tbuckley/cabot-search huggingface dataset:
Phase I Study of GRN1005 in Recurrent Malignant Glioma
Authors: Jan Drappatz, Andrew Brenner, Eric T. Wong, April Eichler, David Schiff, Morris D. Groves, Tom Mikkelsen, Steve Rosenfeld, John Sarantopoulos, Christina A. Meyers, Robert M. Fielding, Kelly Elian, Xiaolin Wang, Betty Lawrence, Mona Shing, Stephen Kelsey, Jean Paul Castaigne, Patrick Y. Wen
Journal: Clinical Cancer Research (2013)

GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma.Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved.Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥ 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥ 200 mg/m(2).GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m(2) every 3 weeks.
Mental imagery doesn't work like that
Authors: Stephen M. Kosslyn, William L. Thompson, Giorgio Ganis
Journal: Behavioral and Brain Sciences (2002)

This commentary focuses on four major points: (1) “Tacit knowledge” is not a complete explanation for imagery phenomena, if it is an explanation at all. (2) Similarities and dissimilarities between imagery and perception are entirely consistent with the depictive view. (3) Knowledge about the brain is crucial for settling the debate. (4) It is not clear what sort of theory Pylyshyn advocates.
ANTIBACTERIAL EFFECTS ASSOCIATED WITH CHANGES IN BACTERIAL CYTOLOGY PRODUCED BY CATIONIC POLYPEPTIDES
Authors: John K. Spitznagel
Journal: The Journal of Experimental Medicine (1961)

The antibacterial action of cationic polypeptides has been found to be correlated with changes which they produce in the cytochemical reactions of the bacterial cells. Bacterial cells ordinarily stain with cationic dyes at pH values above 7. Treatment with cationic polypeptides rendered them stainable with the anionic dye fast green at pH 8.1. This change occurred parallel to loss of bacterial viability. An anionic, biological substance, mucin, was found to inhibit the usual conversion of bacterial cells from strong basophilia to strong acidophilia in the presence of cationic polypeptide. This inhibitory action was paralleled by inhibition of the toxicity of the cationic polypeptides for the bacterial cells. It was found that the basic protein, globin, which has a lesser pK than total calf thymus histone, was less toxic for E. coli and less effective in causing the bacterial cells to become stainable with the anionic dye at high pH. Staining with fast green at pH 8.1 appeared to provide presumptive evidence of lethal interaction between certain bacterial cells and cationic polypeptides such as total histones. It is suggested that the method may prove to be useful in the detection of lethal interaction between cationic polypeptides of the host and bacteria residing in host tissues.
Effects of Long-term Rofecoxib on Gastric Intestinal Metaplasia: Results of a Randomized Controlled Trial
Authors: Wai K. Leung, Enders K.W. Ng, Francis K.L. Chan, Wing Y. Chan, Kui-fat Chan, Alex C.M. Auyeung, Candice C.H. Lam, James Y.W. Lau, Joseph J.Y. Sung
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Gastric cancer and its premalignant gastric lesion, intestinal metaplasia (IM), frequently express cyclooxygenase-2 (COX-2) at high levels. We tested whether long-term use of specific COX-2 inhibitors regress gastric IM. Experimental Design: This is a double-blind, randomized, placebo-controlled trial. Individuals with confirmed IM and Helicobacter pylori clearance were randomized to receive rofecoxib 25 mg daily or placebo. Endoscopy was done at baseline, at the end of year 1, and at the end of year 2, with multiple biopsies taken from the antrum and corpus. The primary end point was the proportion of subjects with regression of IM. Secondary end points were the severity of other histologic variables and the proportion of subjects with complete regression of IM. Results: Two-hundred and thirteen subjects with confirmed IM were randomized. The proportion of subjects with the regression of IM did not differ significantly between rofecoxib and placebo groups (antrum, 24.5% versus 26.9%; P = 0.74; corpus, 4.3% versus 2.2%; P = 0.68). Patients on rofecoxib (19.1%) and on placebo (16.1%) had no IM detected in the stomach (P = 0.59). There was also no significant difference in the severity of IM between the two treatment groups (P ≥ 0.3). Conclusions: There was no trend to suggest that treatment with rofecoxib for 2 years resulted in the regression of gastric IM. Although our findings cast doubt on the reversibility of gastric IM by COX-2 inhibitor, further studies are needed to establish the role of COX-2 inhibitors in different stages of gastric carcinogenesis.
Competition is intrinsically wasteful
Authors: S. M. Crawford
Journal: BMJ (2012)

Some months ago I read a remarkable newspaper story. There is a push for restaurants to reduce waste (www.independent.co.uk/news/uk/home-news/uk-restaurants-waste-600000-tons-of-food-a-year-2108978.html). This is enthusiastically welcomed in some quarters but is causing consternation in others. Apparently, excessive portion size and careless kitchen habits lead to a third of all wasted food coming from diners’ plates—600 000 tonnes of food each year, or 22 tonnes per eatery.

