tbuckley/cabot-search huggingface dataset:
SNS-595 demonstrates clinical activity and dose-proportional pharmacokinetics (PK) in two phase I clinical studies
Authors: H. Hurwitz, M. Gordon, R. Advani, S. Ebbinghaus, D. Mendelson, H. Wakelee, U. Hoch, J. Silverman, N. Havrilla, D. Adelman
Journal: Journal of Clinical Oncology (2006)

3062 Background: SNS-595 is a novel naphthyridine analog with broad and potent activity in preclinical models. Methods: SNS-595 was administered to patients (pts) with advanced solid cancers as an IV infusion over 10 minutes on 2 schedules: (A) qwk x3/1 week off, and (B) q3wks. Pt eligibility included refractory solid tumors and adequate organ function. Results: In study A, 20 patients (pts) were treated in 6 cohorts (dose range 3–24 mg/m 2 /wk). In study B, 41 pts were treated in 9 cohorts (dose range 3–75 mg/m 2 /wk). After the MTD in heavily pretreated (HP) pts was found, dose escalation in minimally pretreated (MP) pts was evaluated. The median ages were 60.5 yrs (A) and 59.5 yrs (B), sex 12F/8M (A), 16F/25M (B). All pts had a ECOG PS 0–2. Neutropenia was the dose limiting toxicity (DLT) for both studies. The MTD for A was 15 mg/m 2 for HP and MP pts; the MTD for B was 48 mg/m 2 for HP and 60 mg/m 2 for MP pts. For both studies 2 pts had grade 4 thrombocytopenia; non-hematological toxicities were all grade 1/2. In A, pharmacokinetics (PK) were assessed on Days 1 and 15 (after the 1st and 3rd doses); exposure increased linearly over an 8-fold dose range (1.6–15 mcghr/mL), CL, Vss and T 1/2 averaged 2 L/hr/m 2 , 49 L/m 2 , 18 hr, respectively, and did not change from Day 1 to 15. In B, PK were assessed on Day 1 after the 1st dose; exposure increased linearly over the 24-fold dose range (1.1–46 mcghr/mL), CL, Vss, and T 1/2 averaged 2 L/hr/m 2 , 53 L/m 2 , and 21 hrs, respectively. For A, best responses were 4 SD (range 13–22 wks); for B, best responses were 1 PR and 12 SD (range 14–56 wks). Conclusion: SNS-595 was well tolerated and showed clinical activity with both qwk and q3wk dosing. The DLT was non-cumulative neutropenia. SNS-595 demonstrated remarkably predictable PK, with low inter-and intra-patient variability. Based on these data, phase 2 studies of SNS-595 as monotherapy are ongoing, and are planned in combination therapy. [Table: see text]
Use of the Pavlik Harness in Nonoperative Management of Congenital Dislocation of the Hip
Authors: M A Smith
Journal: Journal of the Royal Society of Medicine (1981)

The Pavlik harness and its application are described. A series is reported of 25 patients with congenital dislocation of the hip, aged between one day and eight months, all of whom were successfully treated in the harness. Since the harness was found to be effective in treating older infants, it is suggested that treatment of the newborn could be delayed until the age of two or three months, thus avoiding unnecessary treatment of those hips which will reduce spontaneously.
Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8+ Cytolytic T Cell Responses
Authors: Alison Taylor, James A. Harker, Kittiphat Chanthong, Philip G. Stevenson, Elina I. Zuniga, Christopher E. Rudd
Journal: Immunity (2016)

Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
Validation of the Inflammatory Bowel Disease Disability Index in a population-based cohort
Authors: Corinne Gower-Rousseau, Hélène Sarter, Guillaume Savoye, Noémie Tavernier, Mathurin Fumery, William J Sandborn, Brian G Feagan, Alain Duhamel, Nathalie Guillon-Dellac, Jean-Frédéric Colombel, Laurent Peyrin-Biroulet
Journal: Gut (2015)

