tbuckley/cabot-search huggingface dataset:
Six-month progression-free survival as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma patients receiving temozolomide
Authors: M.-Y. C. Polley, K. R. Lamborn, S. M. Chang, N. Butowski, J. L. Clarke, M. Prados
Journal: Neuro-Oncology (2009)

We assessed six-month progression-free survival (PFS) as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma multiforme (GBM) patients receiving temozolomide (TMZ). A total of 183 patients with newly diagnosed GBM enrolled in 3 phase II protocols at the University of California-San Francisco were included. Patients were treated with interventions based on the Stupp regimen, each with the added component of a second oral agent given concurrently with radiotherapy and TMZ, followed by its coadministration with adjuvant TMZ. We examined whether progression status at 2, 4, and 6 months predicted subsequent survival using the landmark analysis. The hazard ratios of death as a function of progression status were estimated based on the Cox proportional hazards model after adjustment for putative prognostic factors. Progression status at 2, 4, and 6 months were all consistently found to be strong predictors of subsequent survival in all studies. The study-specific hazard ratios associated with progression status at 6 months ranged from 2.03 to 3.39. The hazard ratios associated with the earlier time points (2- and 4-month progression) all exceeded 2 in magnitude, ranging from 2.29 to 4.73. P-values were statistically significant for all time points. In this report, we demonstrated a strong association between the endpoints of PFS at 2, 4, and 6 months and survival. Patients who showed the signs of early progression were at significantly higher risk of earlier death. Our analysis suggests that 6-month PFS may be an appropriate primary endpoint in the context of phase II upfront GBM trials in the TMZ era.
Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP
Authors: Yuan Yuan, Yu-Min Liao, Chung-Tsen Hsueh, Hamid R Mirshahidi
Journal: Journal of Hematology & Oncology (2011)

Abstract We reviewed preclinical data and clinical development of MDM2 (murine double minute 2), ALK (anaplastic lymphoma kinase) and PARP (poly [ADP-ribose] polymerase) inhibitors. MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC). Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway. Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor, demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5 other PARP inhibitors currently under active clinical investigation.
Reply to D.A. Hamstra et al and A.P. Sandhu
Authors: Michael J. Zelefsky, Peter Scardino, Andrew Vickers, James Eastham
Journal: Journal of Clinical Oncology (2010)

2 the data do suggest there may be a benefit to improved local control with RP combined with adjuvant or salvage RT.It would be a mistake to dismiss these data, accepting the null hypothesis of no effect, unless randomized trials contradict these findings.Before such randomized trials, we would in the meantime encourage other institutions to analyze their own clinical experiences to confirm or refute these findings.
Microglial Activation in Young Adults With Autism Spectrum Disorder
Authors: Katsuaki Suzuki, Genichi Sugihara, Yasuomi Ouchi, Kazuhiko Nakamura, Masami Futatsubashi, Kiyokazu Takebayashi, Yujiro Yoshihara, Kei Omata, Kaori Matsumoto, Kenji J. Tsuchiya, Yasuhide Iwata, Masatsugu Tsujii, Toshirou Sugiyama, Norio Mori
Journal: JAMA Psychiatry (2012)

<h3>Context</h3>A growing body of evidence suggests that aberrant immunologic systems underlie the pathophysiologic characteristics of autism spectrum disorder (ASD). However, to our knowledge, no information is available on the patterns of distribution of microglial activation in the brain in ASD.<h3>Objectives</h3>To identify brain regions associated with excessively activated microglia in the whole brain, and to examine similarities in the pattern of distribution of activated microglia in subjects with ASD and control subjects.<h3>Design</h3>Case-control study using positron emission tomography and a radiotracer for microglia—[<sup>11</sup>C](R)-(1-[2-chrorophynyl]- N-methyl- N-[1-methylpropyl]-3 isoquinoline carboxamide) ([<sup>11</sup>C](R)-PK11195).<h3>Setting</h3>Subjects recruited from the community.<h3>Participants</h3>Twenty men with ASD (age range, 18-31 years; mean [SD] IQ, 95.9 [16.7]) and 20 age- and IQ-matched healthy men as controls. Diagnosis of ASD was made in accordance with the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview–Revised.<h3>Main Outcome Measures</h3>Regional brain [<sup>11</sup>C](R)-PK11195 binding potential as a representative measure of microglial activation.<h3>Results</h3>The [<sup>11</sup>C](R)-PK11195 binding potential values were significantly higher in multiple brain regions in young adults with ASD compared with those of controls (P &lt; .05, corrected). Brain regions with increased binding potentials included the cerebellum, midbrain, pons, fusiform gyri, and the anterior cingulate and orbitofrontal cortices. The most prominent increase was observed in the cerebellum. The pattern of distribution of [<sup>11</sup>C](R)-PK11195 binding potential values in these brain regions of ASD and control subjects was similar, whereas the magnitude of the [<sup>11</sup>C](R)-PK11195 binding potential in the ASD group was greater than that of controls in all regions.<h3>Conclusions</h3>Our results indicate excessive microglial activation in multiple brain regions in young adult subjects with ASD. The similar distribution pattern of regional microglial activity in the ASD and control groups may indicate augmented but not altered microglial activation in the brain in the subjects with ASD.
Transcriptional Regulation of Inducible Nitric Oxide Synthase in Cultured Neonatal Rat Cardiac Myocytes
Authors: Koh-ichiro Kinugawa, Tatsuya Shimizu, Atsushi Yao, Osami Kohmoto, Takashi Serizawa, Toshiyuki Takahashi
Journal: Circulation Research (1997)

