tbuckley/cabot-search huggingface dataset:
Abstract IA8: BRAF and MEK resistance in melanoma
Authors: Meenhard Herlyn, Jessie Villanueva
Journal: Clinical Cancer Research (2012)

Abstract The melanoma field has had a long history of frustrating experiences in clinical trials. Most of these were in immunotherapy, although all approaches in biotherapy, chemotherapy and radiation therapy have been similarly unsuccessful for the past 30 years with unchanged five-year survival rates of 15% for advanced disease. The therapy arena is dramatically changing with a new generation of BRAF inhibitors. Particularly those with high specificity for the mutant kinase are effective in killing cells carrying the BRAFV600E mutation. Two BRAF inhibitors have increased progression-free survival and overall survival from the disease. Considering the poor success rate from previous trials, the currently accumulated data are dramatic and exciting. However, there are no cures and all treated patients recur due to the development of resistance. In treated melanoma cells with BRAFV600E there are no new mutations, except the appearances of splice variants and mutations in NRAS in some tumors. Instead, cells learn to signal around inhibited BRAF through CRAF or ARAF to activate MEK and ERK. At the same time compensatory signaling activates receptor tyrosine kinases such as IGFR1 and PDGFR, leading to activation of the PI3K pathway. Potentially, additional pathways can be activated likely requiring an individual assessment of the mechanisms of resistance. Inhibition of the newly activated pathways can prevent progression in experimental systems but has not yet been validated in patients. In contrast to inhibitors of BRAF, inhibitors for MEK appear to induce mutations in either MEK 1 or MEK 2. It is not yet clear whether the mutations occur at multiple or unique sites. Likely, similar mutational events as in MEK will occur when inhibitors of ERK are given to cells over prolonged time periods. In summary, the MAPK pathway has emerged as a major driver for melanoma cells. However, when the malignant cells are treated with inhibitors for BRAF/MEK/ERK they develop secondary resistance. Why do some cells survive the drug insult? This question is particularly pertinent for inhibitors of mutant BRAF because all cells invariably contain the mutations. The reasons for this intrinsic or primary resistance are not clear and will require a major investigational effort in future years. Experimental studies in immunodeficient mice have shown that single melanoma cells are sufficient to induce a tumor, thus, the goal has to be the elimination of all cells and not just the majority of cells. Strategies to achieve this goal will in part depend on the mechanisms of survival of a sub-population of malignant cells. It is most likely that non-genetic events are responsible for the survival and they will be discussed.
Marginal to Mainstream: Alternative Medicine in America
Authors: Edzard Ernst
Journal: Journal of the Royal Society of Medicine (2004)

To Mary Ruggie the rise of complementary/alternative medicine (CAM) is a 'social transformation' of healthcare. As indicated by the title, she focuses on the USA—a pity, since most of CAM originates elsewhere. Her book covers such matters as the relation of CAM to conventional medicine, types of evidence, reasons for CAM usage, patterns of growth, research, and the future of CAM— often by asking questions rather than providing answers.

Ruggie sees the growth of CAM in terms of a power struggle: 'CAM poses huge challenges not only to the dominance of biomedicine, but also to the fruits of dominance—status and power in decision making about health care and in the livelihood of physicians'. I can never bring myself to seeing things quite as petty as that. The 'struggle', I always thought, is to find treatments that do more good than harm, and all healthcare providers are united in it. The 'dominance' of biomedicine stems from the evidence rather than Machiavellian intrigues. But this is where we obviously differ: healthcare professionals work to help patients, while medical sociologists watch us doing it and interpret according to their particular prejudices.

Annoyingly, Ruggie perpetuates the notion that 'only about 15% of medical interventions are supported by evidence'. It fits her bill and she is in good company: the Chair of the NHS Alliance recently stated that 'people argue against complementary therapies on the basis of a lack of evidence. But I'd say only 10 percent of what doctors do in primary care is evidence based'. The argument comes from a BMJ editorial of 13 years ago, and even then it was not supported by good data. More recent evidence shows that 70–80% of our treatments are based on evidence. Isn't it time that we all buried this counterproductive myth?

