tbuckley/cabot-search huggingface dataset:
Mitogen-Activated Protein Kinase Inhibition Induces Translocation of Bmf to Promote Apoptosis in Melanoma
Authors: Matthew W. VanBrocklin, Monique Verhaegen, Maria S. Soengas, Sheri L. Holmen
Journal: Cancer Research (2009)

Constitutive activation of the mitogen-activated protein kinase (MAPK) pathway is implicated in the development and progression of many human cancers, including melanoma. Mutually exclusive activating mutations in NRAS or BRAF have been identified in approximately 85% of melanomas, and components of this pathway have been developed as molecular targets for therapeutic intervention. We and others have shown that inhibition of this pathway with specific small molecule MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors induces a wide range of apoptotic responsiveness in human melanoma cells both in vitro and in vivo. To define the molecular mechanism underlying variable apoptotic sensitivity of melanoma cells to MEK inhibition, we examined the expression and subcellular localization of Bcl-2 family members in a comprehensive set of human melanoma cell lines. Whereas the proapoptotic protein Bim was activated and localized to the mitochondrial membrane in all cell lines regardless of apoptotic sensitivity, Bmf activation and cytosolic translocation was exclusive to sensitive cells. In resistant cells, Bmf remained sequestered to the cytoskeleton through dynein light chain 2 (DLC2) binding. Overexpression of Bmf in resistant cells did not enhance apoptosis, whereas expression of mutant BmfA69P, which has decreased binding to DLC2, promoted cell death. Expression of BmfA69P mutants possessing the Bcl-2 homology 3 (BH3) domain mutation L138A, which impairs BH3 interactions, did not enhance apoptosis in resistant cells. RNA interference targeting Bim and Bmf provided protection from apoptosis induced by MEK inhibition. These results show a novel role for Bmf in promoting apoptosis and provide insight into the mechanism of apoptotic resistance to MEK inhibition in melanoma.
Finding a needle in a haystack: whole genome sequencing and mutation discovery in murine models
Authors: Raajit K. Rampal, Ross L. Levine
Journal: Journal of Clinical Investigation (2011)

Acute promyelocytic leukemia (APL) is a malignancy of the bone marrow, in which there is a deficiency of myeloid cells and an excess of immature cells called promyelocytes. APL is most commonly caused by a translocation (15:17) and expression of the promyelocytic leukemia and the retinoic receptor α (PML-RARA) fusion product; however, the events that cooperate with PML-RARA in APL pathogenesis are not well understood. In this issue of the JCI, Wartman and colleagues use an innovative approach to find other relevant mutations in APL. They performed whole genome sequencing and copy number analysis of a well-characterized APL mouse model to uncover somatic mutations in Jak1 and lysine (K)-specific demethylase 6A (Kdm6a, also known as Utx) in mice with APL and validated the ability of Jak1 mutations to cooperate with PML-RARA in APL. The findings implicate the JAK/STAT pathway in the pathogenesis of APL and illustrate the power of whole genome sequencing to identify novel disease alleles in murine models of disease.
Hypersensitivity pneumonitis induced by trimethoprim.
Authors: T Higgins, P M Niklasson
Journal: BMJ (1990)

the meninges and abducens nerve on its long intracranial course.The sixth nerve occupies a superficial position in relation to the fourth ventricle, which communi- cates directly through the foramina of Magendie and Luschka with the subarachnoid space.Dye studies have shown that agents introduced into the spinal canal frequently reach the medulla, which may explain the peculiar affinity of the sixth nerve to palsy.4The contrast agents introduced in the procedure of myelography have a toxicity of their own, and the incidence of cranial nerve palsy is higher than after merely dural puncture.5This may be due to a previously unreported direct neurotoxicity of the contrast agent iopamidol itself.1 Lamb IT.Iohexol versus lopamidol for myelography.
Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors
Authors: Hellmut D. Ottinger, Stanislav Ferencik, Dietrich W. Beelen, Monika Lindemann, Rudolf Peceny, Ahmed H. Elmaagacli, Johannes Hüsing, Hans Grosse-Wilde
Journal: Blood (2003)
LONGEVITY IN BENIGN ESSENTIAL HYPERTENSION
Authors: James P. O'Hare
Journal: JAMA (1952)