Abstract Previous work has demonstrated that inducible NO synthase (iNOS) can be expressed in cardiac myocytes. In this study, we investigated transcriptional regulation of the iNOS gene in these cells. Lipopolysaccharide (LPS) induced iNOS mRNA and protein in cultured neonatal rat cardiac myocytes. H-89, dexamethasone, herbimycin, genistein, staurosporine, or pyrrolidine dithiocarbamate (PDTC) attenuated the iNOS induction by LPS. Forskolin, interleukin (IL)-6, tumor necrosis factor (TNF)-α, or interferon (IFN)-γ enhanced the LPS-induced iNOS expression. Combined stimulation of IL-6 and TNF-α also induced iNOS. The 5′-upstream sequence of the rat iNOS gene contains the nuclear factor-κB (NF-κB) site, CAAT box, IFN-γ activation site (GAS), and IFN regulatory factor (IRF) site. DNase I footprinting assay revealed that the nuclear factors binding to these elements were increased by LPS exposure. Transient transfection assay suggested that these elements were indispensable for transcriptional regulation of the iNOS induction. Electrophoretic mobility shift assay revealed that LPS or TNF-α increased binding activity for the NF-κB site. A slower-migrating complex binding to the CAAT box gave rise after exposure to LPS or forskolin. Competition assay suggested that this slower-migrating complex consisted of a heterodimer between a member of CAAT box/enhancer binding (C/EBP) protein family and cAMP responsive element binding protein (CREB). LPS or IL-6 increased binding complexes for the IRF site, which was compatible with induction of IRF-1. LPS, IL-6, or IFN-γ induced a novel binding complex for GAS, which also existed in the 5′-flanking region of the IRF-1 gene. These data suggest that (1) iNOS induction simultaneously requires both NF-κB activation and IRF-1 induction, and (2) the heterodimer between C/EBP and CREB has synergistic effects on the iNOS induction via the CAAT box.
Hearing impairment in a 5 year old child
Authors: N. Ronan, G. Barrett
Journal: BMJ (2014)

A 5 year old boy was referred to the ear, nose, and throat (ENT) outpatients department by his general practitioner after his school had raised concerns about his hearing and attention. His parents had also noted that he tended to have the television on a loud volume, and they thought that he was a “loud child,” often shouting unnecessarily in quiet situations. On further questioning, it was apparent that his speech was delayed and difficult to understand. He had no history of other ENT problems or ear infections, and he had passed his neonatal hearing screening test. He was otherwise fit and well, had reached his milestones appropriately, and had no family history of note.

On examination, he had dull retracted ear drums with loss of the light reflex on both sides, and tympanometry showed flat traces bilaterally, consistent with no movement of the ear drums. The remainder of the examination was normal.

A pure tone audiogram was obtained (figure⇓).



Pure tone audiogram showing air conduction thresholds (“x” for the left ear and “o” for the right) and masked bone conduction thresholds (“]” for the left and “[” for the right)





### 1. What is the most likely diagnosis?

#### Short answer

Consider all possible causes for childhood hearing loss, including impacted wax, cholesteatoma, and …
Do we have a new early marker of chronic transplant dysfunction now?
Authors: W. Briest
Journal: Cardiovascular Research (2002)

See article by Subramanian et al. [9] (pages 539–548) in this issue. 

