 1.0 0.1 1.0 0.2 1.0 0.012 1.0 0.049 1.0 0.6 T 0.77 (0.58-1.02) 0.07 0.77 (0.56-1.06) 0.1 0.76 (0.40-1.43) 0.4 0.67 (0.51-0.89) 0.006 0.73 (0.54-0.98) 0.04 0.60 (0.22-1.63) 0.3 CTT 0.69 (0.52-0.92) 0.01 0.73 (0.53-0.99) 0.05 0.53 (0.26-1.05) 0.07 0.73 (0.56-0.95) 0.02 0.72 (0.54-0.97) 0.03 0.84 (0.34-2.08) 0.7 No significant financial relationships to disclose.
Abstract 2077: Carbonate prodrugs derived from triterpenoids with high cytotoxic activity
Authors: Petr Dzubak, Renata Burianova, Martina Michalova, Barbora Liskova, Milan Urban, Jan Sarek, Adela Galandakova, Jitka Ulrichova, Marian Hajduch
Journal: Cancer Research (2016)

Abstract Number of active anticancer compounds failed in the drug development due to unfavorable pharmacological properties. Design of pro-drugs is plausible approach to improve drug-like properties of biologically active compounds. Betulinic acid is a well-known representative of triterpenes, which possess a moderate cytotoxic activity and high selectivity towards the tumor cells. However, its pharmacological properties, particularly solubility and bioavailability, are poor. In order to improve pharmacology of betulinic acid derivatives, we have synthesized and tested activities of above 40 carbonate based prodrugs. We have developed methods for activation of “pro-drug” derivatives of betulinic acid by primary rat hepatocytes. Cytotoxicity of pro-drugs and activated metabolites was measured on the sensitive tumor cell line CCRF-CEM (human T-lymphoblastic leukemia). We have identified 21 prodrugs &amp;gt;10 times more cytotoxic to CCRF-CEM cells after pre-incubation with rat hepatocytes. The best candidate pro-drug showed &amp;gt;100 fold increase of cytotoxicity due to metabolic activation and it was cytotoxic to cancer cells in sub-micromolar concentrations. Our concept and predicted mechanisms of pro-drug activation were verified by HPLC-MS/MS where the pro-drugs and corresponding active compounds were identified and quantified. For the most active derivatives we have tested ADME characteristics and in vivo pharmacokinetics which showed significantly improved drug-like properties. Analysis of anti-cancer activities of the pro-drugs is currently being performed. This work was supported by grants LF_2015_031 and by the National Sustainability Program (LO1304). Citation Format: Petr Dzubak, Renata Burianova, Martina Michalova, Barbora Liskova, Milan Urban, Jan Sarek, Adela Galandakova, Jitka Ulrichova, Marian Hajduch. Carbonate prodrugs derived from triterpenoids with high cytotoxic activity. [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 2077.
Response to comment on “Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice”
Authors: Karen Brown, Alessandro Rufini, Andreas Gescher
Journal: Science Translational Medicine (2016)

Low-dose resveratrol did not have the opposite effect on intestinal adenoma development when given in a standard diet instead of a high-fat diet, although we agree on the need for more information on the interaction of diet-derived compounds such as resveratrol and other lifestyle, metabolic and hormonal factors.
Abstract 1918: The role of miR17-92 in the miRegulatory landscape of Ewing sarcoma
Authors: Raphaela Schwentner, Maximilian Kauer, David Herrero-Martin, Heinrich Kovar
Journal: Cancer Research (2016)

