tbuckley/cabot-search huggingface dataset:
13-cis retinoic acid treatment for myelodysplastic syndromes.
Authors: V J Picozzi, G F Swanson, R Morgan, F Hecht, P L Greenberg
Journal: Journal of Clinical Oncology (1986)

To test the biologic activity of 13-cis retinoic acid (13-CRA) in patients with myelodysplastic states (MDS), we administered 13-CRA orally (2.5 mg/kg/d initially, escalated to 4 mg/kg/d) for 8 weeks to 15 consecutive patients. Eight of 15 patients (53%) experienced an increase in peripheral granulocyte counts of greater than 20% (range, 22% to 700%). In five patients, the absolute increase in peripheral granulocyte count was greater than 500 cells/microL. Two of 15 patients experienced a decrease in the circulating granulocyte count of greater than or equal to 20%. Comparable values for peripheral platelet counts were 27% (4/15 patients) greater than 20% increase and 33% (5/15 patients) greater than 20% decrease. No patient experienced a major change in erythrocyte transfusion requirement while receiving 13-CRA in comparison with pretreatment status. Thirteen patients had morphologic and cytogenetic evaluation of marrow cells before 13-CRA treatment, and with one exception, marrow morphologic and cytogenetic abnormalities persisted following 13-CRA administration. The exception occurred in the patient with the most dramatic response, whose granulocyte count increased from 400 to 2,800 cells/microL along with a normalization of the leukocyte alkaline phosphatase score, a morphologic improvement in granulocyte maturation, and a disappearance of the initial chromosome abnormality. These changes did not persist after cessation of 13-CRA administration, but were reproduced following drug readministration. No patients experienced serious decrements in peripheral blood counts or leukemic transformation while receiving 13-CRA. All patients had mild to marked dermatologic toxicity (cheilosis, skin dryness). No other major toxicity was encountered. We conclude that 13-CRA may be safely administered and may increase peripheral granulocyte counts in a proportion of patients with MDS.
Diagnosing chronic obstructive pulmonary disease
Authors: Francesca Conway, Azeem Majeed, Graham Easton
Journal: BMJ (2015)

#### What you need to know A 55 year old man attends surgery with a productive cough for nine months, which he has put down to his smoking. He had “chest infections” the previous winter and takes ramipril for hypertension. His breathing is now preventing him from climbing stairs.
Antiprogestins: Mechanism of Action and Contraceptive
Authors: I M Spitz, H B Croxatto, A Robbins
Journal: The Annual Review of Pharmacology and Toxicology (1996)

Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.Antiprogestins have a 17-alpha substitution, which promotes higher binding affinity to both progesterone and glucocorticoid receptors, and an 11-beta substitution, which appears to be responsible for the antagonistic action. Antiprogestins also exhibit progestin agonistic and even antiestrogenic properties. Induction of a medical abortion in very early pregnancy is the most frequent clinical use of the antiprogestin mifepristone (RU-486). Antiprogestins may someday be used as a contraceptive since very low doses of antiprogestins cause considerable changes in endometrial morphology. At these low doses, they do not affect hormonal secretion or ovulation or bleeding patterns. At high doses, they delay ovulation but are associated with unopposed estrogen action on the endometrium. At low doses, antiprogestins do not always delay ovulation. RU-486 is a very effective and safe postcoital contraceptive. Antiprogestins may be beneficial in treating endometriosis, uterine myoma, and steroid-dependent tumors (e.g., breast cancer). They may be used to induce labor in cases of intrauterine fetal death. Antiprogestins may prove useful in treating Cushing's syndrome due to ectopic adrenocorticotropic hormone secretion, in lowering intraocular pressure in glaucoma, and in preventing the progression of viral diseases in humans. They also appear to have even more potential benefits, such as treatment of burns.
Ultrasound-mediated gastrointestinal drug delivery
Authors: Carl M. Schoellhammer, Avi Schroeder, Ruby Maa, Gregory Yves Lauwers, Albert Swiston, Michael Zervas, Ross Barman, Angela M. DiCiccio, William R. Brugge, Daniel G. Anderson, Daniel Blankschtein, Robert Langer, Giovanni Traverso
Journal: Science Translational Medicine (2015)

