tbuckley/cabot-search huggingface dataset:
Abstract LB-109: Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia
Authors: Rekha M. Rao, Yacoub Abdulraheem, Suman Kambhampati, Siddhartha Ganguly
Journal: Cancer Research (2014)

Abstract Heat shock factor 1 (HSF1) is a stress-activated transcription factor, that up-regulates the transcription of heat shock proteins (Hsps) and a growing list of tumor-promoting genes. HSF1-induced genes promote protein folding and maturation (through Hsps and associated co-chaperones) as well as orchestrate the transcription of tumor-promoting genes (for e.g., VEFGR, HIF1-alpha, GLUT-1, etc). In this study we propose to evaluate the efficacy of inhibiting HSF1 in Chronic Lymphocytic Leukemia (CLL), a disease that invariably relapses after patients show complete or partial response to first line chemotherapy. Consistent with the established tumor-promoting roles of HSF1, we report that CD19+ B cells isolated from relapsed/refractory CLL patients show high levels of immunofluorescent, nuclear HSF1 staining compared to normal CD19+ B cells, where it is weakly expressed and pre-dominantly cytosolic. CD19+ B primary CLL cells also show enhanced expression of HSF1 as assessed by immunoblot analysis compared to normal CD19+ cells. Treatment of cultured and primary CLL CD19+ B cells with the HSF1 inhibitor triptolide causes a dose-dependent increase in apoptosis, while relatively sparing normal CD19+ B cells. Treatment with triptolide results in the reduced expression of Hsp40, Hsp70 and Hsp27 proteins and a concomitant increase in the PARP cleavage and Caspase 3 cleavage in cultured and primary CLL cells. Lentiviral shRNA-mediated knockdown of HSF1 or triptolide treatment decreased the levels of Bcl-XL and pro-survival signaling molecules, phosphorylated STAT3 (Y-705) and AKT (S473). Based on the established role of Hsps in cytoprotection and resistance to chemotherapy, we hypothesized that inhibition of HSF1 would sensitize CLL cells to agents that promote the accumulation of misfolded proteins (for e.g. Hsp90 inhibitors) or inhibit their disposal (for e.g. treatment with autophagy inhibitors) by inducing proteotoxicity. Consistent with this hypothesis, knockdown of HSF1 or co-treatment with triptolide and the autophagy inhibitor chloroquine resulted in superior anti-CLL activity compared to treatment with either agent alone. Similarly, knockdown of HSF1 or its inhibition with triptolide also sensitized CLL cells to the Hsp90 inhibitor, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). These pre-clinical studies provide a strong rationale to test the in vitro and in vivo activity of HSF1 inhibitors in combination with agents that promote proteotoxic stress against CLL. Citation Format: Rekha M. Rao, Yacoub Abdulraheem, Suman Kambhampati, Siddhartha Ganguly. Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-109. doi:10.1158/1538-7445.AM2014-LB-109
Combining anticoagulant drugs with herbal medicines is risky, report says
Authors: R. Dobson
Journal: BMJ (2001)

A review of reported interactions between herbal and conventional drugs has found more than 100 cases but warns that more research is urgently needed.

“Herb-drug interactions occur but are under-researched. In many cases there is no plausible mechanism to explain the observed phenomena and causality is uncertain,” says the report in the British Journal of Clinical Pharmacology (2001;52:587-95).

The aim of the review, by Professor Edzard Ernst of the Department of Complementary Medicine at Exeter University and Adriane Fugh-Berman of George Washington University School of Medicine, Washington, …
An Address ON SOME POINTS IN CONNEXION WITH RENAL DISEASE: Delivered before the Lambeth Division of the British Medical Association
Authors: C. R. Box
Journal: BMJ (1920)

SoME of the recent inves'tigations on nephritis are of prac- tical importance, and I lavo been fortunate in having the opportunity of proving their value both in treatinent and prognosis.The opportunity arose from the fact that Dr. Hugh MacLean and Dr. De Wesselow have been and are still engaged at St. Thomas's Hospital in an investigation on war nephritis.With the greatest readiness they have collaborated in the investigation of my ward cases and placed their knowledge at my disposal.Before going furtlier I lhasten to express my indebtedness to their published results and to them personally for many facts gleaned during conversations with tlhem.It is well known that the predominant symptoms of renal disease fall into two main groups-the oedematous and tlle cardio-vascular.In acute nephritis both sets of symptoms may be present, although not always in equal degree; in chronic nephritis the predominance of symptoms of one or other of these groups enables us to recognize twvo distinct types-the chronic parenchymatous or tubal and the chronic interstitial or granular form.
Abstract 4475: New water-soluble and stable <i>N</i>-mustard-benzeneconjugates with potent antitumor activity, BO-2094, generated via leadoptimization by bioisostere approach.
Authors: Tsann-Long Su, Satishkumar Tala, Tai-Hsin Ou, Kiranben Tala, Rajesh Kakadiya, Yi-wen Lin, Chi-Wei Chen, Te-Chang Lee
Journal: Cancer Research (2013)