The development of chronic transplant dysfunction (CTD) has become a limiting factor for long-term graft survival, and it is today's most important problem in clinical organ transplantation after the first perioperative year. To date, CTD cannot be prevented by current immunosuppressive protocols [1,2]. Depending on the type of organ transplanted (liver, kidney, heart, lung), the incidence of CTD 3 years after engraftment varies from 4 to >50% [3–5]. Irrespective of the organ grafted, graft vessels eventually develop so-called transplant vascular sclerosis (TVS), which is, however, most prominent in cardiac allografts [6,7]. This vascular remodeling process, also called chronic vascular rejection or graft vascular disease, is the main cause of morbidity and mortality in long term survivors of many types of organ transplants. The standard etiology of TVS following organ transplantation is thought to be the local migration and proliferation of medial vascular smooth muscle (VSM) cells in response to inflammatory signals and/or growth factor expression with consequent thickening of the intima. Although this etiology of TVS has never been demonstrated in its entirety, several steps have been documented in vessels with ongoing neointimal formation, including … 

* Tel.: +49-341-971-5500; fax: +49-341-971-5509 briestw{at}medizin.uni-leipzig.de
Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2
Authors: Sophie E. Acton, Jillian L. Astarita, Deepali Malhotra, Veronika Lukacs-Kornek, Bettina Franz, Paul R. Hess, Zoltan Jakus, Michael Kuligowski, Anne L. Fletcher, Kutlu G. Elpek, Angelique Bellemare-Pelletier, Lindsay Sceats, Erika D. Reynoso, Santiago F. Gonzalez, Daniel B. Graham, Jonathan Chang, Anneli Peters, Matthew Woodruff, Young-A. Kim, Wojciech Swat, Takashi Morita, Vijay Kuchroo, Michael C. Carroll, Mark L. Kahn, Kai W. Wucherpfennig, Shannon J. Turley
Journal: Immunity (2012)

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
EEG Synchronization to Modulated Auditory Tones in Schizophrenia, Schizoaffective Disorder, and Schizotypal Personality Disorder
Authors: Colleen A Brenner, Olaf Sporns, Paul H Lysaker, Brian F O'Donnell
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The authors tested whether neural synchronization deficits were present in subjects with schizophrenia and schizotypal personality disorder. METHOD: Amplitude-modulated tones were used to evaluate auditory steady-state evoked potential entrainment in a combined group of 21 subjects with schizophrenia or schizoaffective disorder, 11 subjects with schizotypal personality disorder, and 22 nonpsychiatric comparison subjects. RESULTS: The schizophrenia or schizoaffective disorder group exhibited decreased power compared to the schizotypal personality disorder and nonpsychiatric comparison groups. There were no differences between groups in N100 amplitude. CONCLUSIONS: Subjects with schizophrenia but not subjects with schizotypal personality disorder have deficits in steady-state responses to periodic stimuli, despite an intact response to sensory-evoked potentials (N100). These deficits reflect aberrant neural synchronization or resolution and may contribute to disturbed perceptual and cognitive integration in schizophrenia.
Continuous MLL-ENL Expression Is Necessary to Establish a “Hox Code” and Maintain Immortalization of Hematopoietic Progenitor Cells
Authors: Sarah J. Horton, David G. Grier, Glenda J. McGonigle, Alexander Thompson, Michelle Morrow, Inusha De Silva, Dale A. Moulding, Dimitris Kioussis, Terence R.J. Lappin, Hugh J.M. Brady, Owen Williams
Journal: Cancer Research (2005)

Abstract The t[(11;19)(p22;q23)] translocation, which gives rise to the MLL-ENL fusion protein, is commonly found in infant acute leukemias of both the myeloid and lymphoid lineage. To investigate the molecular mechanism of immortalization by MLL-ENL we established a Tet-regulatable system of MLL-ENL expression in primary hematopoietic progenitor cells. Immortalized myeloid cell lines were generated, which are dependent on continued MLL-ENL expression for their survival and proliferation. These cells either terminally differentiate or die when MLL-ENL expression is turned off with doxycycline. The expression profile of all 39 murine Hox genes was analyzed in these cells by real-time quantitative PCR. This analysis showed that loss of MLL-ENL was accompanied by a reduction in the expression of multiple Hoxa genes. By comparing these changes with Hox gene expression in cells induced to differentiate with granulocyte colony-stimulating factor, we show for the first time that reduced Hox gene expression is specific to loss of MLL-ENL and is not a consequence of differentiation. Our data also suggest that the Hox cofactor Meis-2 can substitute for Meis-1 function. Thus, MLL-ENL is required to initiate and maintain immortalization of myeloid progenitors and may contribute to leukemogenesis by aberrantly sustaining the expression of a “Hox code” consisting of Hoxa4 to Hoxa11.
A Subpopulation of Cardiomyocytes Expressing α-Skeletal Actin Is Identified by a Specific Polyclonal Antibody
Authors: Sophie Clément, Christine Chaponnier, Giulio Gabbiani
Journal: Circulation Research (1999)