Ultrasound enables rapid and local delivery of drugs to the gastrointestinal tract for treatment of inflammatory diseases, such as ulcerative colitis.
Development of amorphous dispersions of artemether with hydrophilic polymers via spray drying: Physicochemical and in silico studies
Authors: Jaywant N. Pawar, Rahul T. Shete, Avinash B. Gangurde, Kailas K. Moravkar, Sharadchandra D. Javeer, Divakar R. Jaiswar, Purnima D. Amin
Journal: Asian Journal of Pharmaceutical Sciences (2015)

Artemether (ARM) is a poorly water soluble and poorly permeable drug effective against acute and severe falciparum malaria, hence there is a strong need to improve its solubility. The objective of the study was to enhance the solubility and dissolution rate of ARM by preparation of solid dispersions using spray-drying technique. Solid dispersions of ARM were prepared with Soluplus, Kollidon VA 64, HPMC and Eudragit EPO at weight ratios of 1:1, 1:2, 1:3 using spray drying technology, and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD) to identify the physicochemical interaction between drug and carrier, as well as effect on dissolution. The prepared solid dispersion of ARM with polymers showed reduced crystallinity as compared to neat ARM, which was confirmed by DSC and XRD. Drug/polymer interactions were studied in-silico by docking and molecular dynamics which indicated formation of van der Waals type of interactions of ARM with the polymers. Based on solubility studies, the optimum drug/Soluplus ratio was found to be 1:3. The dissolution studies of formulation SD3 showed highest drug release up to 82% compared to neat ARM giving only 20% at 60 minutes. The spray-dried products were free of crystalline ARM; possessed higher dissolution rates, and were stable over a period according to ICH guidelines. These findings suggest that an amorphous solid dispersion of ARM could be a viable option for enhancing the dissolution rate of ARM.
Dual Roles of RNF2 in Melanoma Progression
Authors: Kunal Rai, Kadir C. Akdemir, Lawrence N. Kwong, Petko Fiziev, Chang-Jiun Wu, Emily Z. Keung, Sneha Sharma, Neha S. Samant, Maura Williams, Jacob B. Axelrad, Amiksha Shah, Dong Yang, Elizabeth A. Grimm, Michelle C. Barton, Denai R. Milton, Timothy P. Heffernan, James W. Horner, Suhendan Ekmekcioglu, Alexander J. Lazar, Jason Ernst, Lynda Chin
Journal: Cancer Discovery (2015)

Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and prometastatic. Mechanistically, RNF2-mediated invasive behavior is dependent on its ability to monoubiquitinate H2AK119 at the promoter of LTBP2, resulting in silencing of this negative regulator of TGFβ signaling. In contrast, RNF2's oncogenic activity does not require its catalytic activity nor does it derive from its canonical gene repression function. Instead, RNF2 drives proliferation through direct transcriptional upregulation of the cell-cycle regulator CCND2. We further show that MEK1-mediated phosphorylation of RNF2 promotes recruitment of activating histone modifiers UTX and p300 to a subset of poised promoters, which activates gene expression. In summary, RNF2 regulates distinct biologic processes in the genesis and progression of melanoma via different molecular mechanisms.The role of epigenetic regulators in cancer progression is being increasingly appreciated. We show novel roles for RNF2 in melanoma tumorigenesis and metastasis, albeit via different mechanisms. Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes.
Ovarian function following marrow transplantation for aplastic anemia or leukemia.
Authors: J E Sanders, C D Buckner, D Amos, W Levy, F R Appelbaum, K Doney, R Storb, K M Sullivan, R P Witherspoon, E D Thomas
Journal: Journal of Clinical Oncology (1988)

One hundred eighty-seven women between 13 and 49 years of age had ovarian function evaluated from 1 to 15 years (median, 4) after marrow transplant for aplastic anemia or leukemia. Among 43 women transplanted for aplastic anemia following 200 mg/kg cyclophosphamide (CY), all 27 less than 26 years of age, but only five of 16 greater than 26 years of age recovered normal ovarian function. Nine of the 43 have had 12 pregnancies, resulting in eight live births, and two elective and two spontaneous abortions. All eight children are normal. Nine of 144 women transplanted for leukemia following 120 mg/kg CY and 9.20 to 15.75 Gy total body irradiation (TBI) recovered ovarian function. Two of these nine have had three pregnancies, resulting in two spontaneous and one elective abortion. The probability of having ovarian failure was 0.35 by 7 years for patients receiving CY alone and was 1.00 at 1 year for patients receiving CY plus TBI (P less than .0001). By 7 years after transplant the probabilities of having normal ovarian function were 0.92 after CY alone and 0.24 after CY plus TBI (P less than .0001). Multivariate analysis showed that TBI was the only factor significantly influencing ovarian failure and that both TBI and greater patient age at transplant were significantly associated with a decreased probability of recovering normal ovarian function. These data demonstrate that after high-dose CY, recovery of ovarian function occurs in younger women and in a minority of older women, but after CY and TBI, recovery occurs in only a few younger women and none of the older women.
Parenteral and Enteral Nutrition
Authors: H M Shizgal
Journal: Annual Review of Medicine (1991)