This is a report of a study of 100 cases of benign essential hypertension followed personally by us for 10 to 34 years. Our purpose in making this study was threefold: (1) to add to the meager volume of valid published data concerned with the ordinary course of this disorder; (2) to seek clues that might explain the long life and favorable course in these cases, thereby increasing our capacity for making accurate prognoses; and (3) to make physicians more conscious of the fact that the course in many hypertensive patients may be a very benign one, compatible with long and effective living. If this last can be accomplished, judgments concerning patients with high blood pressure will be dominated less by the endstages of this disorder, with its dreaded hemiplegia, heart failure, or uremic poisoning, and patients should receive better and more reasonable therapy than many now do. It is
Jejunal monosaccharide, water, and electrolyte transport in patients with chronic pancreatitis.
Authors: C A Helman, G O Barbezat, S Bank
Journal: Gut (1978)

Jejunal perfusion studies were performed to assess water, electrolyte, d-xylose, and d-glucose transport in 16 patients with chronic calcific pancreatitis (eight with and eight without steatorrhoea) and in 10 control subjects. The patients with steatorrhoea demonstrated significantly less xylose, water, and electrolyte absorption than patients without steatorrhoea and control subjects, when an isosmotic slaine-xylose solution was perfused. On the other hand, when an isosmotic saline-glucose solution was perfused, the patients with steatorrhoea absorbed significantly more glucose, water, and electrolytes than control subjects. Significant correlation was demonstrated between the absorption of xylose as measured by the segmental perfusion technique and the peak serum xylose level during perfusion as well as the five-hour urinary xylose excretion after a 25 g oral dose of xylose. The xylose absorption measured by small bowel perfusion also correlated significantly with pancreatic juice amylase and trypsin concentrations obtained during a standard pancreatic function test.
Mend that gut, STAT!
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2009)

Deep in the gut, STAT3 applies Nature's band aid. According to Pickert et al. on [page 1465][1], the signaling protein heals wounded intestines and promotes recovery after colitis.

![Figure][2] 

STAT3 (red) helps wounded intestines heal.



Eliminating STAT3 from intestinal epithelial cells
Effect of intravenous calcitonin gene related peptide on ischaemia threshold and coronary stenosis severity in humans
Authors: N. G Uren, C. Seydoux, G. J Davies
Journal: Cardiovascular Research (1993)

Objective: Calcitonin gene related peptide (CGRP) is a potent vasodilator found in sensory nerve endings in coronary arteries. The effect of intravenous CGRP on myocardial ischaemia, cardiovascular haemodynamics, and epicardial coronary artery stenoses was studied in patients with angina to investigate the possible role of CGRP in the control of vasodilatation in the coronary circulation. Methods: 12 patients (mean age 60 years) performed exercise tests on consecutive days during intravenous infusions of placebo or CGRP (at 50 pmol·min−1). At cardiac catheterisation (6 patients), consecutive 20 min intravenous infusions of placebo and CGRP were given at a fixed heart rate, with measurement of haemodynamic variables and quantitative arteriography. Results: The time to 0.1 mV ST depression increased from 475(SD 245) to 546(193) s (p < 0.05), and time to 0.2 mV ST segment depression, from 634(266) to 694(202) s (p < 0.05), on placebo and CGRP respectively. Rate-pressure product at 0.1 mV ST segment depression was 18410(4590) and 20750(7270) mm Hg·min−1 (p < 0.05), and at 0.2 mV ST depression it was 21510(6470) and 24080(7380) mm Hg·min−1 (p < 0.01), with placebo and CGRP, respectively. At catheterisation, diastolic blood pressure fell from 93(11) to 83(8) mm Hg (p < 0.05), systemic vascular resistance fell from 26.2(9.4) to 20.7(9.0) units (p < 0.05), and cardiac output increased from 5.94(1.10) to 6.73(1.04) litre·min−1 (p < 0.05), on placebo and CGRP respectively. Minimum luminal diameter increased from 0.66(0.23) to 1.11(0.15) mm (p < 0.01) with CGRP. Conclusions: Intravenous CGRP is a systemic arterial vasodilator which dilates coronary arteries at the site of atheromatous stenoses and delays the onset of myocardial ischaemia during treadmill exercise testing in patients with chronic stable angina. Cardiovascular Research 1993;27:1477-1481
Atypical mole syndrome: Risk factor for cutaneous malignant melanoma and implications for management
Authors: Johnny Slade, Ashfaq A Marghoob, Thomas G Salopek, Darrell S Rigel, Alfred W Kopf, Robert S Bart
Journal: Journal of the American Academy of Dermatology (1995)