Abstract The water solubility of drug candidate plays an important determinant of the bioavailability and supports whether a drug candidate can be successfully developed for clinical application. Previously, we have synthesized a series of water-soluble N-mustards, in which the phenyl N-mustard pharmacophore is linked to a benzamide moiety containing a hydrophilic side-chain at the meta- or para-position of the carboxamide function via a urea spacer. Of these derivatives, the water-soluble BO-1055 HCl exhibits a broad spectrum of antitumor activity and potent therapeutic efficacy against various human solid tumor (such as breast MX-1, colon HCT-116, and prostate PC-3) xenografts. To optimize the antitumor activity of BO-1055 via structural modification by bioisostere approach, we synthesized a series of new N-mustard-benzene conjugates, in which the phenyl N-mustard pharmacophore is linked to a benzene moiety via a urea linker, which can reduce the reactivity of the reactive N-mustard moiety. The benzene ring contains a variety of ω-N,N-dialkylaminoalkylamide or ω-cyclicaminoalkylamide side-chains at the meta- or para-position of the ureido linker. The tertiary amino function on the side-chain can be converted into a variety of water-soluble salts with inorganic or organic acids. The newly synthesized conjugates were subject to antitumor studies both in vitro and in tumor xenograft model. The results showed that these water-soluble conjugates exhibit a broad spectrum of antitumor activity against a panel of human leukemia and solid tumor cell growth in culture. Among these derivatives, BO-2094 [N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-(diethylamino)acetamide], was revealed to be more cytotoxic than BO-1055 in inhibiting various tumor cell growth in vitro. It also showed that this agent is more potent than BO-1055 against human colon HCT-116, prostate PC3, and lung cancer H460 xenografts in mice. Studies on the mechanism of action revealed that BO-2094 is able to induce DNA cross-linking and cell arrest at G2/M phase. The present investigations conclude that BO-2094, a new water-soluble N-mustard-benzene conjugated with more potent therapeutic effect than BO-1055, has high potential to be selected as a candidate for preclinical antitumor studies. Citation Format: Tsann-Long Su, Satishkumar Tala, Tai-Hsin Ou, Kiranben Tala, Rajesh Kakadiya, Yi-wen Lin, Chi-Wei Chen, Te-Chang Lee. New water-soluble and stable N-mustard-benzeneconjugates with potent antitumor activity, BO-2094, generated via leadoptimization by bioisostere approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4475. doi:10.1158/1538-7445.AM2013-4475
Commentary: Fixing the policy may not sort out the politics
Authors: N. Edwards
Journal: BMJ (2011)

There has been growing disquiet about the NHS Health and Social Care Bill and how the reforms will work in practice. Walshe and Ham’s long list of proposals covers many of these.1 Others remain, including changes to the public health system and the Health Protection Agency, concerns about workforce planning and education, and unanswered questions about organisations that will not be able to become foundation trusts. All these points will need to be addressed, but fixing the technical issues is only part of the problem. Fixing the politics, telling the story, and containing the anxiety that has been created may be much harder.

Major reforms require a strong narrative about why the inevitable upheaval they …
Abstract 5683: Blockade of glioma proliferation via allosteric inhibition of JAK2.
Authors: Kunyan He, Qi Qi, Chi-Bun Chan, Ge Xiao, Xia Liu, Carol Tucker-Burden, Liya Wang, Hui Mao, Xiang Lu, Frank E. McDonald, Hongbo Luo, Qi-wen Fan, William A. Weiss, Shi-yong Sun, Daniel J. Brat, Keqiang Ye
Journal: Cancer Research (2013)