Stress and starvation, especially when complicated by sepsis, will give rise to a rapid erosion of the cellular mass, which significantly affects morbidity and mortality. The best clinical evaluation of the nutritional state is obtained from the medical history and the physical examination. In the patient who cannot eat a balanced diet, specialized nutritional support, in the form of either enteral or parenteral nutrition, is required to prevent malnutrition in the normally nourished, or to correct the nutritional state in the malnourished.
Microvascular Invasion in Hepatitis B Virus–Related Hepatocellular Carcinoma
Authors: Ernesto Sparrelid, Marco Del Chiaro
Journal: JAMA Surgery (2015)

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Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women
Authors: Mark A. Espeland, Roberta Diaz Brinton, Christina Hugenschmidt, JoAnn E. Manson, Suzanne Craft, Kristine Yaffe, Julie Weitlauf, Leslie Vaughan, Karen C. Johnson, Claudia B. Padula, Rebecca D. Jackson, Susan M. Resnick
Journal: Diabetes Care (2015)

OBJECTIVE In older women, higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes. We examined whether the effect of postmenopausal hormone therapy (HT) on cognitive impairment incidence differs depending on type 2 diabetes. RESEARCH DESIGN AND METHODS The Women’s Health Initiative (WHI) randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without [i.e., unopposed] 2.5 mg/day medroxyprogesterone acetate) or matching placebo for an average of 4.7–5.9 years. A total of 7,233 women, aged 65–80 years, were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment (mild cognitive impairment or dementia). RESULTS Through a maximum of 18 years of follow-up, women with diabetes had increased risk of probable dementia (hazard ratio [HR] 1.54 [95% CI 1.16–2.06]) and cognitive impairment (HR 1.83 [1.50–2.23]). The combination of diabetes and random assignment to HT increased their risk of dementia (HR 2.12 [1.47–3.06]) and cognitive impairment (HR 2.20 [1.70–2.87]) compared with women without these conditions, interaction P = 0.09 and P = 0.08. These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens. CONCLUSIONS These analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women. The role estrogen plays in suppressing non–glucose-based energy sources in the brain may explain this interaction.
Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment
Authors: A Gratwohl, M Pfirrmann, A Zander, N Kröger, D Beelen, J Novotny, C Nerl, C Scheid, K Spiekermann, J Mayer, H G Sayer, C Falge, D Bunjes, H Döhner, A Ganser, I Schmidt-Wolf, R Schwerdtfeger, H Baurmann, R Kuse, N Schmitz, A Wehmeier, J Th Fischer, A D Ho, M Wilhelm, M-E Goebeler, H W Lindemann, M Bormann, B Hertenstein, G Schlimok, G M Baerlocher, C Aul, M Pfreundschuh, M Fabian, P Staib, M Edinger, M Schatz, A Fauser, R Arnold, T Kindler, G Wulf, A Rosselet, A Hellmann, E Schäfer, O Prümmer, M Schenk, J Hasford, H Heimpel, D K Hossfeld, H-J Kolb, G Büsche, C Haferlach, S Schnittger, M C Müller, A Reiter, U Berger, S Saußele, A Hochhaus, R Hehlmann
Journal: Leukemia (2015)

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.
The twisted survivin connection to angiogenesis
Authors: C. Sanhueza, S. Wehinger, J. Castillo Bennett, M. Valenzuela, G. I. Owen, A. F. G. Quest
Journal: Molecular Cancer (2015)

