tbuckley/cabot-search huggingface dataset:
Hepatic stem cells
Authors: A J STRAIN
Journal: Gut (2000)

For several decades investigators have been addressing the tantalising question, is there a hepatic stem cell?1Despite widespread attempts to identify and characterise such cells in the liver and a plethora of papers, reviews, and monographs on the subject,2-4 doubts as to their very existence have remained. It is only relatively recently that these doubts have been removed, at least in the eyes of most investigators, with convincing evidence from rodent studies and novel developments in the cell biology of the pathogenesis of human liver disease. Moreover, new exciting findings indicate that in tissues, including bone marrow and the brain, there reside cells with an innate ability to differentiate into divergent cell types. The stem cell field is currently a “hot” topic.

Although essentially a quiescent organ, the normal adult liver can fully regenerate following surgical resection or injury. Much of what we have learned about liver growth control derives from the classical two thirds partial hepatectomy model in the rat. The process begins with growth activation of mature hepatocytes; other cell types, including biliary epithelial cells (BEC) and sinusoidal cells, proliferate with a delayed response.5 However, if liver damage is so severe that hepatocytes are largely obliterated or for some reason are prevented from entering the growth cycle by exposure to hepatotoxins or carcinogens, then activation of a liver stem (progenitor) cell population is postulated,2 3 giving rise to so-called “oval” cells. These cells are thought to have both clonogenic and bipotential capacity—that is, the ability to proliferate and differentiate into cells of either hepatocyte or BEC lineage.6 7 There is also evidence that under certain conditions oval cells can be induced to differentiate into non-hepatic lineages including intestinal and pancreatic epithelium.3The origin of oval cells and their precise location within the …
Partial Neutralization of the Acidogenic Western Diet with Potassium Citrate Increases Bone Mass in Postmenopausal Women with Osteopenia
Authors: Sigrid Jehle, Antonella Zanetti, Jürgen Muser, Henry N. Hulter, Reto Krapf
Journal: Journal of the American Society of Nephrology (2006)

Chronic acid loads are an obligate consequence of the high animal/grain protein content of the Western diet. The effect of this diet-induced metabolic acidosis on bone mass is controversial. In a randomized, prospective, controlled, double-blind trial, 161 postmenopausal women (age 58.6 +/- 4.8 yr) with low bone mass (T score -1 to -4) were randomly assigned to 30 mEq of oral potassium (K) citrate (Kcitrate) or 30 mEq of K chloride (KCl) daily. The primary end point was the intergroup difference in mean percentage change in bone mineral density (BMD) at lumbar spine (L2 through L4) after 12 mo. Compared with the women who received KCl, women who received Kcitrate exhibited an intergroup increase in BMD (+/-SE) of 1.87 +/- 0.50% at L2 through L4 (P < 0.001), of 1.39 +/- 0.48% (P < 0.001) at femoral neck, and of 1.98 +/- 0.51% (P < 0.001) at total hip. Significant secondary end point intragroup changes also were found: Kcitrate increased L2 through L4 BMD significantly from baseline at months 3, 9, and 12 and reached a month 12 increase of 0.89 +/- 0.30% (P < 0.05), whereas the KCl arm showed a decreased L2 through L4 BMD by -0.98 +/- 0.38% (P < 0.05), significant only at month 12. Intergroup differences for distal radius and total body were NS. The Kcitrate-treated group demonstrated a sustained and significant reduction in urinary calcium excretion and a significant increase in urinary citrate excretion, with increased citrate excretion indicative of sustained systemic alkalization. Urinary bone resorption marker excretion rates were significantly reduced by Kcitrate, and for deoxypyridinoline, the intergroup difference was significant. Urinary net acid excretion correlated inversely and significantly with the change in BMD in a subset of patients. Large and significant reductions in BP were observed for both K supplements during the entire 12 mo. Bone mass can be increased significantly in postmenopausal women with osteopenia by increasing their daily alkali intake as citrate, and the effect is independent of reported skeletal effects of K.
Smurf2 Regulates the Senescence Response and Suppresses Tumorigenesis in Mice
Authors: Charusheila Ramkumar, Yahui Kong, Hang Cui, Suyang Hao, Stephen N. Jones, Rachel M. Gerstein, Hong Zhang
Journal: Cancer Research (2012)

The E3 ubiquitin ligase Smurf2 mediates ubiquitination and degradation of several protein targets involved in tumorigenesis and induces senescence in human cells. However, the functional role of Smurf2 in tumorigenesis has not been fully evaluated. In this study, we generated a mouse model of Smurf2 deficiency to characterize the function of this E3 ligase in tumorigenesis. Smurf2 deficiency attenuated p16 expression and impaired the senescence response of primary mouse embryonic fibroblasts. In support of a functional role in controlling cancer, Smurf2 deficiency increased the susceptibility of mice to spontaneous tumorigenesis, most notably B-cell lymphoma. At a premalignant stage of tumorigenesis, we documented a defective senescence response in the spleens of Smurf2-deficient mice, consistent with a mechanistic link between impaired senescence regulation and increased tumorigenesis. Taken together, our findings offer the genetic evidence of an important tumor suppressor function for Smurf2.
Reliance on Hormone Receptor Assays of Surgical Specimens May Compromise Outcome in Patients With Breast Cancer
Authors: G. Bruce Mann, Vanessa D. Fahey, Frank Feleppa, Malcolm R. Buchanan
Journal: Journal of Clinical Oncology (2005)