In the NHS we are taught to regard waste as anathema. Some are of the view that making healthcare provider organisations compete with each other will force them to drive down their costs by cutting out waste. Those providers operated by the private sector are expected to be especially good at this. Competition between providers is an important point of the legislation recently passed by parliament.

If any commercial organisations know about competition, restaurants do. Business failures are extremely common …
Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO)
Authors: Marcos Ballester, Gil Dubernard, Fabrice Lécuru, Denis Heitz, Patrice Mathevet, Henri Marret, Denis Querleu, François Golfier, Eric Leblanc, Roman Rouzier, Emile Daraï
Journal: The Lancet Oncology (2011)
Mutations in the Glucokinase Gene of the Fetus Result in Reduced Placental Weight
Authors: Beverley M. Shields, Gill Spyer, Annabelle S. Slingerland, Bridget A. Knight, Sian Ellard, Penelope M. Clark, Sylvie Hauguel-de Mouzon, Andrew T. Hattersley
Journal: Diabetes Care (2008)

OBJECTIVE—In human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin. RESEARCH DESIGN AND METHODS—Birth weight and placental weight were measured in 43 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies. RESULTS—GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r = 0.61, P &amp;lt; 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P &amp;lt; 0.001 for both). CONCLUSIONS—These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy.
Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn's disease
Authors: D A van Heel
Journal: Gut (2005)

Nucleotide binding oligomerisation domain 2 (NOD2; also known as CARD15) mutations are associated with Crohn's disease but how mutations cause disease is poorly understood. Innate immune responses are reportedly enhanced by combined NOD2 ligand (muramyl dipeptide, MDP) and Toll-like receptor 4 ligand (TLR4, lipopolysaccharide) stimulation. Intestinal TLR signalling has a dual role-maintaining intestinal homeostasis and protection from injury as well as initiating inflammatory responses. TLR9 is functional in the intestinal epithelium where it is most strongly expressed in Paneth cells.To study possible interactions between CpG DNA (TLR9 ligand) and MDP using primary human cells of differing NOD2 genotypes.NOD2 wild-type healthy controls (n = 7) and NOD2 homozygous Crohn's disease patients (n = 19), age and sex matched.Peripheral blood mononuclear cells were stimulated with CpG DNA and MDP. Cytokines were measured by enzyme linked immunosorbent assay.Tumour necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) responses to CpG DNA were similar in NOD2 wild-type and homozygous mutant cells. Concomitant NOD2 stimulation had a marked synergistic effect on CpG DNA induced TNF-alpha responses at 10-100 ng/ml MDP. A mean 2.1-fold increase in CpG DNA induced TNF-alpha responses and a mean 3.7-fold increase in IL-8 responses were observed in NOD2 wild-type cells with 10 ng/ml MDP. This effect was abolished in NOD2 homozygous cells.NOD2 stimulation normally enhances innate immune responses to CpG DNA. This marked synergistic effect is lost in Crohn's disease patients homozygous for NOD2 mutations, with implications for TLR mediated intestinal homeostasis and inflammation.
Midfoot and Hindfoot Bone Marrow Edema Identified By Magnetic Resonance Imaging in Feet of Subjects With Diabetes and Neuropathic Ulceration Is Common but of Unknown Clinical Significance
Authors: Chandani Thorning, Wladyslaw M.W. Gedroyc, Philippa A. Tyler, Elizabeth A. Dick, Elaine Hui, Jonathan Valabhji
Journal: Diabetes Care (2010)

OBJECTIVE We conducted a retrospective cohort study assessing the prevalence and clinical and radiological outcome of remote areas of bone marrow edema on magnetic resonance imaging (MRI) in the feet of subjects with diabetes and neuropathic foot ulceration. RESEARCH DESIGN AND METHODS MRIs performed over 6 years looking for osteomyelitis associated with neuropathic lesions were assessed for remote areas of signal change. RESULTS Seventy MRI studies were assessed. Remote areas of signal change were present in 21 (30%) subjects, involved midfoot or hindfoot in 20 subjects, were associated with younger age and renal replacement therapy, and did not predict future Charcot neuroarthropathy or infection at that site. Repeat MRIs in 11 subjects with such areas found that none had progressed, six had improved, and two had resolved; in 29 subjects without such areas, five had developed new areas. CONCLUSIONS Bone marrow edema in the midfoot and hindfoot of subjects with diabetes and neuropathic lesions is common, often transient, and of unknown significance.
The discovery of thyroid replacement therapy. Part 1: In the beginning
Authors: Stefan Slater
Journal: Journal of the Royal Society of Medicine (2011)