Survivin, a member of the inhibitor of apoptosis family of proteins (IAPs) that controls cell division, apoptosis, metastasis and angiogenesis, is overexpressed in essentially all human cancers. As a consequence, the gene/protein is considered an attractive target for cancer treatment. Here, we discuss recent findings related to the regulation of survivin expression and its role in angiogenesis, particularly in the context of hypoxia. We propose a novel role for survivin in cancer, whereby expression of the protein in tumor cells promotes VEGF synthesis, secretion and angiogenesis. Mechanistically, we propose the existence of a positive feed-back loop involving PI3-kinase/Akt activation and enhanced β-Catenin-TCF/LEF-dependent VEGF expression followed by secretion. Finally, we elaborate on the possibility that this mechanism operating in cancer cells may contribute to enhanced tumor vascularization by vasculogenic mimicry together with conventional angiogenesis.
Abstract 1536: Effect of ascites on tumor response in advanced stage ovarian cancer
Authors: Soochi Kim, Anna Kim, Hee Seung Kim, HyeRan Gwak, UnTek Jo, Yong Sang Song
Journal: Cancer Research (2015)

Abstract Background: Ascites can create a progressive microenvironment for tumor cells, whereas there is few evidence on the role of ascites on tumor response in ovarian cancer. Thus, we investigated cellular response by ascites in ovarian cancer cell line, and evaluated the effect of ascites on clinical outcomes in patients with advanced-stage ovarian cancer. Methods: Moreover, we collected clinico-pathologic database of 277 patients with stage IIIC-IV ovarian cancer, and investigated factors affecting overall response (OR) and survival. Furthermore, we collected ascites from four patients with stage IIIC-IV serous adenocarcinoma of the ovary, and cell migration, invasiveness and proliferation by adding ascites were evaluated in SKOV-3. Results: OR rates were not different between patients with ascites and those without ascites (77.8% vs. 89.1%; P = 0.094), and no ascites was associated with better progression-free survival with marginal significance (37.4 vs. 27.1 mons; P = 0.056) in spite of no effect of ascites on overall survival. In multivariate analyses, no ascites was a favorable factor for reducing the risk of non-OR with marginal significance (adjusted OR, 0.286; 95% CI, 0.080-1.018; P = 0.053), whereas ascites was not an independent factor affecting survival. Moreover, ascites increased migration and invasiveness of SKOV-3 (Figs. 1A and 1B). Although proliferation of SKOV-3 was decreased for the first 24 h, it increased in time-dependent manner till 72h (Fig. 1C). Conclusions: Ascites may contribute to invasion, migration and proliferation of ovarian cancer cells. Our clinical findings also support that ascites may affect overall response after primary treatment, suggesting the possibility that ascites can act as a tumor microenvironment related with tumor cell survival. Citation Format: Soochi Kim, Anna Kim, Hee Seung Kim, HyeRan Gwak, UnTek Jo, Yong Sang Song. Effect of ascites on tumor response in advanced stage ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1536. doi:10.1158/1538-7445.AM2015-1536
Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study.
Authors: P Hoskins, E Eisenhauer, S Beare, M Roy, P Drouin, G Stuart, P Bryson, R Grimshaw, V Capstick, B Zee
Journal: Journal of Clinical Oncology (1998)

PURPOSE As topotecan is S-phase-specific, its efficacy is likely schedule-dependent. Therefore, a randomized study using a "pick the winner" design was undertaken to compare two schedules in patients with recurrent ovarian cancer. PATIENTS AND METHODS Patients with recurrent epithelial ovarian cancer previously treated with no more than two separate regimens of chemotherapy, one of which had to be platinum-containing, were randomized to either topotecan 1.5 mg/m2 intravenously (i.v.) over 30 minutes daily for 5 days repeated every 21 days (arm A, the standard arm), or topotecan 1.75 mg/m2 as a 24-hour infusion once a week for 4 weeks repeated every 6 weeks (arm B, the experimental arm). RESULTS Sixty-six patients were eligible and 63 were assessable for response. The response rate in arm A was 22.6% (95% confidence interval [CI], 9.6% to 41.2%), which was significantly superior to that in arm B, 3.1% (95% CI, 0.1% to 16%) (P = .026). The regimens were not equitoxic, with 94% of patients on arm A experiencing grade 3 or 4 granulocytopenia as opposed to 52% on arm B. CONCLUSION The weekly 24 hour infusion of topotecan at 1.75 mg/m2 was ineffective in relapsed ovarian cancer. The daily-times-five schedule remains the schedule of choice. As the regimens were not equitoxic, one cannot differentiate between an ineffective schedule and an ineffective dose as the reason for the differing response rates. However, the degree of myelotoxicity that already occurs will preclude any substantially higher dosing with the weekly regimen.