Abstract MicroRNAs (miRNA) serve to fine-tune gene expression and thus play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a given tissue still poses a significant problem since the presence of a seed sequence in the 3′UTR of an mRNA and its expression modulation upon forced ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in ES. Recently, we reported on the EWS-FLI1 microRNA (miRNA) signature based on knockdown experiments in ES cell lines and on differential expression in primary tumors versus mesenchymal stem cells. Comparison of both datasets revealed the miR17-92 cluster to be the top EWS-FLI1 activated miRNA, which is one of the most potent oncogenic miRNAs. The whole cluster is among the small number of miRNAs down-regulated upon knockdown of EWS-FLI1 in multiple ES cell lines. We now report the use of a combination of AGO2 pull-down experiments by PAR-CLIP - to enrich and sequence RISC-associated RNAs - and of RNAseq upon miRNA depletion by ectopic sponge expression to identify the targetome of miR17-92 in Ewing sarcoma (ES) cells We found a significant enrichment of PAR-CLIP hits for members of the miR-17-92 cluster in the 3′UTRs of genes up-regulated in response to mir-17-92 but not miR9 and 10b specific sponge expression. Among them, we consistently identified known (i.e. CTGF, MXD1, CYLD1) and a multitude of so far unknown targets of the oncomir-1 cluster in ES in three PAR-CLIP experiments. Interestingly, approximately a quarter of these genes annotate to the TGFB/BMP pathway, the majority mapping downstream of SMAD signaling. Gene reporter assays using 3’UTRs of select novel candidate genes showed enhancement of luciferase activity upon transfection of a sponge specific to miR-17-92 and 20a, but not to unrelated miR-9 and 10b. Site directed mutagenesis of seed sequences in these 3’UTR confirmed the direct regulation of these genes by miR17-92. Current research focuses on the functional validation of TGFB pathway modulation by miR17-92. This study provides a paradigmatic approach to the comprehensive definition of the targetome for a defined group of miRNAs under physiological conditions. This study was supported by the 7th framework program of the European Commission (FP7-259348, “ASSET”) and the Austrian Science Fund FWF (24708-B21) Citation Format: Raphaela Schwentner, Maximilian Kauer, David Herrero-Martin, Heinrich Kovar. The role of miR17-92 in the miRegulatory landscape of Ewing sarcoma. [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 1918.
Return to play in elite sport: a shared decision-making process
Authors: H Paul Dijkstra, Noel Pollock, Robin Chakraverty, Clare L Ardern
Journal: British Journal of Sports Medicine (2016)

Illness or injury affected four out of every five athletes on the Great Britain Track and Field Team before, during or immediately after the 2012 Olympic Games.1 The return to play (RTP) decision is a case of risk management, and athletes may continue to train or compete, despite being ill or injured. This begs the question: ‘How is the return to play decision made in elite sport’?

RTP decisions are complex, specific to the athlete and type of sport, and often influenced by ‘decision modification’ factors (eg, pressure to return for a major event).2 In the case of a sprinter with a hamstring strain 2 weeks from the World Championships, the final RTP decision-maker might be the athlete. However, the healthcare professional should be the final RTP decision-maker when athlete decision-making capacity is compromised (eg, concussion). Decisions regarding the immediate medical management (including RTP) of an ill or injured player on the field of play should be made by a healthcare professional. The coach or manager should have no say in whether the medical team should attend the athlete, or in immediate player assessment.3 …
Pneumonia presenting with organ dysfunctions: Causative microorganisms, host factors and outcome
Authors: Rosario Menéndez, Beatriz Montull, Soledad Reyes, Isabel Amara-Elori, Rafael Zalacain, Alberto Capelastegui, Javier Aspa, Luis Borderías, Juan J. Martín-Villasclaras, Salvador Bello, Inmaculada Alfageme, Felipe Rodríguez de Castro, Jordi Rello, Luis Molinos, Juan Ruiz-Manzano, Antoni Torres
Journal: Journal of Infection (2016)
Team medical care for oral anticancer agents induced adverse events
Authors: Mikiko Kosaka, Hiroki Yoshioka, Yoshihiro Mori, Tomoko Takemoto, Ayaka Sakase, Atsuko Kamasaki, Eri Miyagawa, Emi Ino, Yukiko Iwanaga, Takashi Mine
Journal: Annals of Oncology (2015)
Case 1-1972
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Howard Ulfelder, Robert E. Scully
Journal: New England Journal of Medicine (1972)

Presentation of CaseA 33-year-old woman was admitted to the hospital because of abdominal bloating and discomfort of one day's duration.The patient had been well until nine months before admission, when she began to experience intermittent abdominal cramps every two or three weeks. Six months before entry an upper gastrointestinal series was normal. Various medications afforded no relief. Two months before admission she became nauseated and began to vomit two or three times per day. The cramps became more severe, occurring almost daily, and she vomited small amounts of blood on several occasions. Six weeks before entry was admitted . . .
Abstract 2667: Platelet microparticles infiltrating solid tumors transfer miRNAs and modulate tumor angiogenesis and growth
Authors: James V. Michael, Jeremy G.T. Wurtzel, Guang Fen Mao, A. Koneti Rao, Nicholas E. Hoffman, Sudarsan Rajan, Muniswamy Madesh, Fabian Jana, Marvin Nieman, Jesse W. Rowley, Andrew S. Weyrich, Lawrence E. Goldfinger
Journal: Cancer Research (2016)

