tbuckley/cabot-search huggingface dataset:
In vivo inhibition of the mTOR pathway and reversal of Akt-dependent prostate intraepithelial neoplasia requires induction of mitochondrial pathway mediated cell-death
Authors: Pradip K. Majumder, Rachel Bikoff, Raanan Berger, Qi Xue, Judy Shim, Nandita Bhattacharya, Judith Manola, Louis McMahon, Timothy J. McDonnell, Massimo Loda, Heidi A. Lane, William R. Sellers
Journal: Cancer Research (2004)

5128   Loss of PTEN function in human cancers leads to activation of PI3K signaling including activation of Akt. Activation of Akt in the murine prostate results in a highly penetrant prostate intraepithelial neoplasia phenotype associated with the hallmarks of increased mTOR activity. Here, we find that administration of a rapamycin derivative (RAD001; everolimus) selectively inhibits phosphorylation of mTOR pathway substrates and completely reverses the PIN phenotype within 2-weeks. Phenotype reversal was accompanied by decreased rates of proliferation, and by the striking induction of apoptosis within the intraluminal epithelial cells. This mTOR dependent survival pathway is, at least in part, dependent on mitochondrial death effector pathways, as compound mice expressing Akt and Bcl-2, while sensitive to the anti-proliferative activity of mTOR inhibition, were resistant to mTOR-dependent apoptosis. These data raise the possibility that clinical resistance to mTOR inhibition might emerge through expression of Bcl-2 or other pro-survival oncogenes.
UNAIDS replies
Authors: Paul De Lay
Journal: BMJ (2008)

England couldn’t be more wrong that the AIDS epidemic is just another health problem.1

Over 60 million men, women, and children have become infected with HIV since it was first discovered. AIDS has killed 25 million people, and the epidemic continues to outstrip the response.

HIV was and still is an emergency requiring an unprecedented response. AIDS does not fit neatly into a health box but cuts across sectors such as education, labour, and the legal system. It involves particularly sensitive issues—sex, gender inequality, sex work, homosexuality, drug use, stigma, and discrimination. UNAIDS was created precisely to deal with the multisectoral nature of the epidemic.

Resources for public health are desperately deficient, and this is no different for HIV. In 2006, $644 billion was estimated to be available for all public health in low and middle income countries, of which a mere 1.4% was spent on HIV.

Funding for HIV provides a focus and an entry point for strengthening health and social services. HIV services and treatment keep health workers alive, well, and able to work. And HIV treatment reduces admissions, freeing up health workers and valuable resources for other health care.

England’s comments can only damage both the AIDS response and public health more widely. AIDS funding bolsters health systems, which provide essential services for people living with HIV, and both must be supported.
Coordination of self-renewal in glioblastoma by integration of adhesion and microRNA signaling
Authors: Alvaro G. Alvarado, Soumya M. Turaga, Pratheesh Sathyan, Erin E. Mulkearns-Hubert, Balint Otvos, Daniel J. Silver, James S. Hale, William A. Flavahan, Pascal O. Zinn, Maksim Sinyuk, Meizhang Li, Maheedhara R. Guda, Kiran K. Velpula, Andrew J. Tsung, Ichiro Nakano, Michael A. Vogelbaum, Sadhan Majumder, Jeremy N. Rich, Justin D. Lathia
Journal: Neuro-Oncology (2015)

Cancer stem cells (CSCs) provide an additional layer of complexity for tumor models and targets for therapeutic development. The balance between CSC self-renewal and differentiation is driven by niche components including adhesion, which is a hallmark of stemness. While studies have demonstrated that the reduction of adhesion molecules, such as integrins and junctional adhesion molecule-A (JAM-A), decreases CSC maintenance. The molecular circuitry underlying these interactions has yet to be resolved. MicroRNA screening predicted that microRNA-145 (miR-145) would bind to JAM-A. JAM-A overexpression in CSCs was evaluated both in vitro (proliferation and self-renewal) and in vivo (intracranial tumor initiation). miR-145 introduction into CSCs was similarly assessed in vitro. Additionally, The Cancer Genome Atlas dataset was evaluated for expression levels of miR-145 and overall survival of the different molecular groups. Using patient-derived glioblastoma CSCs, we confirmed that JAM-A is suppressed by miR-145. CSCs expressed low levels of miR-145, and its introduction decreased self-renewal through reductions in AKT signaling and stem cell marker (SOX2, OCT4, and NANOG) expression; JAM-A overexpression rescued these effects. These findings were predictive of patient survival, with a JAM-A/miR-145 signature robustly predicting poor patient prognosis. Our results link CSC-specific niche signaling to a microRNA regulatory network that is altered in glioblastoma and can be targeted to attenuate CSC self-renewal.
Spectrophotometry for Xanthochromia
Authors: Axel Petzold, Geoffrey Keir, Lindsay T. Sharpe
Journal: New England Journal of Medicine (2004)