There is a poignant before and after photolithograph of a Victorian lady in the 1878 transactions of the Royal Medical and Chirurgical Society of London ( Figure 1).1



Figure 1

Before (left), aged 21 years in 1870, and seven years later with myxoedema1



This is not the usual celebratory image before and after successful treatment. It is a picture of the woman, aged 21 in 1870, and then seven years later, unrecognizably aged by the effects of undiagnosed and untreated thyroid deficiency. It is poignant because she probably dies of the disease, the introduction in 1891 of effective treatment with subcutaneous injections of thyroid extract by George Murray of Newcastle-upon-Tyne coming too late.2

The images are from a paper by William Ord, physician at St Thomas's Hospital, entitled ‘On Myxoedema, a term proposed to be applied to an essential condition in the “Cretinoid” Affection occasionally observed in Middle-Aged Women’. In this he described a ‘mucous oedema’ of the skin, finding in it an excess of mucin on microscopy and chemical analysis. From this description he coined the term ‘myxoedema’, a name lastingly synonymous with thyroid deficiency.

A number of steps led to the discovery of thyroid replacement therapy: the slow understanding that this debilitating disease, myxoedema, was in some way linked to the thyroid; the acceptance of the notion that the thyroid elaborated some important factor with an endocrine function; the emergence of the principle of replacement therapy; and the introduction of replacement therapy in practice. But, contrary to general belief, Murray was not the first to treat myxoedema effectively.
Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment With the Ankle–Brachial Index in Adults: U.S. Preventive Services Task Force Recommendation Statement
Authors: Virginia A. Moyer
Journal: Annals of Internal Medicine (2013)

Description: Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for peripheral artery disease (PAD). Methods: The USPSTF reviewed the evidence on the use of resting ankle–brachial index (ABI) as a screening test for PAD or as a risk predictor for cardiovascular disease (CVD). The review focused on resting ABI as the sole screening method; the diagnostic performance of ABI testing in primary care populations, unselected populations, and asymptomatic populations; the predictive value of ABI testing for major CVD outcomes in primary care or unselected populations; and the effect of treatment on general CVD and PAD-specific morbidity in patients with asymptomatic or minimally symptomatic PAD. Population: This recommendation applies to asymptomatic adults who do not have a known diagnosis of PAD, CVD, severe chronic kidney disease, or diabetes. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for PAD and CVD risk assessment with the ABI in adults. (I statement)
Behavioural ecology as a basic science for evolutionary psychiatry
Authors: John S. Price
Journal: Behavioral and Brain Sciences (2006)

To the evolutionarily oriented clinical psychiatrist, the discipline of behavioural ecology is a fertile basic science. Human psychology discusses variation in terms of means, standard deviations, heritabilities, and so on, but behavioural ecology deals with mutually incompatible alternative behavioural strategies, the heritable variation being maintained by negative frequency-dependent selection. I suggest that behavioural ecology should be included in the interdisciplinary dialogue recommended by Keller &amp; Miller (K&amp;M).
HLA-DP and coeliac disease: family and population studies.
Authors: C Caffrey, G A Hitman, M J Niven, P G Cassell, P Kumar, L Fry, P Mackintosh, R Gallagher, C Feighery, D Weir
Journal: Gut (1990)

We investigated polymorphism of HLA-DP genes in three DR3 related diseases, confirming an association of coeliac disease with a Bgl II DP alpha polymorphism (a restriction fragment sized 3.5 kb present in 75% of patients compared to 34% of control subjects, p less than 0.001), and finding a weaker association with dermatitis herpetiformis (57% v 34%, p = 0.01) and no association with insulin dependent diabetes mellitus. The association with coeliac disease was further investigated. Msp I DP beta polymorphism was studied in 52 healthy subjects and 59 patients: a 4.9 kb fragment was present in 51% of patients with coeliac disease compared to 11.5% of control subjects (p less than 0.001). Furthermore, nearly all subjects with the DP alpha 3.5 kb fragment also had the DP beta 4.9 kb fragment. However, disease frequency was still increased in the DP alpha 3.5 positive/DP beta 4.9 negative group. In seven families, each with at least two affected members, while the DP alpha 3.5 fragment was frequently present in patients it did not preferentially segregate with any particular HLA haplotype--for example, those associated with DR3 or DR7--and therefore is not part of an extended haplotype associated with coeliac disease. We therefore conclude that a gene(s) in the HLA-DP region predisposes to coeliac disease independently of the HLA-DR/DQ regions.
Seasonal variability of at-home pulse oximetry in children with obstructive sleep apnea
Authors: Nicola Ullmann, Martino Pavone, Elisabetta Verrillo, Valeria Caldarelli, Alessandra Schiavino, Serena Soldini, Renato Cutrera
Journal: European Respiratory Journal (2013)