Abstract Platelet-derived microparticles are associated with enhancement of metastasis and poor cancer outcomes. Platelet microparticles can transfer platelet microRNAs (miRNAs) to vascular cells upon co-incubation in vitro, but the contributions of platelet microparticles and miRNAs to tumor progression are still poorly understood. Tumor vasculature is highly permeable, allowing the possibility of platelet microparticle-tumor cell interaction in primary solid tumors. Here we show that platelet microparticles infiltrate solid tumors in humans and mice, attach to tumor cells, and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo as well as in vitro. MiR-24 was a major species in this transfer. We identified RNA targets of platelet-derived miR-24 in lung carcinoma cells, which included mt-Nd2, a mitochondrial mRNA which lacks a 3’-UTR, and Snora75, a non-coding small nucleolar RNA. These RNAs were depleted in platelet microparticle-treated tumor cells, resulting in mitochondrial dysfunction and tumor cell growth inhibition, in a miR-24-dependent manner. Blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by platelet microparticle transfusion. Thus, platelet microparticles inhibit lung carcinoma cell proliferation and solid tumor growth via transfer of miR-24. However, global depletion of platelet miRNAs by platelet-specific deletion of Dicer1 inhibited tumor angiogenesis, platelet microparticle infiltration, and delayed tumor growth in mice. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via microparticles, regulate tumor cell gene expression, and modulate tumor progression, whereas platelet miRNAs promote tumor angiogenesis. These findings shed novel insight onto mechanisms of horizontal gene transfer and add multiple layers to the regulatory roles of miRNAs and platelet microparticles in tumor progression. Citation Format: James V. Michael, Jeremy G.T. Wurtzel, Guang Fen Mao, A. Koneti Rao, Nicholas E. Hoffman, Sudarsan Rajan, Muniswamy Madesh, Fabian Jana, Marvin Nieman, Jesse W. Rowley, Andrew S. Weyrich, Lawrence E. Goldfinger. Platelet microparticles infiltrating solid tumors transfer miRNAs and modulate tumor angiogenesis and growth. [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 2667.
Abstract 1251: Significant growth suppressive effects of TOPK and MELK inhibitors in kidney cancer
Authors: Taigo Kato, Hiroyuki Inoue, Seiya Imoto, Yoshinori Tamada, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura, Jae-Hyun Park
Journal: Cancer Research (2016)

Abstract Kidney cancer is the seventh most common cancer and the tenth most common cause of cancer death for men, and it is the tenth most common cause of cancer for women. The 5-year disease-specific survival has improved from about 50% in 1975-1977 to 65% in 2000-2005, although that of patients at an advanced stage still remains poor with less than 10%; 30% of patients who underwent surgery of localized kidney cancer develop distant metastasis and have limited therapeutic options such as tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors. In addition, the clinical effects of these drugs are limited and patients often discontinue these drugs due to severe side effects including hand-foot syndrome, liver dysfunction and interstitial pneumonia. Therefore, development of more effective therapy for kidney cancer is eagerly expected. T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) are promising molecular targets that play critical roles in cancer cell proliferation and maintenance of their stemness. In this study, we investigated growth promotive effect of TOPK and MELK in kidney cancer and found a complex feedback mechanism of these two molecules. Blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cell. On the other hand, knockdown and overexpression of FOXM1 caused downregulation and upregulation of both TOPK and MELK mRNA levels, respectively, suggesting that FOXM1 is a critical transcriptional factor for these two molecular targets. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth and the combination of these two compounds additively induced the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 should produce synergistic anti-tumor effects with low risk of side effects. Citation Format: Taigo Kato, Hiroyuki Inoue, Seiya Imoto, Yoshinori Tamada, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura, Jae-Hyun Park. Significant growth suppressive effects of TOPK and MELK inhibitors in kidney cancer. [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 1251.
TAL1 and MYB Abnormalities in Childhood T-Cell Acute Lymphoblastic Leukemia
Authors: Masafumi Seki, Kenichi Yoshida, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Motohiro Kato, Shunsuke Kimura, Ryoji Hanada, Katsuyoshi Koh, Satoru Miyano, Toshihiko Imamura, Keizo Horibe, Nobutaka Kiyokawa, Atsushi Manabe, Akira Ohara, Yasuhide Hayashi, Akira Oka, Seishi Ogawa, Junko Takita
Journal: Blood (2015)
Academics should leave research credentials behind when they move, Stern report says
Authors: Nigel Hawkes
Journal: BMJ (2016)

Some methods used by universities to burnish their research credentials should no longer be permitted within the Research Excellence Framework, a committee chaired by Lord Stern has recommended.1

Under existing rules universities can recruit high ranking academics at the last minute, rather like Premier League football clubs buying top players in the transfer window. These star recruits, sometimes on fractional contracts that involve little real commitment, bring their research excellence scores with them, adding lustre to the universities they join.

In addition, universities can list as many or as few of their staff as they wish, controlling the denominator used in calculating research excellence. By listing only a small number of research high fliers, they can make their research productivity look better than universities that include all or most of their academic staff.

Under Stern’s proposals neither of these devices would be available in …