To the Editor: Xanthochromia, or a yellow appearance of the cerebrospinal fluid, is often used to confirm suspected subarachnoid hemorrhage.1,2 It is associated with the presence of bilirubin, a blood product that arises only in vivo by the enzymatic transformation of hemoglobin. However, visual assessment of the cerebrospinal fluid for xanthochromia is highly subjective and unreliable, especially in cases in which other blood products, such as oxyhemoglobin, are present.1,2 The differential diagnosis may be further complicated by a high protein level and a high cell count, as in meningitis and necrosis, or by the presence of other pigments . . .
Need for consensus guidelines to standardise the assessment of germinal centres and other histopathological parameters in salivary gland tissue of patients with primary Sjögren's syndrome
Authors: Konstantina Delli, Erlin A Haacke, Stephan Ihrler, Bert van der Vegt, Arjan Vissink, Hendrika Bootsma, Frederik K L Spijkervet, Frans G M Kroese
Journal: Annals of the Rheumatic Diseases (2016)

We have read with great interest the letter to the editor by van Roon et al 1 commenting on our paper ‘Towards personalised treatment in primary Sjogren's syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment’.2 The authors argue that there is a need for standardisation of the histopathological characteristics of salivary gland tissue of patients with primary Sjogren's syndrome (pSS), in general, and of the presence of germinal centres (GCs), in particular.

We fully agree with van Roon et al 1 and other authors about the need for consensus guidelines to standardise the histopathological evaluation of salivary gland biopsies in patients with pSS.3 A standardised scoring system may facilitate prognostication and stratification of patients with pSS and is needed for a valid evaluation of various clinical trials.3 In particular, histological definition of GCs in salivary gland tissue is warranted, since these structures can be difficult to detect in diagnostic H&E-stained tissue sections. Detection of GCs in the periductal lymphoid infiltrates of the salivary glands is clinically relevant, because the presence of these structures is associated with more severe disease.4 Importantly, the presence of GCs in minor salivary gland biopsies has been postulated to be a predictor of patients who are at risk of lymphoma development.5 …
190TiP: ELUXA 1: Phase II study of BI 1482694 (HM61713) in patients (pts) with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)
Authors: K. Park, J.-Y. Han, D.-W. Kim, L.A. Bazhenova, S.-H. Ou, Y.-K. Pang, H.S. Hin, O. Juan, J. Son, P. Jänne
Journal: Journal of Thoracic Oncology (2016)
Randomized phase II study of trabectedin (ET-743) given by two different dosing schedules in patients (pts) with leiomyosarcomas (LMS) or liposarcomas (LPS) refractory to conventional doxorubicin and ifosfamide chemotherapy
Authors: B. L. Samuels, D. Rushing, S. P. Chawla, S. M. Schuetze, M. Von Mehren, M. L. Keohan, M. O'Donovan, X. Wei, L.-A. Sternas, G. D. Demetri
Journal: Journal of Clinical Oncology (2004)