<h3>Background</h3> IBDs are chronic destructive disorders that negatively affect the functional status of patients. Recently, the Inflammatory Bowel Disease Disability Index (IBD-DI) was developed according to standard WHO processes. The aims of the current study were to validate the IBD-DI in an independent patient cohort, to develop an index-specific scoring system and to describe the disability status of a well-defined population-based cohort of French patients with IBD. <h3>Methods</h3> From February 2012 to March 2014, the IBD-DI questionnaire was administered to a random sample of adult patients with an established diagnosis of IBD issued from a French population-based registry. The IBD-DI consists of 28 items that evaluate the four domains of body functions, activity participation, body structures and environmental factors. Validation included item reduction and data structure, construct validity, internal consistency, interobserver and intraobserver reliability evaluations. <h3>Results</h3> 150 patients with Crohn9s disease (CD) and 50 patients with UC completed the IBD-DI validation phase. The intraclass correlation coefficient for interobserver reliability was 0.91 and 0.54 for intraobserver reliability. Cronbach9s α of internal consistency was 0.86. IBD-DI scores varied from 0 to 100 with a mean of 35.3 (Q1=19.6; Q3=51.8). IBD-DI scores were highly correlated with Inflammatory Bowel Disease Questionnaire (−0.82; p&lt;0.001) and SF-36 (–0.61; p&lt;0.05) scores. Female gender (p&lt;0.001), clinical disease activity (p&lt;0.0001) and disease duration (p=0.02) were associated with higher IBD-DI scores. <h3>Conclusions</h3> The IBD-DI has been validated for use in clinical trials and epidemiological studies. The IBD-DI showed high internal consistency, interobserver reliability and construct validity, and a moderate intraobserver reliability. It comprises 14 questions and ranges from 0 to 100. The mean IBD-DI score was 35.3 and was associated with gender, clinical disease activity and disease duration. Further research is needed to confirm the structural validity and to assess the responsiveness of IBD-DI. <h3>Trial registration number</h3> 2011-A00877-34
Digitalis Poisoning and Its Treatment
Authors: Burton M. Cohen
Journal: New England Journal of Medicine (1952)

Because digitalis preparations, acetylcholine or vagal stimulation may cause identical electrocardiographic changes in normal persons,113 early efforts were directed toward vagal paralysis with atropine. In fact, some experimental data purported to show that atropine might aid in modifying the myocardial lesions produced by digitalis.69 Clinical results were conflicting. Resnik observed a reversion to regular sinus rhythm from digitalis-induced auricular fibrillation within sixty-eight minutes after a hypodermic injection of 2 mg. of atropine75; Gold and Otto described similar success in interrupting 5 cases of digitalis bigeminy.43 On the other hand, Robinson and Wilson could not modify the toxic effects of . . .
Abstract 19700: MRI Based Non-Invasive Detection of Cardiomyocyte Hypertrophy and Cell Volume Changes
Authors: Otavio Coelho-Filho, Ravi Shah, Richard Mitchell, Hector Moreno, Raymond Kwong, Michael Jerosch-Herold
Journal: Circulation (2012)

BACKGROUND: Cardiac hypertrophy results from cardiomyocyte cell hypertrophy and expansion of the extracellular matrix. To elucidate the tissue phenotype requires a combined assessment of these characteristics. The goal of this study was to validate a novel MRI-based approach for the combined assessment of extra-cellular matrix expansion and cell size. METHODS: Hypertension was induced by L-NAME (3mg/ml) in 17 wild-type mice (body-weight=37.2±2.3g). 13 mice (body-weight=37.5±2.5g) received placebo. Transaortic constriction (TAC) was performed in 11 male-wild-type (body-weight=25.2±2.0 g) mice. Mice were imaged at baseline, 7-weeks after L-NAME treatment, and 2 weeks after TAC at ≥4.7T. T1 was quantified with a Look-Locker cine technique, pre and post gadolinium. The intra-cellular lifetime of water (τic), a-cell size dependent parameter, and the extracellular volume fraction (ECV) were determined by fitting R1 in tissue, against R1 in the blood pool, with a 2-site model for transcytolemmal water exchange. Minor (Dmin) and major (Dmaj) cell-diameters were determined by image analysis of FITC-wheat germ agglutinin stained sections. RESULTS: The hearts of L-NAME-treated and TAC mice developed hypertrophy (LV mass: TAC 113±16 and L-NAME 163.6 μg; all p&lt;0.05 vs. controls). τic was significantly higher in L-NAME-treated animals (0.453±0.10 s; p&lt;0.0001) and in TAC mice (0.255±0.04 s; p&lt;0.001), compared to controls (0.193±0.07 s). τic correlated with the minor cell diameter (r=0.77, P&lt;0.001), the major cell-diameter (r=0.5, p=0.02), and with LV mass (r=0.76, p&lt;0.001). ECV in L-NAME-treated mice (0.395±0.047) was significantly higher (p&lt;0.001) than in TAC (0.248±0.033; n.s. vs. controls) mice and controls (0.269±0.029). CONCLUSION: We validated a combined and non-invasive quantification of cell size and extra-cellular space expansion. The results in TAC mice demonstrate the ability to detect changes in cellular hypertrophy before expansion of the extracellular space and development of cardiac (interstitial) fibrosis.
Pleural effusions in patients treated with dasatinib: Results from two institutions, risk factors and management
Authors: J. H. Lipton, L. Sriharsha, S. Bogomilsky, L. Casciaro, A. Keating, H. Messner, P. Laneuville
Journal: Journal of Clinical Oncology (2007)

