tbuckley/cabot-search huggingface dataset:
Nucleo-cytoplasmic transport as a therapeutic target of cancer
Authors: Giovanni Luca Gravina, William Senapedis, Dilara McCauley, Erkan Baloglu, Sharon Shacham, Claudio Festuccia
Journal: Journal of Hematology & Oncology (2014)

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.
Bloody diarrhoea in a hunger striker: starvation colitis
Authors: Stephen Malnick, Ali Abdul-Hai, Ali Abdullah, Yazid Gharaba, Avital Brand, Alon Basevitz, Pavel Alin, Yuval Binder, Ofer Raz, Ehud Melzer, Nadia Ziv-Sokolowski, Marina Somin
Journal: The Lancet (2015)
Clinical End Points and Response Criteria in Mycosis Fungoides and Sézary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer
Authors: Elise A. Olsen, Sean Whittaker, Youn H. Kim, Madeleine Duvic, H. Miles Prince, Stuart R. Lessin, Gary S. Wood, Rein Willemze, Marie-France Demierre, Nicola Pimpinelli, Maria Grazia Bernengo, Pablo L. Ortiz-Romero, Martine Bagot, Teresa Estrach, Joan Guitart, Robert Knobler, José Antonio Sanches, Keiji Iwatsuki, Makoto Sugaya, Reinhard Dummer, Mark Pittelkow, Richard Hoppe, Sareeta Parker, Larisa Geskin, Lauren Pinter-Brown, Michael Girardi, Günter Burg, Annamari Ranki, Maartan Vermeer, Steven Horwitz, Peter Heald, Steve Rosen, Lorenzo Cerroni, Brigette Dreno, Eric C. Vonderheid
Journal: Journal of Clinical Oncology (2011)

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.
THE MOLECULAR GENETICS OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A AND RELATED SYNDROMES
Authors: Jeffrey F. Moley, MD
Journal: Annual Review of Medicine (1997)

Identification of RET gene mutations in patients at-risk for the development of the hereditary forms of medullary thyroid carcinoma has simplified management and expanded the scope of indications for surgical intervention. Patients who carry this mutation can be offered thyroidectomy at a very young age, hopefully at a point when the cancer has not yet developed or spread. Those who are found not to have inherited the mutation are spared further genetic and biochemical screening. This achievement marks a new paradigm in surgery--the recommendation that an operation be performed based on the result of a genetic test. Experience with management of patients with multiple endocrine neoplasia types 2A and 2B and with familial, non-multiple endocrine neoplasia medullary thyroid carcinoma will provide information that will aid in the future management of patients with other hereditary cancers.
Phase II Study of Feasibility of Dose-Dense FEC Followed by Alternating Weekly Taxanes in High-Risk, Four or More Node-Positive Breast Cancer
Authors: Chau T. Dang, Gabriella M. D’Andrea, Mary E. Moynahan, Maura N. Dickler, Andrew D. Seidman, Monica Fornier, Mark E. Robson, Maria Theodoulou, Diana Lake, Violante E. Currie, Arti Hurria, Katherine S. Panageas, Larry Norton, Clifford A. Hudis
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. Experimental Design: Patients with ≥4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m2, respectively, ×6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2) ×18. Results: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26–63 years), median number of positive nodes was 9 (range, 4–32), and median tumor size was 2.5 cm (range, 0.6–11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. Conclusion: FEC ×6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.
Association between GLUT9 and gout in Japanese men
Authors: W. Urano, A. Taniguchi, N. Anzai, E. Inoue, C. Sekita, H. Endou, N. Kamatani, H. Yamanaka
Journal: Annals of the Rheumatic Diseases (2010)

Recently, the association between single nucleotide polymorphisms (SNPs) in GLUT9 and the serum levels of uric acid (sUA) or gout has been shown in Caucasians.1,–,5 However, the associations have not been replicated in other ethnicities. Here, we report an association between GLUT9 and the development of gout in Japanese men.