9000 Background: Trabectedin (Yondelis), a marine-derived alkaloid, has shown antitumor activity as therapy for advanced STS in pts refractory to conventional chemotherapy. LMS and LPS pts were selected for further study since these subtypes appeared to have somewhat higher rates of clinical benefit than other STS subtypes. Methods: To evaluate the efficacy and tolerability of ET-743 administered either as a 3-hr IV infusion given weekly for 3 consecutive weeks in a 4 week cycle (Arm A) or as a 24-hr IV infusion q 3 weeks (Arm B) to pts following progression despite prior doxorubicin plus ifosfamide chemotherapy. Pts with PS 0–1, normal bilirubin and alkaline phosphatase (AP) levels, and measurable LMS or LPS were eligible for study. Patients were pretreated with dexamethasone.The ET-743 dose was reduced if any abnormal elevation of bilirubin or AP was noted between cycles, or if any other unacceptable toxicity occurred. Histology will be centrally reviewed and patients whose diagnosis cannot be confirmed will be replaced. Results: 60 pts have been accrued so far, at 16 sites, in this multicenter trial. At this time, 29 pts are eligible for evaluation of response. Despite the small number of pts evaluable so far, activity has been noted using both schedules, with 3 pts on the 24 hr infusion schedule exhibiting partial responses. Tolerability overall has been acceptable and consistent with prior experience with this agent. Conclusion: ET-743 given by either of these two schedules of administration can induce objective responses in a subset of refractory pts with LMS or LPS. Disease control as demonstrated by stable disease will be an important additional endpoint to evaluate in this population of pts with disease that was objectively progressing at study entry. This trial is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Pharmaceutical R & D Johnson & Johnson Pharmaceutical R & D; Novartis Oncology; PharmaMarc Johnson & Johnson Pharmaceutical R & D Janssen; Novartis; PharmaMar Johnson & Johnson PharmaMar
A phase II study evaluating the safety and efficacy of patupilone in patients with platinum refractory/resistant ovarian, primary fallopian, or peritoneal cancer
Authors: W. M. Smit, J. Sufliarsky, T. L. Werner, D. Dizon, M. Wagnerova, H. W. Hirte, R. Delaney, J. Li, D. Weber, J. H. Schellens
Journal: Journal of Clinical Oncology (2009)

5563 Background: Patients with ovarian cancer that relapse or recur within 6 months after platinum plus taxane therapy have a poor prognosis. Patupilone, a natural epothilone isolated from myxobacterium, is a microtubule targeting agent that was found to be safe and well tolerated, with clinical activity in refractory or resistant ovarian cancer. Methods: Patients were treated with a dose of patupilone 10 mg/m 2 , given intravenously over 10–20 minutes once every 3 weeks, which was found safe in a previous phase I study. Results: Total 113 women enrolled and 112 were treated. The median age was 56 years (range 18–85 years), and 11 % had WHO Performance Status (PS) of 2. Most patients (104) had ovarian cancer, while 5 were peritoneal and 2 each of fallopian or other origin. All patients had received prior platinum and taxane, and 50% had progressed in less than 3 months after prior platinum therapy. Patients received a median of 4 cycles (range 1–16) of patupilone with median average dose per cycle of 9.97 mg/m 2 , resulting in a median dose intensity of 100%. The most common grade 3/4 toxicity was diarrhea (21%/3%), fatigue (10%/1%), intestinal obstruction (5%/3%), anorexia (5%/1%), and vomiting (8%/0%). About 38% patients developed neuropathy, which was mostly grade 1 (in 22%), with only 4% patients at grade 3. A total of 6 patients (5.4%) discontinued due to serious adverse event. There were 4 (3.6%) deaths on study, none of which were considered treatment related. The best overall response rate (by RECIST criteria) was 7.1% (95% CI: 3.0%, 14.0%) with no patient having complete response and 8 patients with partial response. Also, 46 patients (41%) had stable disease and 39 (34.8%) progressed, while response was unknown or could not be evaluated in 19 patients. The median PFS is 2.5 months (95% CI: 1.4, 3.5), and median overall survival is 11.2 months (95% CI: 8.3, 14.9), with 33% patients censored. Conclusions: Patupilone 10mg/m 2 administered at q3wk was safe and well tolerated. It showed promising activity in patients with refractory/resistant ovarian cancer. [Table: see text]
Climate Change and Health: A Position Paper of the American College of Physicians
Authors: Ryan A. Crowley
Journal: Annals of Internal Medicine (2016)

Climate change could have a devastating effect on human and environmental health. Potential effects of climate change on human health include higher rates of respiratory and heat-related illness, increased prevalence of vector-borne and waterborne diseases, food and water insecurity, and malnutrition. Persons who are elderly, sick, or poor are especially vulnerable to these potential consequences. Addressing climate change could have substantial benefits to human health. In this position paper, the American College of Physicians (ACP) recommends that physicians and the broader health care community throughout the world engage in environmentally sustainable practices that reduce carbon emissions; support efforts to mitigate and adapt to the effects of climate change; and educate the public, their colleagues, their community, and lawmakers about the health risks posed by climate change. Tackling climate change is an opportunity to dramatically improve human health and avert dire environmental outcomes, and ACP believes that physicians can play a role in achieving this goal.
Surgical Management of Massive Acute Upper Gastrointestinal Hemorrhage
Authors: Claude E. Welch, Arthur W. Allen, Gordon A. Donaldson
Journal: New England Journal of Medicine (1955)