17503 Background: Dasatinib (SPRYCEL, formerly BMS354825) is a multi-targeted kinase inhibitor that has been shown to be very effective in the therapy of imatinib-resistant and -intolerant Ph-positive CML/ALL patients, frequently resulting in hematologic and cytogenetic remissions. Therapy with kinase inhibitors has been limited to some extent by fluid retention, the type of which is dependent on the individual drug. Pleural effusions have been relatively more common with dasatinib. We report on the experience at two large teaching hospitals - incidence, risk factors and management. Methods: 27 patients were treated on 5 BMS Phase 2 Studies (2CP, 1AP, 1BP-M, 1BP-L, 1ALL) - 17 CP, 5 AP, 3 BP-M, 2 BP-L/ALL. All patients started on a dose of 70mg BID of dasatinib. Results: In all 13 patients developed effusions. All but 1 were Grade 2; grades 2–4 are symptomatic and require intervention. Of the 14 who did not, 9 were either withdrawn from study because of CML progression (3) or dose-reduced because of hematological toxicity (6). The development of effusions was more common in patients with more advanced disease (BC&gt;AP&gt;CP), in those with previous lung problems (smoking, infections), and in those maintained on starting doses of dasatinib. Effusions could develop even 1–2 years (1&gt;100d, 2&gt;200, 2&gt;300d, 1&gt;500d) after starting therapy often triggered by a lung infection. Effective management included ongoing combinations of diuretics, temporary drug discontinuation, dose reduction, and more recently a once daily drug dosing schedule (Hochhaus et al , Blood 2006, 108: 166a). One patient required thoracentesis and chest tube. Conclusions: Dose monitoring and adjustments and management of the effusions have permitted continuation of the therapy in 10 of the 13 patients with good hematological outcomes. A change in dose schedule will be most effective. No significant financial relationships to disclose.
Patterns of ribosomal RNA evolution in salamanders.
Authors: A Larson, A C Wilson
Journal: Molecular Biology and Evolution (1989)

Sequence comparisons are presented for four segments of the large subunit of ribosomal RNA, including divergent domains D7a and D7b, portions of the large divergent domains D2, D3, and D8, and evolutionarily conservative sequences flanking divergent domains. These results resolve phylogenetic relationships among exemplars of seven families of salamanders and the three amphibian orders. Phylogenetic analysis confirms the prediction that divergent domains feature the highest relative rates of base substitution and length variation within the ribosome, but the divergent domains evolve more slowly than nuclear noncoding DNA and the silent sites of structural genes. Base substitutions demonstrate approximately twice as many transitions as transversions and an uneven distribution among sites within the divergent domains but no apparent bias in base composition. Length mutations are primarily small insertions and deletions, with deletions predominating. The divergent domains appear to be a good source of phylogenetic information for evolutionary events occurring approximately 100-200 million years ago.
Tumours associated with gastrointestinal stromal tumors (GIST): A case report
Authors: S. Fayaz, T. George, M. Mohammad, S. Samir
Journal: Journal of Clinical Oncology (2007)