Abstract Gliomas are the most common primary brain tumors. Glioblastoma multiforme (GBM), WHO grade IV, is the most frequent and aggressive form, with a median survival of approximately 12 months following aggressive treatment with surgical resection, radiation and chemotherapy. Epidermal growth factor receptor (EGFR) is frequently amplified and mutated in human cancers including GBM. While the rationale for treating GBM patients with EGR inhibitors is strong, the efficacy of anti-EGFR small molecular inhibitors or monoclonal antibodies in treating gliomas with PTEN mutation or deletion has been modest. Here we show a novel approach to inhibiting EGFR that involves a small molecule (G5-7) that selectively blocks JAK2 phosphorylation of EGFR, inhibits cell proliferation and reduces VEGF secretion, and leads to glioma shrinkage via apoptosis and anti-angiogenesis. G5-7 inhibited EGFR and STAT3 tyrosine phosphorylation by JAK2 through binding to its N-terminal FERM domain. Interestingly, G5-7 selectively inhibited the proliferation of U87MG/EGFRvIII cells and human GBM explant neurosphere cultures but only weakly affected U87MG/PTEN cells or normal neural progenitor cultures. Moreover, oral administration of this compound markedly diminishes the brain tumor volumes in both subcutaneous and intracranial models, supporting that this compound itself and/or the metabolites might be able to penetrate the brain-blood barrier and exert the anti-proliferative actions through blocking the oncogenic pathways in vivo. Chronic treatment of mice with 50 mg/kg G5-7 exhibits no obvious toxicity in the animals. Our finding demonstrates that G5-7 is a novel allosteric JAK2 inhibitor with potent anti-tumor activity for GBM. Our report not onlyidentify a novel drug for treating the GBM, but also provide insight into the molecular mechanisms of how these small molecules impinge on the EGFR/PTEN signaling. Optimization of these novel compounds will lead to new treatments for the patients with these devastating tumors. [K.H. and Q.Q. contributed equally to this work.] Citation Format: Kunyan He, Qi Qi, Chi-Bun Chan, Ge Xiao, Xia Liu, Carol Tucker-Burden, Liya Wang, Hui Mao, Xiang Lu, Frank E. McDonald, Hongbo Luo, Qi-wen Fan, William A. Weiss, Shi-yong Sun, Daniel J. Brat, Keqiang Ye. Blockade of glioma proliferation via allosteric inhibition of JAK2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5683. doi:10.1158/1538-7445.AM2013-5683
Post-traumatic Cerebral Venous Infarct Mimicking an Infiltrative Glioma
Authors: Denis J. Gradinscak, Michael J. Fulham, Michael Besser, Armin Mohamed
Journal: Clinical Nuclear Medicine (2004)

An 18-year-old man presented with right hemiparesis after a minor head injury while wake boarding. Computed tomography of the brain and cervical spine were normal. However, a magnetic resonance (MR) image of the brain revealed an unusual lesion, thought to be an infiltrative tumor in his left cerebral hemisphere. He was placed on steroids and the hemiparesis improved. A craniotomy was performed. During surgery a swollen, left cingulate gyrus was sampled and a large, thrombosed vein was identified. Frozen section and histopathology revealed necrotic brain tissue consistent with a venous infarct. The preoperative fluorodeoxyglucose positron emission tomography and MR images are presented.
Two Cases of Thromboembolic Disease Associated with Oral Contraceptives
Authors: N. McIntyre, M. J. Phillips, J. C. Voigt
Journal: BMJ (1962)

MEDICAL JO01URNALRecording the results by age-groups for each sex (see Table ) showed a higher proportion of normals for females, and this is most marked for the age-group of 11 to 20 years.In this last group almost two-thirds of the appendices removed were judged to be normal, whereas only a quarter of those from males of the same age-group were so judged.In most, if not all, of these patients a wrong diagnosis of appendicitis had been made.Such errors occur at all ages and in both sexes, but they are much commoner in young females.In this last group the symptoms that are mistaken for those of appendicitis are not uncommonly derived from the ovary-for example, they are sometimes related to rupture of a follicle.In many cases I believe that they have a large psychological element-leaving the smoother life of school to start wor.k, having a job that is not liked, quarrelling with a boy friend, and other emotional upsets commone-r at this age than at others.It is, however, outside my province to determine the reasons for these mistakes in diagnosis: I wish to draw attention to the frequency of error in this group so that clinicians may be especially wary when making a diagnosis of acute appendicitis in young females.Summary A mistaken diagnosis of acute appendicitis is made much more often in females aged 11 to 20 years than in any other age-group.Figures are given to show that as many as two out of three appendices removed from this group may be quite normal.
Natural killer lymphocyte blast crisis of chronic myelogenous leukemia
Authors: M. J. Warzynski, C. White, M. G. Golightly, R. Steingart, R. N. Otto, A. E. Podgurski, M. L. Johnson, P. Glynn, D. E. Smith
Journal: American Journal of Hematology (1989)

