tbuckley/cabot-search huggingface dataset:
LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin
Authors: Prue A. Cowin, Joshy George, Sian Fereday, Elizabeth Loehrer, Peter Van Loo, Carleen Cullinane, Dariush Etemadmoghadam, Sarah Ftouni, Laura Galletta, Michael S. Anglesio, Joy Hendley, Leanne Bowes, Karen E. Sheppard, Elizabeth L. Christie, Richard B. Pearson, Paul R. Harnett, Viola Heinzelmann-Schwarz, Michael Friedlander, Orla McNally, Michael Quinn, Peter Campbell, Anna deFazio, David D.L. Bowtell
Journal: Cancer Research (2012)

Abstract High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res; 72(16); 4060–73. ©2012 AACR.
Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report
Authors: JH Laver, JC Barredo, M Amylon, M Schwenn, J Kurtzberg, BM Camitta, J Pullen, MP Link, M Borowitz, Y Ravindranath, SB Murphy, J Shuster
Journal: Leukemia (2000)
Desert island books: Self-fulfilment denied
Authors: G M Carstairs
Journal: BMJ (1976)

violence ?I shudder at the many children's programmes detonating with violence, as well as those adult programmes to which children are exposed round about bedtime.Parents have told me of their fears that the impact of this violence, in motion and with sound and colour, will be greater, its influence more permanent, than that of the most hair-raising fairy tales.Proof is elusive but such fears are widespread.It seems to me, however, that broadcasting of any sort, however unexceptionable its theme, risks another and more insidious mischief, one that is overlooked.It can be a bane and a blight-simply by keeping the child away from people, from active participation in social activities.Among these is the bedtime story.For TV there is need for only one flesh and blood person; for bedtime stories, two.Bedtime story-telling is another cottage industry in danger of being overwhelmed by mass -production.But I cannot believe that it will cease.Deeply embedded in children is the craving to listen to stories and in adults, the urge to tell them; and where more cosily and delightfully than tucked up in bed?
TUBERCULAR JOINTS AND THEIR TREATMENT.
Authors: DAVID C. PEYTON
Journal: JAMA (1904)

The frequency of tubercular disease of the joints, and the necessity for early diagnosis, serve as an excuse for this paper on a subject about which so much has been written. The writer desires to emphasize the fact that the present article is intended only as a resume of some of the more important well-proven and accepted conditions which make it an imperative duty of both the general practitioner and surgeon to be able to recognize a tubercular joint in its incipiency, for on our ability to diagnose this trouble early depends the success of treatment. We must recognize that joint tuberculosis is at first a local manifestation. We must disabuse our minds of the idea that it originates only in the children of tuberculous parents, and of the idea that all joint pain is rheumatic.  Tuberculosis in the region of a joint is essentially of the bone, although it
Oral Bioavailability of Chromium from a Specific Site
Authors: Charlotte M. Witmer, Raymond Harris, Saul I. Shupack
Journal: Environmental Health Perspectives (1991)

Analysis of soil from a specific site in New Jersey indicated a low level of sodium and chromium present as a calcium compound. Chromium was then administered orally to young, mature male rats at a level of 240 micrograms/kg for 14 days as chromium-contaminated soil, as CaCrO4, and as an equimolar mixture of the soil and calcium salts for 14 days. The rats were sacrificed 24 hr after the last dosing, and tissues were taken immediately for chromium analysis. Blood, muscle, and liver contained the highest levels of chromium in these animals, although kidney contained the highest concentration per gram of tissue. The total amount of chromium in the tissues was less than 2% of the administered chromium. In a study of the excretion of chromium, the animals were dosed orally for 8 days (with CaCrO4 or contaminated soil, each at the level of 240 mumole Cr/kg), and the chromium in feces and urine was determined on days 1, 2, 7, and 8. After cessation of dosing for 27 days, the same rats were dosed for 2 days at the same level, and chromium in urine and feces was determined for the 2 days. The animals administered the chromium in soil had higher levels of chromium in both urine and feces on all days compared to the group fed the CaCrO4. The total recovery of chromium in any of the 2-day periods was less than 50% of the chromium administered during that period.
The liver in the acquired immunodeficiency syndrome: A clinical and histologic study
Authors: Edward Lebovics, Swan N. Thung, Fenton Schaffner, Paul W. Radensky
Journal: Hepatology (1985)