The incidence of malignant melanoma is increasing faster than that of any other cancer. It is important to identify subsets of the population at high risk of its development so that they can be observed more closely to identify early melanomas when they are curable. It has been reported worldwide that persons with the atypical mole (dysplastic nevus) syndrome are such a subset at increased risk. A risk gradient for the development of melanoma exists and varies from persons with one or two atypical moles and no family history of melanoma at one end of the spectrum to persons with the familial atypical multiple-mole melanoma syndrome at the other. Guidelines for the management of atypical mole syndrome are presented.
Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong
Authors: Christl A Donnelly, Azra C Ghani, Gabriel M Leung, Anthony J Hedley, Christophe Fraser, Steven Riley, Laith J Abu-Raddad, Lai-Ming Ho, Thuan-Quoc Thach, Patsy Chau, King-Pan Chan, Tai-Hing Lam, Lai-Yin Tse, Thomas Tsang, Shao-Haei Liu, James HB Kong, Edith MC Lau, Neil M Ferguson, Roy M Anderson
Journal: The Lancet (2003)
STUDIES ON A PROTEOLYTIC ENZYME IN HUMAN PLASMA
Authors: Oscar D. Ratnoff, Robert C. Hartmann, C. Lockard Conley
Journal: The Journal of Experimental Medicine (1950)

A fraction of globulin was prepared from human plasma which was deficient in prothrombin, thrombin, fibrinogen, plasma thromboplastin, and accelerator globulin. The preparation of globulin contained considerable potential proteolytic activity which could be activated by streptococcal fibrinolysin. This fraction of globulin accelerated the clotting of normal platelet-deficient plasma. However, the clot-accelerating effect of the globulin fraction was the same whether or not its proteolytic property had been activated. The addition of streptococcal fibrinolysin to normal platelet-deficient plasma did not accelerate coagulation. Nor did the addition of streptococcal fibrinolysin to hemophilic platelet-deficient plasma promote its coagulation. The data presented suggest that proteolysis by activated plasma proteolytic enzyme is not an essential stage in the coagulation of the blood.
Murine embryonic stem cells without pig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion.
Authors: V Rosti, G Tremml, V Soares, P P Pandolfi, L Luzzatto, M Bessler
Journal: Journal of Clinical Investigation (1997)

Paroxysmal nocturnal hemoglobinuria (PNH) develops in patients who have had a somatic mutation in the X-linked PIG-A gene in a hematopoietic stem cell; as a result, a proportion of blood cells are deficient in all glycosyl phosphatidylinositol (GPI)-anchored proteins. Although the PIG-A mutation explains the phenotype of PNH cells, the mechanism enabling the PNH stem cell to expand is not clear. To examine this growth behavior, and to investigate the role of GPI-linked proteins in hematopoietic differentiation, we have inactivated the pig-a gene by homologous recombination in mouse embryonic stem (ES) cells. In mouse chimeras, pig-a- ES cells were able to contribute to hematopoiesis and to differentiate into mature red cells, granulocytes, and lymphocytes with the PNH phenotype. The proportion of PNH red cells was substantial in the fetus, but decreased rapidly after birth. Likewise, PNH granulocytes could only be demonstrated in the young mouse. In contrast, the percentage of lymphocytes deficient in GPI-linked proteins was more stable. In vitro, pig-a- ES cells were able to form pig-a- embryoid bodies and to undergo hematopoietic (erythroid and myeloid) differentiation. The number and the percentage of pig-a- embryoid bodies with hematopoietic differentiation, however, were significantly lower when compared with wild-type embryoid bodies. Our findings demonstrate that murine ES cells with a nonfunctional pig-a gene are competent for hematopoiesis, and give rise to blood cells with the PNH phenotype. pig-a inactivation on its own, however, does not confer a proliferative advantage to the hematopoietic stem cell. This provides direct evidence for the notion that some additional factor(s) are needed for the expansion of the mutant clone in patients with PNH.
TCT-659 Clinical Outcomes of Patients Presented with Sirolimus-eluting Stent Failure and Treated with Additional Drug-eluting Stent
Authors: Hideaki Ota, Marco A. Magalhaes, lakshmana Pendyala, Thibault Lhermusier, Sa'ar Minha, Nevin C. Baker, Ricardo O. Escarcega, Wenjie Tian, Rebecca Torguson, Fang Chen, Lowell F. Satler, William O. Suddath, Augusto Pichard, Ron Waksman
Journal: Journal of the American College of Cardiology (2014)
BACTERIOSTASIS BY MIXTURE OF DYES
Authors: John W. Churchman
Journal: The Journal of Experimental Medicine (1923)