What is the impact of this sort of book? Sadly, I am not sure that it is negligible. When writing about CAM, sociologists sometimes endorse treatments that are not necessarily safe or effective and can have disadvantageous consequences. For instance, Ruggie declares about meditation: 'There is a large and growing literature on the biology of meditation and, despite the inevitable methodological inconsistencies, there is mounting evidence of health benefits'. The truth is that the evidence is unconvincing. Her final conclusion is less than arresting: 'If patients continue to use and demand CAM, if research proves the safety and efficacy of CAM, if physicians accept CAM, if the benefits of CAM extend to cost savings, and if insurers and healthcare plans offer CAM coverage, integrative clinics will prosper and grow.' So is this book all bad? Taken with several pinches of salt, it can serve as a reasonable, mostly well-written, introduction to CAM. And it allows intriguing insights into the often strange logic of sociologists who dabble in the subject.
Skeletal metastases from cerebellar medulloblastoma.
Authors: B. Corrin, J. C. Meadows
Journal: BMJ (1967)

MEDICAL JOURNALFIG.IV.-Left ventricular angiocardiogram (systolic phase), lateral projection (left) and frontal projection (right), in hypertrophic obstructive cardiomyopathy, showing normal aorta and aortic valve, large coronary arteries, and narrowing of ventricular cavity with intrusion of large muscle masses into the cavity, especially in the region of the septum and papillary muscles (
Interleukin 1α Promotes Th1 Differentiation and Inhibits Disease Progression in <i>Leishmania major</i>–susceptible BALB/c Mice
Authors: Esther von Stebut, Jan M. Ehrchen, Yasmine Belkaid, Susanna Lopez Kostka, Katharina Mölle, Jürgen Knop, Cord Sunderkötter, Mark C. Udey
Journal: The Journal of Experimental Medicine (2003)

Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in lymph nodes of L. major–infected BALB/c mice was ∼3-fold lower than that in C57BL/6 mice. Local injections of IL-1α during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major–infected BALB/c mice, IL-1α administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1α and IL-12 treatments were similarly effective, and IL-1α efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1α acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains.
Insect bite-like reactions in a patient with B-cell chronic lymphocytic leukaemia: fluorescence<i>in situ</i>hybridization analysis revealed neoplastic B cells within the skin infiltrate
Authors: C. Mitteldorf, M. Tronnier, H. Merz, H.A. Haenssle, H.P. Bertsch, M.P. Schön, K.M. Kaune
Journal: British Journal of Dermatology (2012)
Blood lead concentrations in United Kingdom have fallen substantially since 1984
Authors: H T Delves, S J Diaper, S Oppert, P Prescott-Clarke, J Periam, W Dong, H Colhoun, D Gompertz
Journal: BMJ (1996)

EDITOR,—Shilu Tong and colleagues show that the effects of low level environmental exposure to lead, especially on the longer term cognitive development of children, are still of concern.1 We have carried out the first major study for eight years to monitor lead concentrations in Britain. We report here our early results, which show a large fall in blood lead concentrations.

As part of the 1995 health survey of England, blood samples were collected for lead analysis from 6868 subjects from eight regions throughout England; the subjects were considered to be a geographically representative sample of the whole population. Most of the subjects (95%) were adults aged >/=16, of whom 3139 (45.7%) …
Pseudofolliculitis Barbae
Authors: Maurice S. Conte
Journal: JAMA (1979)