20529 Background: Much progress has been made in the diagnosis and treatment of GIST but the rarity of second neoplasms in association with gastro intestinal tumours (GIST) have rarely been reported. Methods: We present three case reports of breast cancer, Hodgkin's disease and thyroid cancer associated with GIST Results: The first pt, aged 50 underwent left lumpectomy and axillary clearance for infiltrating ductal carcinoma. Estrogen and Progesterone receptors were positive. Adjuvant chemotherapy , radiotherapy and tamoxifen was administered .Three years later patent was operated for a sub mucous nodule in the stomach which was reported as GIST, CD117+ve,CD34 positive and the patient was followed up. The second pt, male aged 50 was operated for a large intrabdominal GIST tumour (16x16cm) arising from the stomach and later on referral found to have a Rt Supraclavicular node with a nodule in the thyroid. He under went total thyroidectomy with functional node dissection for papillary carcinoma. This was followed Radioactive iodine ablation and eltroxin. Three months later he presented with thoraco abdominal metastasis and treatment with Imatnib was begun, but he soon progressed and succumbed to his disease. The third pt, female, with a history of Hodgkin's disease treated with chemotherapy on follow up. Twelve years later the pt was subjected to extensive debulking for pelvic GIST (16cmx15cm).CD117 positve.She was kept on follow up. A ct chest abdomen and pelvis eight months following surgery was unremarkable. Conclusions: Very few cases have been reported in literature regarding association of second tumours with GIST .And no correlation can be made to generate a hypothesis regarding these associations. No significant financial relationships to disclose.
Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts
Authors: Irene Scarfò, Elisa Pellegrino, Elisabetta Mereu, Ivo Kwee, Luca Agnelli, Elisa Bergaggio, Giulia Garaffo, Nicoletta Vitale, Manuel Caputo, Rodolfo Machiorlatti, Paola Circosta, Francesco Abate, Antonella Barreca, Domenico Novero, Susan Mathew, Andrea Rinaldi, Enrico Tiacci, Sara Serra, Silvia Deaglio, Antonino Neri, Brunangelo Falini, Raul Rabadan, Francesco Bertoni, Giorgio Inghirami, Roberto Piva
Journal: Blood (2015)
Decline in HIV infections in Thailand. The authors reply [letter]
Authors: Nelson Ke, Celentano Dd
Journal: New England Journal of Medicine (1996)

A public health program in Thailand worked to prevent HIV infection by promoting condom use and encouraging the reduction of high-risk sexual relations.  The authors believe that the intervention brought about behavior change which resulted in the recent decline in HIV infection rates among 21-year-old men in Thailand.  Brody however believes that the decline in HIV infection rates is due to the decreased infectivity of HIV and is not related to changes in individual high-risk sexual behavior.  Independent data suggest that the use of condoms during commercial sexual relations has increased and is now the rule in northern Thailand.  The high rates of condom use claimed by men in the authors study were confirmed through interviews with female prostitutes in the region.  In a study of condom breakage during commercial sexual relations the more than 90% frequency of condom use was confirmed through the collection of used condoms.
Analysis of prognostic value of biomarkers in gastric MALT lymphomas.
Authors: T. Tousseyn, E. Haesevoets, K. Geboes, G. De Hertogh, E. Van Cutsem, X. Sagaert
Journal: Journal of Clinical Oncology (2010)