We reviewed the clinical data and hepatic histologic findings of 25 patients with the acquired immunodeficiency syndrome who underwent 29 liver biopsies. Our experience indicates that the only hepatic feature characteristic of acquired immunodeficiency syndrome is serologic evidence of exposure to the hepatitis B virus. The most common histologic finding was macrovesicular steatosis. Granulomas appeared in seven patients and were due to mycobacterial disease (3 patients), histoplasmosis (1 patient), adverse reaction to sulfonamide (2 patients) and unknown causes (1 patient). The clinical indication for liver biopsy was not significantly different in the patients without or with granulomas or with granulomas secondary to mycobacteria or fungi. Mycobacteria were cultured from all histologically positive specimens and one histologically negative specimen. Liver biopsy should be performed in any patient with acquired immunodeficiency syndrome who has unexplained fever, hepatomegaly or abnormal results of serum biochemical liver tests, and all specimens should be stained and cultured for mycobacteria and fungi.
Lessons from the Pearce affair: handling scientific fraud
Authors: S. Lock
Journal: BMJ (1995)

Last week Malcolm Pearce, a British gynaecologist, was removed from the medical register for fraud: he had published two papers in the British Journal of Obstetrics and Gynaecology describing work that had never taken place (p 1554).1 Less than nine months had elapsed between the whistle being blown on Pearce and his removal from the register. Outside observers might therefore conclude that, like other countries, Britain has established methods of preventing, detecting, and managing misconduct in research. They would be wrong. That the Pearce affair was handled well was unusual: the principal of Pearce's medical school knew what to do and was determined to do it—speedily and while protecting the rights of both the accused and the whistleblower. In most other medical institutions in Britain nothing would have happened2; the affair would have been brushed under the carpet, and the whistleblower would probably have been hounded out of his or her job.

Despite a report from the Royal College of Physicians,3 Britain has learnt little about handling fraud since the Darsee affair in the United States first brought the subject into prominence in 1983.4 This is despite a succession of other major scientific frauds in biomedicine.For example, the Office of Research Integrity, a branch of the US Public Health Service set up to investigate fraud, considered 73 cases in 1994.5 One particular abuse has indeed been tackled in Britain. Several general practitioners who engaged in fraud during drug trials have been struck off by the General Medical Council,6 but this has been largely because their frauds emerged through pharmaceutical companies' thorough auditing procedures and because the companies have taken an aggressive approach towards tackling fraud. The same has not applied within academia or the NHS. Until the Pearce …
Clinical predictors of hypoxaemia in Gambian children with acute lower respiratory tract infection: prospective cohort study
Authors: S. Usen, M. Weber, K. Mulholland, S. Jaffar, A. Oparaugo, C. Omosigho, R. Adegbola, B. Greenwood
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objectives:</b> To determine clinical correlates and outcome of hypoxaemia in children admitted to hospital with an acute lower respiratory tract infection. <b>Design:</b> Prospective cohort study. <b>Setting:</b> Paediatric wards of the Royal Victoria Hospital and the hospital of the Medical Research Council9s hospital in Banjul, the Gambia. <b>Subjects:</b> 1072 of 42 848 children, aged 2 to 33 months, who were enrolled in a randomised trial of a <i>Haemophilus influenzae</i> type b vaccine in the western region of the Gambia, and who were admitted with an acute lower respiratory tract infection to two of three hospitals. <b>Main outcome measures:</b> Prevalence of hypoxaemia, defined as an arterial oxygen saturation &lt;90% recorded by pulse oximetry, and the relation between hypoxaemia and aetiological agents. <b>Results:</b> 1072 children aged 2-33 months were enrolled. Sixty three (5.9%) had an arterial oxygen saturation &lt;90%. A logistic regression model showed that cyanosis, a rapid respiratory rate, grunting, head nodding, an absence of a history of fever, and no spontaneous movement during examination were the best independent predictors of hypoxaemia. The presence of an inability to cry, head nodding, or a respiratory rate 90 breaths/min formed the best predictors of hypoxaemia (sensitivity 70%, specificity 79%). Hypoxaemic children were five times more likely to die than non-hypoxaemic children. The presence of malaria parasitaemia had no effect on the prevalence of hypoxaemia or on its association with respiratory rate. <b>Conclusion:</b> In children with an acute lower respiratory tract infection, simple physical signs that require minimal expertise to recognise can be used to determine oxygen therapy and to aid in screening for referral. The association between hypoxaemia and death highlights the need for early recognition of the condition and the potential benefit of treatment.
The detection of atrial and ventricular septal defects with electrocardiographically synchronized magnetic resonance imaging.
Authors: D G Lowell, D A Turner, S M Smith, G H Bucheleres, B A Santucci, R J Gresick, D O Monson
Journal: Circulation (1986)