Pseudofolliculitis barbae possibly affects 45% of all black servicemen and is a source of much misunderstanding and social unrest in the military. A recent study of 96 cases of pseudofolliculitis barbae has elucidated a successful shaving technique. It employs a 30-day period of beard regrowth to eliminate ingrown hairs, twice-daily use of a new polyester skin-cleansing pad, and use of solely electric hair clippers for facial hair removal. Ninety-six percent of those using this technique could thereafter conform to the Air Force grooming code.
Pulmonary Suppressor of Cytokine Signaling-1 Induced by IL-13 Regulates Allergic Asthma Phenotype
Authors: Satoru Fukuyama, Takako Nakano, Takafumi Matsumoto, Brian G. G. Oliver, Janette K. Burgess, Atsushi Moriwaki, Kentaro Tanaka, Masato Kubo, Tomoaki Hoshino, Hiroyuki Tanaka, Andrew N. J. McKenzie, Koichiro Matsumoto, Hisamichi Aizawa, Yoichi Nakanishi, Akihiko Yoshimura, Judith L. Black, Hiromasa Inoue
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Th2 cytokines play an important role in allergic diseases. These cytokines activate signal transduction pathways, including Janus kinase/signal transducer and activator of transcription (STAT) signaling. Although the suppressor of cytokine signaling (SOCS) family protein, a negative regulator of the Janus kinase/STAT signaling pathway, contributes to helper T cell differentiation during immune responses, the role of SOCS proteins within the structural cells of a target organ has not been clarified in allergy.To study the local function of SOCS in the development of asthma.We used mouse models of IL-13- and ovalbumin (OVA)-induced allergic airway disease. Airway smooth muscle cells were cultured from patients with asthma.The administration of IL-13 induced not only airway responses but also SOCS1 expression at the local inflammatory site. The up-regulated SOCS1 markedly suppressed IL-13-dependent STAT6 activation and eotaxin expression and subsequently down-regulated IL-13-induced airway inflammatory responses. The inactivation of SOCS1 induced airway hyperresponsiveness after IL-13 treatment even in hyporesponsive C57BL/6 background mice. In an OVA-induced model of allergic airway disease, allergen exposure up-regulated local SOCS1 expression, and the induction of SOCS1 in the airways attenuated allergen-induced airway responses. Inactivation of IL-13 inhibited SOCS1 induction in a model of allergic airway disease. Interestingly, airway smooth muscle cells from individuals with asthma had impaired up-regulation of SOCS1 after IL-13 stimulation.SOCS1 induction by IL-13 in airway structural cells is critical to negatively control allergic airway disease.
Role of hypoxemia and pulmonary mechanics in exercise limitation in interstitial lung disease.
Authors: A O Harris-Eze, G Sridhar, R E Clemens, T A Zintel, C G Gallagher, D D Marciniuk
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

We have previously shown that respiratory factors (arterial hypoxemia and/or pulmonary mechanics) contribute to limit maximal incremental exercise in interstitial lung disease (ILD). In this study, we tested the hypothesis that arterial hypoxemia, not pulmonary mechanics, primarily limits maximal exercise in subjects with ILD. Seven subjects with ILD underwent two incremental exercise tests in random order. Test 1: breathing room air (RA); Test 2: breathing 60% O2 with added external dead space (O2VD). Added VD was used to prevent the fall in minute ventilation (VI) while breathing O2. All subjects demonstrated impaired exercise performance (maximal oxygen uptake [VO2], 56 +/- 13% predicted) while breathing RA. There was a significant increase in peak VI (RA, 64.9 +/- 22.3 L/min versus O2VD, 71.0 +/- 20.6; p < 0.05), maximal work rate (RA, 99 +/- 12 watts versus O2VD, 109 +/- 15 watts; p < 0.01), exercise duration (RA, 383 +/- 67 s versus O2VD; 426 +/- 72 s; p < 0.0005) and maximal VO2 (RA, 1.25 +/- 0.21 L/min versus O2VD, 1.39 +/- 0.26; p < 0.05) during the O2VD exercise test. There was a significant correlation between the percent increase in exercise duration during the O2VD test and the DLCO (r = -0.813, p < 0.05). At matched levels of ventilation, subjects demonstrated a significantly deeper and slower pattern of breathing during the O2VD test. Because subjects with ILD were able to further improve their exercise and further increase their VI during the O2VD exercise study, we conclude that arterial hypoxemia, and not respiratory mechanics, predominantly limits maximal incremental exercise in subjects with ILD.
Tales from the crypt
Authors: Eric A. Schon
Journal: Journal of Clinical Investigation (2003)