To assess the concordance of breast cancer immunohistochemical receptor assays on core biopsy and surgical specimens.We identified 100 patients whose core biopsy and definitive surgical specimens were processed in our hospital. New sections, with core and surgical specimens on the same slides, were stained for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC). Two pathologists assessed the sections independently. Raw scores and clinically significant groupings were compared.Concordance for ER, PR, overall hormone receptor (HR), and HER-2 status was seen in 86%, 83%, 90%, and 80% of patients, respectively. The core was positive, while the surgical specimen was negative in 13%, 11%, 9%, and 1% of patients, respectively. Using a log-linear model, differences in ER, PR, and HER-2 staining were all in the direction of stronger staining in the cores, and were statistically significant. Nine percent (95% CI, 4.2% to 16.4%) of women in this group would have had endocrine therapy inappropriately withheld if management decisions were based on surgical specimen results alone.ER and PR assays on core biopsy specimens are more reliable than assays on surgical specimens. Receptor IHC should be performed on core biopsy specimens to avoid patients with HR positive cancers not receiving appropriate hormonal therapy and being overtreated with systemic chemotherapy. Biopsy should be considered in patients with "receptor negative" cancer and recurrent disease.
Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement
Authors: Rebecca A. Whipple, Michael A. Matrone, Edward H. Cho, Eric M. Balzer, Michele I. Vitolo, Jennifer R. Yoon, Olga B. Ioffe, Kimberly C. Tuttle, Jing Yang, Stuart S. Martin
Journal: Cancer Research (2010)

Epithelial-to-mesenchymal transition (EMT) is associated with increased breast tumor metastasis; however, the specific mechanisms by which EMT promotes metastasis remain somewhat unclear. Despite the importance of cytoskeletal dynamics during both EMT and metastasis, very few current studies examine the cytoskeleton of detached and circulating tumor cells. Specific posttranslational α-tubulin modifications are critical for adherent cell motility and implicated in numerous pathologies, but also remain understudied in detached cells. We report here that EMT induced through ectopic expression of Twist or Snail promotes α-tubulin detyrosination and the formation of tubulin-based microtentacles in detached HMLEs. Mechanistically, EMT downregulates the tubulin tyrosine ligase enzyme, resulting in an accumulation of detyrosinated α-tubulin (Glu-tubulin), and increases microtentacles that penetrate endothelial layers to facilitate tumor cell reattachment. Confocal microscopy shows that microtentacles are capable of penetrating the junctions between endothelial cells. Suppression of endogenous Twist in metastatic human breast tumor cells is capable of reducing both tubulin detyrosination and microtentacles. Clinical breast tumor samples display high concordance between Glu-tubulin and Twist expression levels, emphasizing the coupling between EMT and tubulin detyrosination in vivo. Coordinated elevation of Twist and Glu-tubulin at invasive tumor fronts, particularly within ductal carcinoma in situ samples, establishes that EMT-induced tubulin detyrosination occurs at the earliest stages of tumor invasion. These data support a novel model where the EMT that occurs during tumor invasion downregulates tubulin tyrosine ligase, increasing α-tubulin detyrosination and promoting microtentacles that could enhance the reattachment of circulating tumor cells to the vascular endothelium during metastasis.
Impact of Age and Primary Disease Site on Outcome in Women With Low-Grade Serous Carcinoma of the Ovary or Peritoneum: Results of a Large Single-Institution Registry of a Rare Tumor
Authors: David M. Gershenson, Diane C. Bodurka, Karen H. Lu, Lisa C. Nathan, Ljiljana Milojevic, Kwong K. Wong, Anais Malpica, Charlotte C. Sun
Journal: Journal of Clinical Oncology (2015)

Low-grade serous carcinoma of the ovary (LGSOC) or peritoneum (LGSPC) is a rare subtype of ovarian or peritoneal cancer characterized by young age at diagnosis and relative resistance to chemotherapy. The purpose of this study is to report our updated experience with women diagnosed with LGSOC or LGSPC to assess the validity of our original observations.Eligibility criteria for patients from our database were: stage I to IV LGSOC or LGSPC, original diagnosis before January 2012, and adequate clinical information. All patients were included in progression-free survival, overall survival, and multivariable Cox regression analyses. A subset analysis was performed among patients with stage II to IV low-grade serous carcinoma treated with primary surgery followed by platinum-based chemotherapy.We identified 350 eligible patients. Median progression-free survival was 28.1 months; median overall survival was 101.7 months. In the multivariable analysis, compared with women age ≤ 35 years, those diagnosed at age > 35 years had a 43% reduction in likelihood of dying (hazard ratio, 0.53; 95% CI, 0.37 to 0.74; P < .001). Having disease present at completion of primary therapy was associated with a 1.78 increased hazard of dying compared with being clinically disease free (P < .001). Similar trends were noted in the smaller patient cohort. In this cohort, women with LGSPC had a 41% decreased chance of dying (hazard ratio, 0.59; 95% CI, 0.36 to 0.98; P = .04) compared with those with LGSOC.Women age < 35 years with low-grade serous carcinoma and those with persistent disease at completion of primary therapy have the worst outcomes. Patients with LGSPC seem to have a better prognosis than those with LGSOC.
Human Brain Malformations and Their Lessons for Neuronal Migration
Authors: M Elizabeth Ross, Christopher A Walsh
Journal: Annual Review of Neuroscience (2001)