We isolated genomic DNA from 181 Japanese male patients with gout6 and from 595 Japanese male controls.7 The genotypes of intronic SNPs in GLUT9 (rs1014290, rs6449213, rs7442295, rs6855911, rs737267), previously reported as associated with sUA or gout,1,–,5 and non-synonymous SNPs (rs1680979, rs3733591, rs2280205) were determined using the TaqMan method (Applied Biosystems, Foster City, California, USA). Statistical analysis was made by χ2 test, …
Relationship Between Acute Stress Disorder and Posttraumatic Stress Disorder Following Mild Traumatic Brain Injury
Authors: Richard A. Bryant, Allison G. Harvey
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The aim of this study was to index the frequency of occurrence of acute stress disorder following mild traumatic brain injury and to determine its utility in predicting posttraumatic stress disorder (PTSD). METHOD: Consecutive adult patients who sustained a mild traumatic brain injury following a motor vehicle accident (N=79) were assessed for acute stress disorder within 1 month of their trauma with the Acute Stress Disorder Inventory, a structured clinical interview based on DSM-IV criteria. Patients were followed up 6 months after the trauma (N=63) and were administered the PTSD module of the Composite International Diagnostic Interview. RESULTS: Acute stress disorder was diagnosed in 14% of patients, and at follow-up 24% satisfied criteria for PTSD. Six months after the trauma PTSD was diagnosed in 82% of patients who had been diagnosed with acute stress disorder and in 11% of those who had not been diagnosed with acute stress disorder. CONCLUSIONS: These findings point to the frequency of PTSD following mild traumatic brain injury. While the criteria for acute stress disorder are useful in identifying those individuals who are at risk of developing chronic PTSD, the findings suggest that current criteria require modification in order to optimally predict PTSD following mild traumatic brain injury.
OCULAR MANIFESTATIONS OF LESIONS OF THE FIFTH CRANIAL NERVE
Authors: R. F. Moore
Journal: BMJ (1932)

BRITISHT' 783 this and in all other parts of physiology Great Britain is holding her own.But no science, least of all those on which medicine is based, belongs to one country, and neither we nor any other nation can claim to occupy a pre- eminent position in physiology such as might have been granted us three centuries ago as the result of Harvey's epoch-making discovery.
High Protein Intake Associates with Cardiovascular Events but not with Loss of Renal Function
Authors: Nynke Halbesma, Stephan J.L. Bakker, Desiree F. Jansen, Ronald P. Stolk, Dick De Zeeuw, Paul E. De Jong, Ronald T. Gansevoort
Journal: Journal of the American Society of Nephrology (2009)

The long-term effects of higher dietary protein intake on cardiovascular and renal outcomes in the general population are not clear. We analyzed data from 8461 individuals who did not have renal disease and participated in two or three subsequent screenings (6.4-yr follow-up) in a prospective, community-based cohort study (Prevention of Renal and Vascular ENd-stage Disease [PREVEND]). We calculated daily protein intake from 24-h urinary urea excretion (Maroni formula) and used Cox proportional hazard models to analyze the associations between protein intake, cardiovascular events, and mortality. We used mixed-effects models to investigate the association between protein intake and change in renal function over time. The mean +/- SD daily protein intake was 1.20 +/- 0.27 g/kg. Protein intake was significantly associated with cardiovascular events during follow-up. The associations seemed U-shaped; compared with intermediate protein intake, individuals with either higher or lower protein intake had higher event rates. All-cause mortality and noncardiovascular mortality also were significantly associated with protein intake; individuals with low protein intake had the highest event rates. We found no association between baseline protein intake and rate of renal function decline during follow-up. In summary, in the general population, high protein intake does not promote accelerated decline of renal function but does associate with an increased risk for cardiovascular events.
Ciprofloxacin v placebo for treatment of Yersinia enterocolitica triggered reactive arthritis
Authors: J A A Hoogkamp-Korstanje
Journal: Annals of the Rheumatic Diseases (2000)