Intestinal colonic crypts are derived from a stem cell population located at the base of each crypt. A new analysis of mitochondrial function and of the rates of mitochondrial DNA (mtDNA) mutation in individual crypts shows that mtDNA mutations arise in stem cells — and at a surprisingly high frequency. Because crypts turn over extremely rapidly (about once per week), somatic mtDNA mutations can “take over the system” and even become homoplasmic, in a manner similar to what has been shown to occur in tumors.
Nonuniform Nighttime Distribution of Acute Cardiac Events
Authors: Cynthia E. Lavery, Murray A. Mittleman, Mylan C. Cohen, James E. Muller, Richard L. Verrier
Journal: Circulation (1997)

Background Although 250 000 myocardial infarctions and 38 000 sudden cardiac deaths occur at night annually, this public health problem is underappreciated and poorly understood. We examined whether the incidence of myocardial infarction, sudden cardiac death, and automatic implantable cardioverter-defibrillator (AICD) discharge was nonuniform, a result that may implicate physiological triggers such as sleep-state dependent changes in autonomic nervous system activity. Methods and Results We conducted a review of the circadian pattern of the onset of myocardial infarction (n=19), sudden cardiac death (n=12), and AICD discharge (n=7). The nighttime period was chosen a priori as midnight to 5:59 am. These reports documented 11 633 nocturnal myocardial infarctions (20% of the total myocardial infarctions), 1981 nocturnal sudden cardiac deaths (14.6% of the total sudden cardiac deaths), and 1200 nocturnal AICD discharges (15.0% of the total discharges). The distributions of myocardial infarction, sudden cardiac death, and AICD discharge were each significantly nonuniform ( P &lt;.001). The peak incidence of myocardial infarction and AICD discharge occurred between midnight and 0:59 am , whereas the peak incidence of sudden cardiac death was between 1:00 and 1:59 am. The trough in incidence occurred between 4:00 and 4:59 am for sudden cardiac death and between 3:00 and 3:59 am for myocardial infarction and AICD discharge. Conclusions Nocturnal myocardial infarction, sudden cardiac death, and AICD discharge exhibit nonuniform distributions. This finding is consistent with the hypothesis that sleep-state dependent fluctuations in autonomic nervous system activity may trigger the onset of major cardiovascular events and provides further impetus for more directly testing this hypothesis at population, individual, and mechanistic levels. A better understanding of nocturnal triggers may make it possible to reduce the incidence of myocardial infarction, ventricular tachyarrhythmias, and sudden cardiac death during the nocturnal period.
Neurological deficits in primary polycythaemia.
Authors: D G Sims, E M Husband
Journal: BMJ (1972)

without substitution maximum level of 17 1. of urine daily, 70 mOsm/l., with a free water clearance of 9-09 ml/min.The maximum therapeutic effect of Pitressin-tannate in oil twice daily and, sub- sequently, intranasal vasopressin (up to 70 drops daily; 1 ml=50 IU) reduced urine output to only 5-6 l./day.The specific gravity of the urine never rose above 1006 and the patient was not relieved of symptoms of thirst and depression.Shortly after each administration there were strong, painful, and very prolonged uterine contractions.B- cause of the contraction she was switched over to intranasal drops of aqueous DDAVP.A dose of 15 ,ug DDAVP (three drops) was given eight hours into the nose.Her daily urine out- put immediately came down to 2 1. a day and urine specific gravity increased to 1010-1027, maximum 900 mOsm/L There was no utero- tonic or other reaction to this dosage, and thirst and depression disappeared.When antithyroid drugs were omitted the daily urine output on the same DDAVP dosage increased to 3 L a day.A fortnight before her calculated term, the patient gave spontaneous birth to a fully- developed baby.The patient continues to be maintained on DDAVP at her own in- sistence, and shows no signs even of local mucosal irritations in the nose.The results are su naried in the Figure .-Iam, etc.,
The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific
Authors: Julia Benckert, Nina Schmolka, Cornelia Kreschel, Markus Josef Zoller, Andreas Sturm, Bertram Wiedenmann, Hedda Wardemann
Journal: Journal of Clinical Investigation (2011)