The NH(2)-terminal decapeptide of alpha-skeletal actin that contains a primary sequence specific for this isoform was used to raise a polyclonal antibody in rabbits. Using sequential affinity chromatography, we recovered from serum antibodies reacting exclusively with alpha-skeletal actin when tested by immunoblotting and immunofluorescence. Epitope mapping by means of competition assays with synthetic peptides indicated that the acetyl group and the first 9 amino acids are essential for specificity. The monospecific antibody was then used to investigate the distribution of alpha-skeletal actin in the myocardium of newborn and normal or hypertensive (with or without fibrotic areas) adult rats. Immunostaining of normal heart revealed that alpha-skeletal actin is diffusely distributed within practically all myocardial fibers of the newborn rat, whereas it is restricted to a small proportion of adult rat cardiomyocytes, which appear intensely stained. A correlation, albeit not complete, was found between the distribution of alpha-skeletal actin and beta-myosin heavy chain. During cardiac hypertrophy induced by aortic ligature between the renal arteries, the expressions of alpha-skeletal actin mRNA and protein were increased. The distribution of immunostaining had a focal pattern similar to that of normal adult rats, reactive fibers being more numerous and more intensely stained compared with normal myocardium. Positive fibers were particularly abundant at the periphery of fibrotic areas. Using this antibody, we have demonstrated for the first time the differential distribution of alpha-skeletal actin in heart tissues. Changes in the distribution of this isoform in hypertrophic heart provide new insight into the mechanisms by which the heart adapts to work overload. This antibody will prove useful in exploring the mechanisms of expression of alpha-skeletal actin and in defining its role in physiological and pathological situations.
Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes
Authors: Pai-Feng Hsu, Shih-Hsien Sung, Hao-Min Cheng, Jong-Shiuan Yeh, Wen-Ling Liu, Wan-Leong Chan, Chen-Huan Chen, Pesus Chou, Shao-Yuan Chuang
Journal: Diabetes Care (2012)

Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown.The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998-2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63-2.67]), all-cause hospitalization (2.51 [2.00-3.16]), and total mortality (2.48 [1.41-4.38]).Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.
Removal of Sutures
Authors: A. D. Wright
Journal: BMJ (1952)

<h3>Objective</h3> Preclinical research suggests that the combined use of radiofrequency ablation and balloon dilation (CURB) could create stable interatrial communications without device implantation. This study examined the first in-human use of CURB for modified atrial septostomy in patients with severe pulmonary arterial hypertension (PAH). <h3>Methods</h3> Between July 2018 and October 2021, CURB was performed in 19 patients with severe PAH (age: 31.5±9.1 years; mean pulmonary artery pressure: 73 mm Hg (IQR: 66–92); pulmonary vascular resistance: 18.7 Wood units (IQR: 17.8–23.3)). Under guidance of intracardiac echocardiography and three-dimensional location system, (1) fossae ovalis was reconstructed and ablated point-by-point with radiofrequency; (2) then graded balloon dilation was performed after transseptal puncture and the optimal size was determined according to the level of arterial oxygen saturation (SatO<sub>2</sub>); (3) radiofrequency ablation was repeated around the rims of the created fenestration. The interatrial fenestrations were followed-up serially. <h3>Results</h3> After CURB, the immediate fenestration size was 4.4 mm (IQR: 4.1–5.1) with intracardiac echocardiography, systolic aortic pressure increased by 10.2±6.9 mm Hg, cardiac index increased by 0.7±0.3 L/min/m<sup>2</sup> and room-air resting SatO2 decreased by 6.2±1.9% (p&lt;0.001). One patient experienced increased pericardiac effusion postoperatively; the others had no complications. On follow-up (median: 15.5 months), all interatrial communications were patent with stable size (intraclass correlation coefficient=0.96, 95%CI:0.89 to 0.99). The WHO functional class increased by 1 (IQR: 1–2) (p&lt;0.001) with improvement of exercise capacity (+159.5 m, P&lt;0.001). <h3>Conclusion</h3> The interatrial communications created with CURB in patients with severe PAH were stable and the mid-term outcomes were satisfactory. <h3>Trial registration number</h3> NCT03554330.
Perimenopausal women's views on hormone replacement therapy.
Authors: A Z Kadri
Journal: BMJ (1990)

accordingly.The advent of HIV infection has obviously forced a reappraisal of this, but as yet we see no reason to alter a system that is working very well.In our experience, people who inject opiates can, and do, change their behaviour for the better, and our philosophy is to enhance and encourage this process; prescribing street drugs inhibits it and hinders the formation of useful therapeutic relationships.Prescribing also creates a situation in which it becomes very difficult or impossible to distinguish between reported and actual behavioural change.It is completely misleading and unjustified, therefore, to infer that, simply because a medical practitioner does not unquestioningly embark on Dr Greenwood's commonsense approach of prescribing maintenance drugs, there is no medical intervention or that no useful therapeutic work is being done.Quite the opposite, in fact.