SHORTLY after World War II the therapy of acute massive upper gastrointestinal hemorrhage changed radically throughout this country. Repeated generous whole-blood transfusions and early feeding replaced the method of infrequent transfusions and starvation. In a number of hospitals, coupled with these innovations, a vigorous surgical attack was carried out on many patients.In the Massachusetts General Hospital the management of these cases has evolved into the following pattern. On the ward services most patients with other than trivial hemorrhage are admitted to the Surgical Service, where they remain either until surgery is carried out or until a few days have . . .
Failure to Improve Effective Ventilation on Shifting from Mouth to Tracheostomy Breathing in Clinically Stable Emphysema
Authors: John M. Tyler
Journal: New England Journal of Medicine (1961)

THE use of tracheostomy in the therapy of patients with pulmonary emphysema has become a well established practice. The benefits are gained from the easy removal of secretions in the acutely ill patients and its short-term use has been recommended after chest trauma,1 in the operative management of patients with obstructive disease of the lungs2 and in the treatment of those with bronchial pneumonia as an exacerbation of their underlying emphysema.3 Recently, however, it has been advocated on a long-term basis in chronically ill patients who have secretions that are difficult to eliminate.4 There is another potential advantage to the . . .
P-248 Evaluation of the use and effectiveness of adjuvant chemotherapy in patients with stage II colon cancer: data from the Hospital of Lithuanian University of Health Sciences
Authors: D. Vaitiekus, L. Simaskaite, S. Liutkauskiene, D. Janciauskas, E. Juozaityte, R. Janciauskiene
Journal: Annals of Oncology (2015)
Medical Aspects of the Persistent Vegetative State -- A Correction
Authors: Stephen Ashwal, Ron Cranford
Journal: New England Journal of Medicine (1995)

To the Editor: Isenberg and colleagues (March 2 issue) 1 demonstrated the effectiveness of povidone-iodine prophylaxis against ophthalmia neonatorum but limited their observation of side effects to local toxic reactions.Were the systemic effects of povidone-iodine, such as alterations in thyroid metabolism, evaluated in a pilot study?Topical application of povidone-iodine has been known to cause transient hypothyroidism in newborns as a result of iodine excess. 2 Iodine-induced hyperthyroidism has also been described in a newborn exposed to large doses of iodine. 3Although probably unimportant in most cases, the systemic effects of the conjunctival application of povidone-iodine should be thoroughly evaluated before the use of this form of prophylaxis becomes widespread, with special attention given to its impact on thyroid function in newborns.
Altered Platelet Calcium Metabolism as an Early Predictor of Increased Peripheral Vascular Resistance and Preeclampsia in Urban Black Women
Authors: Michael B. Zemel, Paula C. Zemel, Stan Berry, Gwendolyn Norman, Carol Kowalczyk, Robert J. Sokol, Paul R. Standley, Mary F. Walsh, James R. Sowers
Journal: New England Journal of Medicine (1990)

Although preeclampsia is an important and relatively common medical problem, its pathophysiology remains unresolved and the search for a biochemical marker that precedes the hemodynamic abnormalities of preeclampsia continues. We designed a study to investigate the hemodynamic changes that characterize preeclampsia and to evaluate the metabolism of platelet intracellular calcium as a possible predictor of the development of preeclampsia.
Lymphocyte-Mediated Cytolysis and Disease
Authors: Chau-Ching Liu, Lucy H.Y. Young, John Ding-E Young
Journal: New England Journal of Medicine (1996)