Patients with yersinia triggered reactive arthritis were double blind randomly allocated to receive treatment with ciprofloxacin 500 mg twice daily orally or placebo during three months. The diagnosis was made by serology (specific IgA and IgG antibodies to yersinia outer membrane proteins (yops)), positive culture, and/or demonstration of <i>Yersinia enterocolitica</i> antigen in colon biopsy specimens. Patients were evaluated monthly during and after treatment up to 12 months. Of 18 patients enrolled, all could be evaluated for safety, 16 for efficacy. There was a tendency towards faster remission and relief of pain in those receiving ciprofloxacin. <i>Y enterocolitica</i> was eliminated from the gut associated lymphoid tissue in six of seven patients receiving ciprofloxacin compared with none of nine patients receiving placebo. Patients receiving placebo had more and prolonged circulating IgA antibodies against yops than patients treated with ciprofloxacin.
Effects of Manganese Superoxide Dismutase Silencing on Androgen Receptor Function and Gene Regulation: Implications for Castration-Resistant Prostate Cancer
Authors: Nima Sharifi, Elaine M. Hurt, Suneetha B. Thomas, William L. Farrar
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Advanced prostate cancer is first treated with androgen deprivation therapy. However, tumors become resistant to and grow despite castrate levels of testosterone. Growth and proliferation of CRPC is mediated by gain-of-function changes in the AR and AR reactivation. Expression of manganese superoxide dismutase (SOD2), which regulates cellular ROS, is markedly down-regulated in CRPC when compared with hormone-responsive tumors. Experimental Design: Here, we knocked down SOD2 expression in AR-expressing LNCaP prostate cancer cells and determined gene expression changes, transcription factor binding, and AR transcription activity in SOD2 knockdown cells. Results: SOD2 knockdown results in an increase in ROS. Gene expression changes induced by SOD2 knockdown results in the up-regulation of genes that are also androgen responsive and 46% of genes up-regulated 2-fold by the androgen ligand R1881 are also up-regulated to the same extent with SOD2 knockdown. The induction of many of these genes with SOD2 knockdown, such as VEGFA and FKBP5, is reversible with the antioxidant N-acetylcysteine, suggesting that this mechanism is directly linked to ROS. Furthermore, an array for transcription factor DNA-binding activity shows that SOD2 knockdown induces DNA binding by several transcription factors, including AR. SOD2 knockdown-induced AR activation was confirmed by electrophoretic mobility shift assay and luciferase activity, and both were readily reversible with N-acetylcysteine. Conclusions: These findings show that down-regulation of SOD2 induces AR activity in a ROS-dependent manner, and suggest that there may be a role for antioxidant therapy in CRPC.
Ankylosing Spondylitis in Sisters
Authors: T. N. Fraser
Journal: Annals of the Rheumatic Diseases (1950)

The incidence of ankylosing spondylitis appears to be on the increase and during the recent war a large number of cases was observed among the forces.Boland and Present (1945) reported that 18 per cent. of soldiers admitted to a U.S. Army General Hospital with chronic back complaints were found to have this disease.Graham and Ogryzlo (1947) also noted in the Toronto Arthritis Centre the high ratio of one case of ankylosing spondylitis to every 2 8 cases of rheumatoid arthritis.This apparent increase in the incidence of the disease is undoubtedly due, in part, to quicker diagnosis, with the result that many cases which have not advanced beyond a very early stage are now being recognized.Ankylosing spondylitis is predominantly a disease of young men.Buckley (1931) reported a sex incidence of ten males to one female.This is the average figure given, although Graham and Ogryzlo (1947) reported a ratio of 16 to 1 and Bauer (1939) 20 to 1 respectively in their series.On the other hand, Fletcher (1944) found that 47 per cent. of 68 patients with the disease were females, a finding which he was unable to explain.The sex incidence in my own series was three males to one female.Evidence is available, though by no means conclusive, to support the view that ankylosing spondylitis is a familial disease (Stecher and Hauser, 1946; Campbell, 1947; Rogoff and Freyberg, 1949) and its occurrence in brothers has been reported from time to time.Ray (1932) recorded the disease in twin brothers; Stecher and Hauser (1946) also described two brothers and cited three other instances of the disease affecting brothers.Campbell (1947) stated that in his series of 25 cases two of his patients were identical male twins, another two were brothers, a fifth had a brother who had died from the disease, and a sixth had an uncle and a brother with the disease.Tegner and Lloyd (1949) noted that all three children of one family (two brothers and a sister) were suffering from ankylosing spondylitis.The occurrence of ankylosing spondylitis in sisters, however, is so rare that the presentation of the following is thought to be justified.I have noticed only one report in the literature of the disease affecting sisters (Scott, 1942), but no details are given.This rarity of " sister " cases might, of course, reasonably be explained by the low incidence of the disease in females.231
A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis
Authors: Shuang Chen, Yu Zhang, Liang Zhou, Yun Leng, Hui Lin, Maciej Kmieciak, Xin-Yan Pei, Richard Jones, Robert Z. Orlowski, Yun Dai, Steven Grant
Journal: Blood (2014)
Ribonucleotide Reductase Small Subunit p53R2 Facilitates p21 Induction of G1 Arrest under UV Irradiation
Authors: Lijun Xue, Bingsen Zhou, Xiyong Liu, Yvonne Heung, Jennifer Chau, Emilie Chu, Shan Li, Chunglin Jiang, Frank Un, Yun Yen
Journal: Cancer Research (2007)