It is possible to mix two dyes of opposite selective bacteriostatic powers and obtain a mixture which combines the powers of the two components. This possibility has been established by experiments with a mixture of gentian violet, which has a predilection for Gram-positive organisms, and acriflavine, which has a predilection for Gram-negatives; a mixture of these two dyes is quite bactericidal for both groups of bacteria. The weakness of each dye, when used alone, is thus, in the mixture, fortified by the strength of the other.
SERUM PROPHYLAXIS OF EPIDEMIC PAROTITIS
Authors: JOSEPH C. REGAN
Journal: JAMA (1925)

It is generally conceded that epidemic parotitis is not a severe disease in its typical form. In most cases, especially in children, the disease evolutes without serious complications and without mortality. This malady is not, however, always so mild, and in certain epidemics has been known to assume a malignant form.  In the usual case the main complication is orchitis, and this is almost entirely limited to adult patients. It is a most painful condition, however, and, besides prolonging the duration of the acute attack for a week or two, may be followed by atrophic changes in the involved glands. Acute ovarian inflammation may occur in the female, but far more uncommonly than orchitis in the male. Recently, much attention has been drawn to the occurrence of meningitis as a complication. As a matter of fact, mental disturbances and delirium are not unusual in patients with mumps orchitis. Albuminuria has
French AIDS group criticises treatment of immigrants
Authors: A. Dorozynski
Journal: BMJ (1996)

The French national AIDS council has protested about the treatment of HIV positive illegal immigrants in France. The protest follows publication of a report criticising French detention centres for alleged mistreatment of detainees.

About 500 illegal immigrants who are HIV positive have been identified by the French ministry of health. About 300 of them could legally be deported unless they are …
A pain in the neck
Authors: J. A. Finegold, R. Belcher, S. Noor, D. Mort
Journal: BMJ (2010)

A 49 year old right handed builder presented to the emergency department after an episode of vomiting and unsteadiness, with falling to the right side. This resolved after 10 minutes, but was followed 30 minutes later by pins and needles in the right face, arm, and leg. The symptoms had been preceded by bilateral neck stiffness for the previous three days, after the patient experienced minor trauma to the neck. His medical history was of well controlled essential hypertension. His family history was relevant—his father had a stroke in his 50s.

At initial assessment the patient was found to have right sided paraesthesia, with no evidence of weakness. He had no cranial nerve lesions and no higher cortical dysfunction. Initial observations were normal, with a blood pressure of 135/90 mm Hg. A 12 lead resting electrocardiogram showed sinus rhythm. Computed tomography of the head on admission showed no abnormality.

The next day the patient had residual paraesthesia in his right hand only. Fasting glucose and cholesterol concentrations were within normal limits, and his erythrocyte sedimentation rate was 10 mm/h. He underwent magnetic resonance imaging (fig 1⇓) and magnetic resonance angiography (fig 2⇓).



Fig 1 Magnetic resonance imaging of the brain





Fig 2 Magnetic resonance angiography 





### 1 What two abnormalities are seen on the magnetic resonance images?

#### Short answer

An intraluminal clot in the right vertebral artery and infarction of the right medullary pyramid can be seen on the magnetic resonance images.