Lymphocytes are equipped to eradicate noxious agents (microbes, cancer cells, and grafts) that disturb the body's equilibrium, but when their cellular activity is excessive, the results are harmful. The list of abnormalities known to be caused by excessive lymphocyte activity is extensive. We review two distinct pathways that account for most of the cellular injury induced by lymphocytes, with an emphasis on their clinical implications.The Molecular Basis of Lymphocyte-Mediated CytolysisUnlike humoral immune responses, which are mediated through antibodies and complement and can be transferred in serum to unimmunized subjects, cellular immune responses require the direct participation of effector . . .
Evidence for a Defect in Tryptophan Metabolism in Chronic Alcoholism
Authors: Robert E. Olson, Deha Gursey, John W. Vester
Journal: New England Journal of Medicine (1960)

IN addition to being a substrate for protein synthesis in the body, dietary tryptophan is metabolized to at least two physiologically important compounds, nicotinic acid and serotonin, via the intermediates outlined in Figure 1. The major urinary metabolites of these two compounds are respectively N-methylnicotinamide (and its 6-pyridone)1 and 5-hydroxyindoleacetic acid (5-HIAA).2 In this paper we wish to report a reduced rate of 5-HIAA excretion in the urine of patients with chronic alcoholism. Since the rate of N-methylnicotinamide formation from tryptophan was unchanged, the reduced 5-HIAA excretion may signify a defective conversion of tryptophan to serotonin in these addicts.MethodsThe . . .
Effective Inhibition Of Tumor Microenvironment Interactions In CLL Patients Treated With The BTK Inhibitor Ibrutinib Results In Sustained Inhibition Of Tumor Proliferation and Survival Pathways
Authors: Sarah E. M. Herman, Rashida Z Mustafa, Sabrina E. Martyr, Jennifer Gyamfi, Janet Valdez, Susan Soto, Mohammed Farooqui, Adrian Wiestner
Journal: Blood (2013)
Renal Function after Recovery from Acute Renal Failure
Authors: John T. Finkenstaedt, John P. Merrill
Journal: New England Journal of Medicine (1956)

A NUMBER of investigators have studied the recovery of renal function after acute renal failure.1 2 3 4 5 6 7 8 9 10 The clearance of inulin, thiosulfate, mannitol, creatinine, para-aminohippurate and iodopyracet (Diodrast) have been found to be low early in the diuretic phase during recovery. After this, the clearance of these substances increases and returns toward the normal state.Lowe5 has reported a long-term follow-up study of 14 cases of acute renal failure. In his series, clinical recovery was good, but clearance values remained below the lower limit of normal for as long as three years.This paper records another long-term follow-up study of 16 patients . . .
Spasm and Fibrosis of the Sphincter and Due to Reflex Action
Authors: Francis C. Newton, Charles A. Macgregor
Journal: New England Journal of Medicine (1948)

SPASM and fibrosis of the anal sphincter associated with a long history of marked constipation, tenesmus, mild intermittent abdominal cramps and an almost daily intake of cathartics is a rather frequently observed clinical entity about which little has been written, but which is important enough on occasions to suggest major but unnecessary surgery.1 2 3Twenty-one cases are reviewed in the present study. These patients were first seen because of variable complaints. Some sought advice because of constipation alone. Others complained of tenesmus. The majority, however, complained of vague abdominal discomfort, intermittent mild abdominal cramps, a sense of pelvic fullness, anorexia, flatus . . .
Capillary Permeability and Blood Flow in Skeletal Muscle of Patients with Diabetes Mellitus and Genetic Prediabetes
Authors: Joseph S. Alpert, Jay D. Coffman, Marios C. Balodimos, Lajos Koncz, J. Stuart Soeldner
Journal: New England Journal of Medicine (1972)

Abstract Disturbances in microvascular function were studied by measurement of capillary diffusion capacity (CDC), capillary filtration coefficients (CFC) and resting and hyperemic skeletal muscle blood flows in normal persons and patients with prediabetes and diabetes with and without microangiopathy. Blood flow, CDC and CFC were determined by calf venous-occlusion plethysmography and 133Xe and 131l clearances from hyperemic anterior tibial muscle. Diabetic patients with microangiopathy had significantly larger CDC's and 131l clearances than the normal controls (p less than 0.01) and diabetic patients without microangiopathy (p less than 0.05). Normal persons had hyperemic muscle flows (133Xe) significantly greater than those in the other groups (p less than 0.05). Resting flows and CFC's did not differ significantly among the groups. Three of 11 prediabetic subjects had very abnormal CDC's. The finding of normal CFC and abnormal CDC in diabetic patients with microvascular disease suggests that small ves...