To evaluate the detectability of cardiac septal defects by electrocardiographically synchronized (ECG-gated) magnetic resonance imaging (MRI), 48 subjects were imaged, including 18 normal and 30 abnormal subjects in whom 22 ventricular septal defects (VSDs) and nine atrial septal defects (ASDs) had been diagnosed angiographically. Two radiologists with ECG-gated cardiac MRI experience read the scans in a blinded fashion, and the results were evaluated by receiver operator characteristic curve analysis. The detectability of VSDs appeared greater than that of ASDs, although statistical significance at the .05 level was not achieved. The reported sensitivity and specificity of echocardiography in the detection of VSDs is comparable to MRI, whereas echocardiography probably is superior to MRI for detection of ASDs. Although MRI is potentially valuable in the diagnosis of various complex congenital cardiac defects, echocardiography is probably superior in the detection of VSDs and ASDs.
Effect of allergen provocation on inflammatory cell profile and endothelin‐like immunoreactivity in guinea‐pig airways
Authors: S. E. Andersson, C. Zackrisson, K. Behrens, A. Hemsen, K. Forsberg, M. Linden, J. M. Lundberg
Journal: Allergy (1995)

The effect of allergen challenge on the number of leucocytes and the concentration of endothelin 1‐like immunoreactivity (ET‐LI) in bronchoalveolar lavage fluid (BALE) was investigated in guinea‐pigs sensitized to Ascaris suum. The animals were twice exposed to allergen aerosol. All animals responded to the second challenge with bronchoconstriction. Twelve hours later, a significant increase in the number of eosinophilic granulocytes in BALE, compared to unsensitized and unprovoked control animals, was noted. Twenty‐four hours after provocation, there was also an elevation of ET‐LI concentration and content of neutrophils. During the first day post‐challenge, the ET‐LI values were moderately correlated to the eosinophil levels. One week after challenge, the ET‐LI level and the neutrophil count did not differ from corresponding values in control animals whereas the number of eosinophils remained elevated. Pretreatment with dexamethasone before the second allergen challenge did not consistently affect the parameters studied during the first 24 h. Bronchoconstriction induced by carbachol aerosol affected significantly neither the ET‐LI concentration nor the number of inflammatory cells in BALE. It is concluded that the allergen‐induced inflammation in the guinea‐pig airways causes an elevation in the ET‐LI concentration in BALE and that this is moderately correlated to the influx of eosinophils during the first 24 h.
Effect of Plethora and Hemorrhage on Left Ventricular Volume and Pressure
Authors: J. P. HOLT, J. Allensworth, J. Diana, David Collins, Helga Kines
Journal: Circulation Research (1957)

By combining conventional methods for recording pressures from the left ventricle and pleural cavity with a new procedure for estimating end-diastolic volume (EDV) and end-systolic volume (ESV) of the left ventricle it was found in the closed-chest dog that plethora increased EDV, ESV and stroke volume while hemorrhage had the opposite effect. There were linear relationships between EDV and ESV, and between EDV and stroke volume. There was little change in left ventricular "effective" end-diastolic pressure when the EDV changed over a wide range, beginning with the smallest EDV consistent with life; but after a certain large EDV had been reached, large increases in effective end-diastolic pressure were associated with little or no further increase in EDV.
Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter
Authors: Baodong Sun, Haoyue Zhang, Luis M. Franco, Talmage Brown, Andrew Bird, Ayn Schneider, Dwight D. Koeberl
Journal: Molecular Therapy (2005)

Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid α-glucosidase (GAA; acid maltase) deficiency. An AAV2 vector pseudotyped as AAV6 (AAV2/6 vector) transiently expressed high-level human GAA in GAA-knockout (GAA-KO) mice without reducing glycogen storage; however, in immunodeficient GAA-KO/SCID mice the AAV2/6 vector expressed high-level GAA and reduced the glycogen content of the injected muscle for 24 weeks. A CD4+/CD8+ lymphocytic infiltrate was observed in response to the AAV2/6 vector in immunocompetent GAA-KO mice. When a muscle-specific creatine kinase promoter was substituted for the CB promoter (AAV-MCKhGAApA), that AAV2/6 vector expressed high-level GAA and reduced glycogen content in immunocompetent GAA-KO mice. Muscle-restricted expression of hGAA provoked only a humoral (not cellular) immune response. Intravenous administration of a high number of particles of AAV-MCKhGAApA as AAV2/7 reduced the glycogen content of the heart and skeletal muscle and corrected individual myofibers in immunocompetent GAA-KO mice 24 weeks postinjection. In summary, persistent correction of muscle glycogen content was achieved with an AAV vector containing a muscle-specific promoter in GAA-KO mice, and this approach should be considered for muscle-targeted gene therapy in Pompe disease.
Diabetes in General Practice
Authors: F. I. Powell, R. E. Blair
Journal: BMJ (1960)

Curcumin (diferuloylmethane), which has no discernible toxicity, inhibits initiation, promotion and progression of carcinogenesis. 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but produces an incomplete response resulting in survival of cells (chemo-surviving cells) that may lead to cancer recurrence. The present investigation was, therefore, undertaken to examine whether addition of curcumin to FOLFOX is a superior therapeutic strategy for chemo-surviving cells. Forty-eight-hour treatment of colon cancer HCT-116 and HT-29 cells with FOLFOX resulted in 60-70% survival, accompanied by a marked activation of insulin like growth factor-1 receptor (IGF-1R) and minor to moderate increase in epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2) as well as v-akt murine thymoma viral oncogene homolog 1 (AKT), cyclooxygenase-2 (COX-2) and cyclin-D1. However, inclusion of curcumin to continued FOLFOX treatment for another 48 h greatly reduced the survival of these cells, accompanied by a concomitant reduction in activation of EGFR, HER-2, IGF-1R and AKT, as well as expression of COX-2 and cyclin-D1. More importantly, EGFR tyrosine kinase inhibitor gefitinib or attenuation of IGF-1R expression by the corresponding si-RNA caused a 30-60% growth inhibition of chemo-surviving HCT-116 cells. However, curcumin alone was found to be more effective than both gefitinib and IGF-1R si-RNA mediated growth inhibition of chemo-surviving HCT-116 cells and addition of FOLFOX to curcumin did not increase the growth inhibitory effect of curcumin. Our data suggest that inclusion of curcumin in conventional chemotherapeutic regimens could be an effective strategy to prevent the emergence of chemoresistant colon cancer cells.
Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients: authors’ reply to comments by Zacharowski et al.
Authors: Konrad Reinhart, Anders Perner, Charles L. Sprung, Roman Jaeschke, Frederique Schortgen, A. B. Johan Groeneveld, Richard Beale, Christiane S. Hartog
Journal: Intensive Care Medicine (2012)
Reduced arteriolar conducted vasoconstriction in septic mouse cremaster muscle is mediated by nNOS-derived NO
Authors: R MCKINNON, D LIDINGTON, M BOLON, Y OUELLETTE, G KIDDER, K TYML
Journal: Cardiovascular Research (2005)