#### Long answer

The axial T1 weighted magnetic resonance image shows a focal …
Algorithm for modified alkaline diuresis in salicylate poisoning.
Authors: S W Coppack, C S Higgens
Journal: BMJ (1984)

but a low titre to the porcine agent.3Before operation a test dose was given to ascertain the therapeutic response and to detect side effects.4In this case shivering, nausea, and back pain occurred but were rapidly relieved by oral chlorpheniramine.During the early post- operative period we gave 100 mg hydrocortisone and 10 mg chlorpheniramine intravenously before each infusion, later using chlor- pheniramine alone.The platelet count remained unchanged.Altogether 270 000 units of porcine factor VIII were given without any appreciable rise in the titre of antibodies to this agent or an increased tendency towards side effects.Though a prolonged conservative approach to management of a pseudotumour may be successful, it was clearly failing in this patient.The new porcine factor enabled us to overcome the problem of achieving and maintaining haemostasis during and after major surgery.We thank Professor R B Duthie and Dr C Rizza for permission to report on their patient
A Secretion Trap Screen in Yeast Identifies Protease Inhibitor 16 as a Novel Antihypertrophic Protein Secreted From the Heart
Authors: Robert J.A. Frost, Stefan Engelhardt
Journal: Circulation (2007)

Background— Cardiomyocyte hypertrophy is of central importance in the development of congestive heart failure. Whether proteins secreted from the myocardium itself contribute to myocardial hypertrophy is largely unknown. Methods and Results— We performed a genetic yeast secretion trap screen using a murine cardiac cDNA library and identified 54 cardiac proteins that contained a secretion signal. When determining their mRNA expression in the myocardium of failing hearts, we found protease inhibitor 16 (PI16) to be strongly upregulated in hypertrophic and failing myocardium. PI16, a 489–amino acid protein with an unknown function, also displayed enhanced expression on the protein level after serum stimulation of primary cardiomyocytes and in failing myocardium. We found PI16 to be secreted rapidly by primary cardiomyocytes into the culture medium, where it inhibited cardiomyocyte growth. RNA interference–mediated suppression of endogenous PI16 in primary cardiomyocytes significantly enhanced cardiomyocyte size. Transgenic mice overexpressing PI16 in a cardiomyocyte-specific manner showed normal cardiac function but had smaller hearts with hypotrophic cardiomyocytes. Conclusions— Taken together, we identified 54 putatively secreted cardiac proteins. PI16, a novel protein secreted from the heart, is strongly upregulated early in heart failure and inhibits growth of cardiomyocytes both in vitro and in vivo. PI16 might represent a novel therapeutic target in heart failure.
Comment on Hedderson et al. Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus. Diabetes Care 2014;37:1296–1303
Authors: Norbert Stefan, Andreas Peter, Hans-Ulrich Häring
Journal: Diabetes Care (2014)

Hedderson et al. (1) recently found that lower sex hormone–binding globulin (SHBG) concentrations measured, on average, 6 years before pregnancy were associated with increased odds of the development of gestational diabetes mellitus (GDM). Because this relationship was independent of known risk factors of GDM, they concluded that circulating SHBG may represent a potentially useful new biomarker for identifying who is at risk for GDM beyond the currently established clinical and demographic risk factors, in particular insulin resistance.

While the study appears to be well performed and the data are very interesting, the conclusion with respect to insulin resistance may be overstated. In their study, Hedderson et al. could estimate …
Amiloride
Authors: MARCIA B. BULL, JOHN H. LARAGH
Journal: Circulation (1968)

Amiloride, a new, well-tolerated oral natriuretic and mild diuretic agent, has been evaluated alone and in combination with other diuretics. Its remarkable ability to promote retention rather than loss of potassium makes it a useful adjunct in the management of even the most severe edematous states. It also retards the alkalosis produced by certain of the stronger diuretics by blocking hydrogen secretion and promoting bicarbonate loss. In addition to being a valuable adjunctive agent, the compound may be useful alone because of the advantages inherent in steady, sustained natriuretic therapy with a mild diuresis as opposed to incurring precipitous alterations in fluid and electrolyte balance with the intermittent use of more potent agents. In certain patients it was mildly antihypertensive. Amiloride produced marked increases in aldosterone secretion with lesser rises in plasma renin. The adrenal stimulation therefore appeared to result from both potassium retention and renin activation consequent to natriuresis. The compound appears to act primarily in the distal nephron, blocking both sodium-hydrogen exchange and sodium-potassium exchange. Like triamterene, but unlike spirolactone, amiloride has the characteristics of a noncompetitive inhibitor of aldosteronedirected sodium and potassium transport. Because of this, it may be expected to produce more predictable effects than spirolactone and at least in certain instances to be more powerful. It may also be preferable to spirolactone for the acute control of derangements in potassium balance because of its more rapid onset and disappearance of action. No significant toxicity was encountered; however, serum potassium values should be carefully monitored, especially in situations involving impaired renal function.