Abstract p53R2, which is one of the two known ribonucleotide reductase small subunits (the other being M2), is suggested to play an important role in supplying deoxynucleotide triphosphates (dNTP) for DNA repair during the G1 or G2 phase of the cell cycle. The ability of p53R2 to supply dNTPs for repairing DNA damages requires the presence of a functional p53 tumor suppressor. Here, we report in vivo physical interaction and colocalization of p53R2 and p21 before DNA damage. Mammalian two-hybrid assay further indicates that the amino acids 1 to 113 of p53R2 are critical for interacting with the NH2-terminal region (amino acids 1–93) of p21. The binding between p21 and p53R2 decreases inside the nucleus in response to UV, the time point of which corresponds to the increased binding of p21 with cyclin-dependent kinase-2 (Cdk2), and the decreased Cdk2 activity in the nucleus at G1. Interestingly, p53R2 dissociates from p21 but facilitates the accumulation of p21 in the nucleus in response to UV. On the other hand, the ribonucleotide reductase activity increases at the corresponding time in response to UV. These data suggest a new function of p53R2 of cooperating with p21 during DNA repair at G1 arrest. [Cancer Res 2007;67(1):16–21]
Evolution of Diaphragm Thickness during Mechanical Ventilation. Impact of Inspiratory Effort
Authors: Ewan C. Goligher, Eddy Fan, Margaret S. Herridge, Alistair Murray, Stefannie Vorona, Debbie Brace, Nuttapol Rittayamai, Ashley Lanys, George Tomlinson, Jeffrey M. Singh, Steffen-Sebastian Bolz, Gordon D. Rubenfeld, Brian P. Kavanagh, Laurent J. Brochard, Niall D. Ferguson
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Diaphragm atrophy and dysfunction have been reported in humans during mechanical ventilation, but the prevalence, causes, and functional impact of changes in diaphragm thickness during routine mechanical ventilation for critically ill patients are unknown.Objectives: To describe the evolution of diaphragm thickness over time during mechanical ventilation, its impact on diaphragm function, and the influence of inspiratory effort on this phenomenon.Methods: In three academic intensive care units, 107 patients were enrolled shortly after initiating ventilation along with 10 nonventilated intensive care unit patients (control subjects). Diaphragm thickness and contractile activity (quantified by the inspiratory thickening fraction) were measured daily by ultrasound.Measurements and Main Results: Over the first week of ventilation, diaphragm thickness decreased by more than 10% in 47 (44%), was unchanged in 47 (44%), and increased by more than 10% in 13 (12%). Thickness did not vary over time following extubation or in nonventilated patients. Low diaphragm contractile activity was associated with rapid decreases in diaphragm thickness, whereas high contractile activity was associated with increases in diaphragm thickness (P = 0.002). Contractile activity decreased with increasing ventilator driving pressure (P = 0.01) and controlled ventilator modes (P = 0.02). Maximal thickening fraction (a measure of diaphragm function) was lower in patients with decreased or increased diaphragm thickness (n = 10) compared with patients with unchanged thickness (n = 10; P = 0.05 for comparison).Conclusions: Changes in diaphragm thickness are common during mechanical ventilation and may be associated with diaphragmatic weakness. Titrating ventilatory support to maintain normal levels of inspiratory effort may prevent changes in diaphragm configuration associated with mechanical ventilation.
Enhanced <i>S</i> -Nitroso-Albumin Formation From Inhaled NO During Ischemia/Reperfusion
Authors: Ella S.M. Ng, David Jourd’heuil, Joe M. McCord, Daniel Hernandez, Mitsukuni Yasui, Derrice Knight, Paul Kubes
Journal: Circulation Research (2004)

In the present study, we investigated whether inhaled nitric oxide (NO) was transported by plasma proteins, such as S-nitroso-albumin (SNO-Alb), in the feline circulation and whether this molecule delivers NO to the periphery under conditions of stress, specifically ischemia/reperfusion (I/R). A flow probe was interposed between the femoral and superior mesenteric artery for blood flow measurements, and a branch of the superior mesenteric vein was cannulated for arterial-venous sampling. In animals breathing room air, SNO-Alb was below detection level in arterial or venous blood. NO inhalation resulted in a significant arterial-venous gradient for SNO-Alb. Concomitant with this loss of SNO-Alb across the intestinal vasculature was an increase in nitrite (NO2-). However, this release of NO was not sufficient to alter intestinal blood flow. I/R during NO inhalation caused a very large increase in arterial SNO-Alb that permitted a 5-fold increase in SNO-Alb consumption and significant generation of NO2- within the postischemic intestinal vasculature. The increased SNO-Alb consumption was sufficient to dramatically improve intestinal blood flow. The very large burst of arterial SNO-Alb during I/R was completely blocked by the administration of superoxide dismutase, suggesting that oxidative stress contributed to the increased SNO-Alb formation. Our data suggest that inhaled NO can increase nitrosothiol production and these molecules may be a functional NO delivery system during cardiovascular disease.