Abstract We describe for the first time a case report documenting a chronic myelogenous leukemia (CML) patient who developed a blast crisis of natural killer (NK) lymphocytes. Many of the blasts exhibited large granular lymphocytic (LGL) morphology. Single parameter immunophenotyping results determined that the granulated as well as the agranulated blast cells were NK lymphocytes (CD45, NKH1, CD2, LEU 17, and CD16 positive; CD3, CD8, and LEU 7 negative). Dual parameter flow cytometric testing also determined that some of the blasts expressed the CD11b and CD11c markers as reported for some types of NK lymphocytes. Approximately 10% of the cells were in the S phase of the cell cycle as determined by a modified Vindelov DNA content analysis test and may theoretically reflect some of those cells expressing CD11b and CD11c. The cells did not express in vitro NK lymphocyte functional activity against a K562 target and therefore similar to other reported cases of presumably immature NK lymphocytic leukemias. The NK lymphocyte blast crisis was successfully treated with vincristine and prednisone. The patient's disease eventually relapsed and transformed to a progenitor stem cell before she died (CD45, 13, CD38, and CD34 positive). The flow cytometric immunophenotyping results contributed significantly as an important adjunct in determining the appropriate diagnosis, helping to select the type of therapy, and monitoring the patient with this unusual type of blast crisis.
More on "Oturia"
Authors: Charles Nuttall
Journal: JAMA (1975)

<h3>To the Editor.—</h3> In reference to the recent QUESTIONS AND ANSWERS regarding "Oturia—An Etymological Evanescence" (231:869, 1975), I am aware of one case reported nearly 150 years ago of a young woman who was frustrated in her attempts to micturate in the usual manner by a prolapsed uterus. Evacuation of the bladder was achieved by intermittent catheterization, but if this was not performed regularly, the urine sought other avenues of escape, including the lumbar sweat glands, the stomach, the right nipple, the left eye, and both ears, particularly the right ear. Laboratory evidence that the fluid was urine is given in that, when thrown against a heated shovel, it "gave off the odour so peculiar to urine, indicating the presence of urea."1 Apparently, our early 19th century predecessors were fascinated by the passage of what appeared to be urine from unlikely orifices, as evidenced by other articles of the period.
Gene Expression Profiling in Seminoma and Nonseminoma
Authors: M. Port, H.U. Schmelz, M. Stockinger, C. Sparwasser, P. Albers, T. Pottek, M. Abend
Journal: Journal of Clinical Oncology (2004)

Gene expression profiles of seminoma were compared with nonseminoma to get insights into tumorigenesis.Eleven testicular tumor biopsies (five pure seminoma, six nonseminoma; pT1N0M0 to pT2N2M1) and biopsies from unaffected sites were analyzed once per patient using a macroarray (1,176 genes). On the same patients, six genes were validated using real-time quantitative (RTQ) polymerase chain reaction (PCR). Additionally, in a separate cohort of 19 patients, 24 genes selected from the macroarray were measured using RTQ-PCR.(1) The agreement in gene expression was 94% between the two methods and two different patient cohorts. (2) Two features in gene expression were independent of the tumor entity: Most changes of gene expression occurred in five functional groups like "cell cycle" and "apoptosis." Genes within these groups were almost similarly (> 80%) up- or downregulated. (3) Nonseminoma were characterized by downregulated genes (75%), but in seminoma, upregulated genes (64%) prevailed. Furthermore, 64.4% of those genes that were differentially expressed in both tumor entities were usually upregulated in seminoma but downregulated in nonseminoma. A reverse pattern was found in 24.4% of such genes. Eleven percent of these genes showed a similar up- or downregulation in gene expression in both tumor entities.Seminoma in this preliminary study can be differentiated from nonseminoma due to almost opposing gene expression profiles (89% of the significantly differentially expressed genes) and are in line with the histological discrimination of both tumor entities. Underlying mechanisms and implications regarding the origin and tumor progression of both entities are discussed.
GIANT CARDIAC LYMPHANGIOMA WITH COMPLETE ENCASEMENT OF THE RIGHT CORONARY ARTERY: IMAGING AND THERAPEUTIC APPROACH
Authors: Carlos L. Alviar, Sean Heffron, Benjamin Geisler, David Altszuler, Matthew Augustine, Lawrence Adler, Christopher Towe, Aubrey Galloway, Adam Skolnick
Journal: Journal of the American College of Cardiology (2014)
Management of Emotional Disorders in Pediatric Practice: With a Focus on Techniques of Interviewing
Authors: Robert B. Kugel
Journal: JAMA (1968)