Increased nitric oxide (NO) production in sepsis precipitates microcirculatory dysfunction. We aimed (i) to determine if NO is the key water-soluble factor in the recently discovered sepsis-induced deficit in arteriolar conducted vasoconstriction, (ii) to identify which nitric oxide synthase (NOS) isoforms account for this deficit, and (iii) to examine the potential role of connexin37 (Cx37, a hypothesized signaling target of NO) in arteriolar conduction.Using intravital microscopy and the cecal ligation and perforation 24-h model of sepsis, arterioles in the cremaster muscle of male C57BL/6 wild-type (WT), iNOS-/-, eNOS-/-, nNOS-/- and Cx37-/- mice were locally stimulated with KCl to initiate conducted vasoconstriction. We used the ratio of conducted constriction (500 microm upstream) to local constriction as an index of conduction (CR500). NOS enzymatic activity and protein expression were determined in control and septic cremaster muscles.Sepsis reduced CR500 in WT mice [from 0.77 +/- 0.05 to 0.20 +/- 0.02 (means +/- SE) independent of the site of stimulation along the arteriole], in iNOS-/- and eNOS-/- mice, but not in nNOS-/- mice. The nNOS inhibitor 7-nitroindazole or NO scavenger HbO2 restored CR500 in septic WT mice, but blockade of soluble guanylate cyclase had no effect. Sepsis increased cNOS (eNOS + nNOS) activity in WT mice (from 340 +/- 40 to 490 +/- 30 pmol/mg/h) and in eNOS-/-, but not in nNOS-/- mice (iNOS activity was negligible in all mice). Sepsis did not alter nNOS protein expression in WT mice. CR500 in non-septic Cx37-/- mice (0.15 +/- 0.1) was similar to that observed in septic WT mice.Increased nNOS activity and the resultant increased NO production in the septic mouse cremaster muscle are the key factors responsible for the deficit in conducted vasoconstriction along the arteriole. Deletion of Cx37 results in reduced CR500, which is consistent with the hypothesis that Cx37 in the arteriole could be a target of NO signaling.
The Poor Physician.
Authors: Albert S. Ashmead
Journal: JAMA (1897)

New York, Feb. 1, 1897. <h3>To the Editor:</h3> —While we are discussing the question of capital and the farmer, why not touch on the interesting question of the poor physician? His case is truly, if you look at it closely, which nobody seems inclined to do, a very, very lamentable one. Think of this: A man who has made his millions, by fair means or else by hook or by crook, it does not matter, feels that he has done nearly enough for this world and that some of his thoughts and deeds might be now reasonably employed to do something to result in dividends in another world possibly to come. The recipe for the cure of such morbid anxieties is an old and hackneyed one. No necessity for breaking one's head, as he had done before on Wall street matters, or about Standard oil wells in the West. Oh,
Acute systemic sarcoidosis complicating ustekinumab therapy for chronic plaque psoriasis
Authors: J. B. Powell, P. Matthews, R. Rattehalli, F. Woodhead, P. Perkins, G. Powell, W. Szczecinska, J. E. Gach
Journal: British Journal of Dermatology (2014)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, Ustekinumab is a human monoclonal antibody, which binds to and inhibits interleukin (IL)‐12p40, and is used to treat moderate‐to‐severe psoriasis and psoriatic arthritis. Sarcoidosis is a systemic granulomatous disease in which IL‐12 levels are elevated in tissues, serum and bronchoalveolar lavage samples of affected patients.1 Therefore, there is a rationale for the use of ustekinumab in treating sarcoidosis. The paradoxical induction of a wide range of autoimmune processes such as lupus erythematosus, vasculitis, sarcoidosis and psoriasis, developing after the initiation of antitumour necrosis factor (anti‐TNF) biological therapies, is increasingly being reported.2 We present the first reported case, to our knowledge, of sarcoidosis developing in a patient receiving ustekinumab for chronic plaque psoriasis (or indeed any indication). A 42‐year‐old white female patient with psoriatic arthritis and severe, difficult‐to‐control, chronic plaque psoriasis [Psoriasis Area and Severity Index (PASI) 19·3 and Dermatology Life Quality Index (DLQI) 26 at initiation of therapy] had been treated with ustekinumab 45 mg subcutaneously for 14 months when she presented with lethargy, weight loss, night sweats, a dry cough, dyspnoea and painful lesions on the lower legs. Previous treatments included phototherapy, ciclosporin, acitretin, adalimumab and infliximab (both biologics in combination with methotrexate). Methotrexate 20 mg weekly was continued while ustekinumab was initiated.