Mucosal antibody responses play a major role in mediating homeostasis with the intestinal flora. It has been suggested that imbalance in the IgA+ and IgG+ intestinal B cell repertoire may be associated with the development of diseases such as inflammatory bowel disease. Despite this, little is known about the antibody specificity of human intestinal plasmablasts. Here, we have determined the reactivity profile of single isolated IgA+ and IgG+ plasmablasts from human terminal ileum using antibody cloning and in vitro expression. We found that approximately 25% of intestinal IgA and IgG plasmablast antibodies were polyreactive; the majority were antigen-specific. Antigen specificity was not only directed against enteropathogenic microbes but also against commensal microbes and self antigens. Regardless of their reactivity, all intestinal antibodies were somatically mutated and showed signs of antigen-mediated selection, suggesting that they developed from antigen-specific B cell responses. Together, our data indicate that antigen-specific immune responses to intestinal microbes are largely responsible for the maintenance of intestinal homeostasis and thus provide a basis for understanding the deregulated immune responses observed in patients with inflammatory bowel disease.
Is transesophageal echocardiography necessary for cardiac source of embolus in patients with sinus rhythm and without structural heart disease?
Authors: Melda S. Dolan, Alan R. Maniet, Noel Rubio, Masarrath Moinuddin, Tracy J. Huckin, Dinesh Kumar, Jeanette St. Vrain, Arthur J. Labovitz
Journal: Journal of the American College of Cardiology (2003)
SAFETY, LEFT VENTRICULAR REVERSE REMODELING AND LONG-TERM OUTCOME AFTER CARDIAC RESYNCHRONIZATION THERAPY IN THE ELDERLY
Authors: Ulas H&ouml;ke, Joep Thijssen, Rutger van Bommel, Enno Van Der Velde, Victoria Delgado, Martin Schalij, Jeroen Bax, Nina Marsan
Journal: Journal of the American College of Cardiology (2012)
Regional myocardial blood flow in patients with sick sinus syndrome randomized to long-term single chamber atrial or dual chamber pacing—effect of pacing mode and rate
Authors: Jens Cosedis Nielsen, Morten Bøttcher, Torsten Toftegaard Nielsen, Anders Kirstein Pedersen, Henning Rud Andersen
Journal: Journal of the American College of Cardiology (2000)
A Population-Based Cross-Over Randomized Controlled Trial of Breast Cancer Screening with Alternate Mammography and Ultrasound for Women Aged 40 to 49 Years in Taiwan.
Authors: C. Huang, C. Fann, G. Hsu, M. Ho, K. Chang, S. Chen, S. Kon, T. Chen
Journal: Cancer Research (2009)

Abstract Background: As there is paucity of data on population-based screening for breast cancer using mammography and ultrasound for oriental young women aged 40-49 years, the peak of incidence rate and high proportion of dense breast, we aimed to evaluate the relative performance of detecting breast cancer between ultrasound and mammography and also to assess complementary efficacy of ultrasound to mammography screening.Methods: A total of 79,691 female residents aged 40-49 years were invited from community in Taiwan since late 2003. These participants were first randomly assigned to mammography (n=20040), ultrasound (n=20088), and control group (n=39563). The two former groups were further done by a cross-over design with mammography and ultrasound on alternate year until 2008. Detection rate and annual incidence rate of interval cancer as a percentage of the control group (I/E ratio) were compared between mammography and ultrasound.Results: The attendance rate of the first round was 59% (11921/20040) for mammography and 56% (11249/20088) for ultrasound. The repeated attendance rate of both groups was 85% in the second round and 91% in the third round. In the first round of screen, the detection rate of breast cancer for the mammography group (0.34%) was 1.5-fold compared with the ultrasound group (0.22%). The additional detection rate was 0.16% contributed from a subsequent ultrasound screen and 0.36% contributed from a subsequent mammogram screen. The combination of mammography with ultrasound was as three to four times as likely to detect breast cancer compared with the control group (annual incidence rate was 0.17%). The I/E ratio was lower after mammography screening than that after ultrasound screening.Conclusion: The current randomized controlled trial not only demonstrated higher detection rate and better performance using mammography but also indicated the complementary role of ultrasound applied to young Taiwanese women. This further suggests the optimal screening modality for young women in Asian country is to combine mammography with ultrasound. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 73.