Indroduction: nocturnal pulse oximetry has a high positive predictive value for polysomnographically-diagnosed obstructive sleep apnea(OSA) and is increasingly used as first screening test.  Objectives: the aim of this study was to evaluate the intersubjects seasonal variability of at-home pulse oximetry in children.  Methods: at-home nocturnal pulse oximetry recording was consecutively performed on children referred for suspected OSA from February 2009 and October 2011. Patients with significant comorbidities were excluded. For each exam the McGill Oximetry Score(MOS) was also categorized.  Results: 270 children(169 males), aged 4.5 yrs ± 2.5(mean ±SD), were included. A significant difference was found between winter(Wi) vs spring(Sp), and winter vs summer(Su) for percentage of total effective recording time spent(TERT) with SpO2  Conclusions: Our data suggest the presence of seasonal differences in pulse oximetry study with winter identified as the most critical period. Seasonal differences need to be taken into account when nocturnal pulse oximetry is used to guide clinical decisions in children with suspected OSA.
Aluminum and Renal Osteodystrophy
Authors: H G Nebeker, J W Coburn
Journal: Annual Review of Medicine (1986)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal
Authors: Jakub Godlewski, Michal O. Nowicki, Agnieszka Bronisz, Shanté Williams, Akihiro Otsuki, Gerard Nuovo, Abhik RayChaudhury, Herbert B. Newton, E. Antonio Chiocca, Sean Lawler
Journal: Cancer Research (2008)

Abstract MicroRNAs (miR) show characteristic expression signatures in various cancers and can profoundly affect cancer cell behavior. We carried out miR expression profiling of human glioblastoma specimens versus adjacent brain devoid of tumor. This revealed several significant alterations, including a pronounced reduction of miR-128 in tumor samples. miR-128 expression significantly reduced glioma cell proliferation in vitro and glioma xenograft growth in vivo. miR-128 caused a striking decrease in expression of the Bmi-1 oncogene, by direct regulation of the Bmi-1 mRNA 3′-untranslated region, through a single miR-128 binding site. In a panel of patient glioblastoma specimens, Bmi-1 expression was significantly up-regulated and miR-128 was down-regulated compared with normal brain. Bmi-1 functions in epigenetic silencing of certain genes through epigenetic chromatin modification. We found that miR-128 expression caused a decrease in histone methylation (H3K27me3) and Akt phosphorylation, and up-regulation of p21CIP1 levels, consistent with Bmi-1 down-regulation. Bmi-1 has also been shown to promote stem cell self-renewal; therefore, we investigated the effects of miR-128 overexpression in human glioma neurosphere cultures, possessing features of glioma “stem-like” cells. This showed that miR-128 specifically blocked glioma self-renewal consistent with Bmi-1 down-regulation. This is the first example of specific regulation by a miR of a neural stem cell self-renewal factor, implicating miRs that may normally regulate brain development as important biological and therapeutic targets against the “stem cell–like” characteristics of glioma. [Cancer Res 2008;68(22):9125–30]
The Impact of Common Gene Variants on the Response of Biomarkers of Cardiovascular Disease (CVD) Risk to Increased Fish Oil Fatty Acids Intakes
Authors: Jacqueline Madden, Christine M. Williams, Philip C. Calder, Georg Lietz, Elizabeth A. Miles, Heather Cordell, John C. Mathers, Anne Marie Minihane
Journal: Annual Review of Nutrition (2011)

The cardioprotective actions of the fish oil (FO)-derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated, and dose-response relationships have been defined. However, there is a substantial and well-recognized within-population heterogeneity in response to FO, the etiology of which is poorly understood. Genetic variation may influence responsiveness. Here we review the available literature relating to gene variants shown to influence tissue LC n-3 PUFA status and response to FO intervention. From this review we conclude that the available evidence is relatively limited. A number of individual genotype × LC-n3 PUFA × phenotype associations have been described, but few have been investigated in subsequent cohorts or confirmed in independent studies. In the context of a more stratified approach to the provision of dietary advice, there is a need for further research to refine current dietary EPA and DHA recommendations.
The Burden of Loss: Unexpected Death of a Loved One and Psychiatric Disorders Across the Life Course in a National Study
Authors: Katherine M. Keyes, Charissa Pratt, Sandro Galea, Katie A. McLaughlin, Karestan C. Koenen, M. Katherine Shear
Journal: American Journal of Psychiatry (2014)

Unexpected death of a loved one was associated with heightened vulnerability for virtually all commonly occurring psychiatric disorders, including depression, PTSD, manic episodes, phobias, panic disorder, and substance use disorders in one of the first population-based studies to examine these relations across the lifespan.