"Controversial" and "confusing" best describe this book by Schulman on emotional disorders in children. Illustrative of the controversial aspect is the opening paragraph, "it is not necessary to understand any personality theory to its ultimate depths in order to deal effectively with emotional problems." To what extent can one treat without knowing theory? Some of the techniques advocated in this book may be useful, but having too meager or too superficial knowledge with respect to their genesis may cause great misunderstanding. The third chapter of this book deals with special behavioral syndromes such as school phobia and anorexia nervosa. Many readers will be disappointed to find that there is no discussion, for example, of such a common disorder as enuresis. Strong advice is given for management which will be contrary to the kind of advice that many would suggest. For example, the author insists that in cases of school phobia
Diurnal variations in lower leg subcutaneous blood flow rate in patients with chronic venous leg ulcers
Authors: J.H. SINDRUP, J. KASTRUP, J.K. KRISTENSEN
Journal: British Journal of Dermatology (1991)

The blood flow rate in subcutaneous adipose tissue was measured on the lower legs of 11 patients with chronic lower‐leg venous insufficiency and ulceration and in eight age‐matched control subjects for 12–20 h, under ambulatory conditions, using the 133Xe wash‐out technique with portable Cadmium telluride (CdTe(Cl)) detectors. In both groups, the change from an upright to a supine position at the beginning of the night period elicited an instantaneous increment in the blood flow rate of 30–40% with a decrease in the central and local postural sympathetic vasoconstrictor activity. After approximately 1 h of sleep, a considerable increase in blood flow rate was seen in both patient and control groups which persisted for nearly 100 min. In the patient group, the mean increase was 137% compared to a mean increase of 68% in the control group (P<0·01). The blood flow then returned to the same level as at the beginning of the night and remained stable until the subjects woke in the morning. The differences between this nocturnal hyperaemic phase and the adjacent phases were highly significant in both groups (P <0·0001 and P < 0·005, respectively). The blood flow levels measured on the second day were of the same magnitude as those registered on the first day. The mean values of the wash‐out rate constants (k) of the two groups were of the same magnitude in all phases of subcutaneous blood flow level, except in the hyperaemic phase, where it was significantly higher in the patient group (P<0·01). The pattern of the nocturnal blood flow rate corresponded to that described previously in a younger healthy population, but with quantitative differences, which suggests that the abnormality occurs in the neural, humoral or metabolic factors involved in the nocturnal hyperaemic response.
Death row prisoners sue FDA for allowing unapproved execution drug to be imported
Authors: C. Dyer
Journal: BMJ (2011)

<h3>Abstract</h3> <h3>Background</h3> Altered resting state functional connectivity (FC) involving the anterior insula (aINS), a key node in the salience network, has been reported consistently in autism. <h3>Method</h3> Here we examined, for the first time, FC between the aINS and the whole brain in a sample of full-term, postmenstrual age (PMA) matched neonates (mean 44.0 weeks, SD=1.5) who due to family history have high likelihood (HL) for developing autism (n=12) and in controls (n=41) without family history of autism (low likelihood, LL). Behaviors associated with autism were evaluated between 12 and 18 months (M=17.3 months, SD=2.5) in a subsample (25/53) of participants using the First Year Inventory (FYI). <h3>Results</h3> Compared to LL controls, HL neonates showed hypoconnectivity between left aINS and left amygdala. Lower connectivity between the two nodes was associated with higher FYI risk scores in the social domain (r(25) = −.561, p=.003) and this association remained robust when maternal mental health factors were considered. Considering that a subsample of LL participants (n=14/41) underwent brain imaging during the fetal period at PMA 31 and 34 weeks, in an exploratory analysis, we evaluated prospectively development of the LaINS-Lamy connectivity and found that the two areas strongly coactivate throughout the third trimester of pregnancy. <h3>Conclusions</h3> The study identifies left lateralized anterior insula - amygdala connectivity as a potential target of further investigation into neural circuitry that enhances likelihood of future onset of social behaviors associated with autism during neonatal and potentially prenatal periods.