e14552 Background: 80% of MALT lymphomas regress in response to H. pylori eradication therapy. Molecular mechanisms of resistance to H. pylori eradication therapy and resistance to more aggressive therapies such as chemo- and radiotherapy remain unclear. To clarify this issue, we investigated H. pylori infection status, FOXP1 expression, microsatellite instability (MSI), and the t(11;18)-status in 29 patients with gastric low-grade MALT lymphoma. Methods: 29 gastric MALT lymphomas, diagnosed between 2003 and 2009, were retrieved from the archives of our Department of Pathology. All cases were clinically documented and further investigated by immunohistochemistry for the presence/absence of H. pylori, presence/absence of FOXP1 expression, presence/absence of BCL10 expression, and the presence/absence of MSI (MLH1, MSH2, MSH6), as well as by RT-PCR for the presence/absence of t(11;18). Results: 7/29 gastric MALT lymphomas (24%) were positive for t(11;18). The latter cases were positively associated with nuclear BCL10 expression. H. pylori was detected in 16/29 gastric MALT lymphomas (55%). No response to H. pylori eradication therapy was observed in 37.5% (6/16) of H pylori-positive cases : 3/3 or 100% in the t(11;18)-positive cases, compared to 3/13 or 23% in the t(11;18)-negative cases. In the group of H pylori-negative lymphomas, relapse or resistance to first line therapy was observed in 5 of 11 treated cases (45%) : 4/4 or 100% in the t(11;18)-positive cases, compared to 14% or 1/7 in the t(11;18)-negative cases. 10/29 gastric MALT lymphomas (34%) showed moderate to strong nuclear FOXP1 expression, 6 of them being H pylori positive. All 3 t(11;18)-negative lymphomas not responding to H. pylori eradication showed a strong nuclear FOXP1 expression, compared to only 1 of 10 cases (10%) in the responding group. Interestingly, 6/29 (20%) cases, all of them being t(11;18)-negative, showed absence for one or more of the DNA mismatch repair enzymes. Conclusions: In gastric MALT lymphoma the presence of t(11;18) predicts resistance to or relapse after first-line therapy. In t(11;18)-negative cases, FOXP1 expression predicts resistance to H. pylori eradication therapy. MSI may represent an alternative pathway for t(11;18)-negative MALT lymphomas. No significant financial relationships to disclose.
P0270 : SerpinB3 and Yap interplay increases Myc oncogenic activity
Authors: C. Turato, S. Cannito, D. Simonato, V. Gianmarco, L. Terrin, S. Quarta, A. Biasiolo, M. Ruvoletto, S. Fasolato, G. Zanus, U. Cillo, A. Gatta, M. Parola, P. Pontisso
Journal: Journal of Hepatology (2015)
Effects of 3 Months' Neoadjuvant Hormonal Treatment with a GnRH Analogue (Triptorelin) prior to Radical Retropubic Prostatectomy on Prostate-Specific Antigen and Tumour Volume in Prostate Cancer
Authors: G Aus, S Brändstedt, M Häggman, K Pedersen, M de la Torre, J Hugosson
Journal: European Urology (1994)
Prenatal Diagnosis of Genetic Disorders
Authors: Aubrey Milunsky
Journal: New England Journal of Medicine (1976)

New medical technologic advances may experience long delays before patients in general may benefit. The advent of prenatal genetic diagnosis a decade ago exemplifies the gap between the available technology and its use by society. In Massachusetts, for example, only 4.1 per cent of women 35 years of age and over had prenatal chromosomal studies in 1974. Available information suggests that women with advanced maternal age have been studied even less frequently elsewhere. Concern about the safety of amniocentesis and the accuracy of prenatal diagnosis, unawareness of the indications for studies and objections to the abortion of defective fetuses have . . .
Chimeric antigen receptor-engineered T cells in CLL: the next chapter unfolds
Authors: Michael Kalos
Journal: Journal for ImmunoTherapy of Cancer (2016)

The long-standing promise for the application of engineered T lymphocytes to target and eradicate malignancy has begun to be realized recently, with remarkable clinical success reported by a number of groups using Chimeric Antigen Receptor -engineered T cells to target CD19-positive hematologic malignancies. In the September 2 issue of Science Translational Medicine, Porter et al. present the clinical data and correlative analyses for 14 CLL patients treated at the University of Pennsylvania under the pilot clinical trial recently completed at that institution. The initial reports from this trial, published in 2011 documented robust clinical activity in a small cohort of treated patients accompanied by logarithmic expansion, contraction, and long-term functional persistence of engineered T cells, along with cytokine release syndrome as a side-effect of the treatment. In this latest report, updated data are presented from the initial cohort of patients, as well as clinical and correlative data from the remainder of the treated cohort. The robust clinical activity observed in the initial cohort continued to be observed in a subset of the subsequently-treated patients, with molecular remissions documented in that subset; however, in the expanded cohort a subset of partial and non-responding patients was also identified. Collectively, the results from this exciting trial provide evidence to suggest that cellular immunotherapy using engineered T cells is a viable option for treating CLL, reveal a likely requirement for robust in-vivo activation and persistence of engineered cells to effect complete responses, and also highlight the need for a more complete mechanistic understanding of the immune- and tumor- specific processes that define and dictate the success of this powerful treatment modality.
Evidence is important but should not be the only consideration: patients' and clinicians' views matter too
Authors: David I Tovey
Journal: BMJ (2007)

Health systems need to use resources to their maximum effect. This naturally leads them towards evidence based medicine, since those interventions that have been shown in well conducted (randomised) studies to be most effective should usually be prioritised over those where high quality evidence is lacking.

Problems arise where systems have to juggle alternative choices where the …