▪ Abstract The developmental steps required to build a brain have been recognized as a distinctive sequence since the turn of the twentieth century. As marking tools for experimental embryology emerged, the cellular events of cortical histogenesis have been intensively scrutinized. On this rich backdrop, molecular genetics provides the opportunity to play out the molecular programs that orchestrate these cellular events. Genetic studies of human brain malformation have proven a surprising source for finding the molecules that regulate CNS neuronal migration. These studies also serve to relate the significance of genes first identified in murine species to the more complex human brain. The known genetic repertoire that is special to neuronal migration in brain has rapidly expanded over the past five years, making this an appropriate time to take stock of the emerging picture. We do this from the perspective of human brain malformation syndromes, noting both what is now known of their genetic bases and what remains to be discovered.
Haemodynamic effects of supraventricular tachycardias and their alterations by electrically and verapamil induced termination
Authors: M. SCHLEPPER, H. G. WEPPNER, H. MERLE
Journal: Cardiovascular Research (1978)

The haemodynamic effects of electrically initiated supraventricular tachycardias were studied in 10 otherwise healthy patients. With the beginning of the dysrhythmia there was a sharp decrease of systemic arterial and left ventricular systolic pressure, dP/dtmax, cardiac index, and stroke volume. Then, these parameters except stroke volume exhibited an increase, but were statistically different from control until the tachycardia was electrically stopped at the tenth minute. Mean pulmonary artery pressure rose steadily and remained on an elevated level which was reached between the third and fifth minute. After cessation there was a short augmentation of systemic arterial and left ventricular systolic pressure as well as of dP/dtmax and cardiac index. Mean pulmonary artery pressure steadily decreased and for all parameters control values were reached at about the third minute. When the tachycardia was terminated at about the same time by an i.v. injection of 10 mg of verapamil the 'post-tachycardial potentiation' was less marked or even absent. Mean arterial and left ventricular pressure was lower and mean pulmonary artery pressure remained elevated as compared with the values observed after electrical termination. Cardiac index and dP/dtmax showed no significant differences. It can be concluded that verapamil in a dosage sufficient to terminate the arrhythmia did not exhibit additional negative inotropic effects.
Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids
Authors: Robert F. Lemanske, David T. Mauger, Christine A. Sorkness, Daniel J. Jackson, Susan J. Boehmer, Fernando D. Martinez, Robert C. Strunk, Stanley J. Szefler, Robert S. Zeiger, Leonard B. Bacharier, Ronina A. Covar, Theresa W. Guilbert, Gary Larsen, Wayne J. Morgan, Mark H. Moss, Joseph D. Spahn, Lynn M. Taussig
Journal: New England Journal of Medicine (2010)

For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)
Management of septic shock.
Authors: J D Edwards
Journal: BMJ (1993)

There have been important advances in the resuscitation of patients in septic shock in recent years. Survival can be improved by earlier recognition and therefore eradication of the sepsis combined with logical supportive measures. As with any acutely ill patient consultation with intensive care unit staff may be useful. Consultation with the intensive care unit does not necessarily imply the need for admission and mechanical ventilation; helpful advice may be forthcoming. Equally, referral to the intensive care unit does not mean an admission of failure but merely a recognition that additional skills and technical facilities are necessary for the patient9s survival.
Interaction of NADPH oxidase 1 with Toll-like receptor 2 induces migration of smooth muscle cells
Authors: Jee Hyun Lee, Jung Hee Joo, Jinoh Kim, Hee Jung Lim, Sunah Kim, Linda Curtiss, Je Kyung Seong, Wenhao Cui, Chihiro Yabe-Nishimura, Yun Soo Bae
Journal: Cardiovascular Research (2013)

NADPH oxidase (Nox) isozymes that generate intracellular reactive oxygen species (ROS) and Toll-like receptor 2 (TLR2), an inflammatory mediator, are both involved in the development of atherosclerotic lesions. To identify the molecular connection between TLR2 and Nox isozymes in vascular remodelling, we analysed generation of ROS and pro-inflammatory cytokines in aortic smooth muscle cells from Nox1-deficient mice in response to the synthetic triacylated lipoprotein Pam3CSK, a TLR2 agonist. We showed that TLR2 signalling stimulates progression of the pro-inflammatory phenotype in mouse aortic smooth muscle cells (MASMCs) through activation of Nox1. We demonstrated the interaction of TLR2 with Nox1 using yeast two-hybrid and co-immunoprecipitation assays. MASMCs from Nox1-deficient mice failed to generate of ROS in response to Pam3CSK4, indicating that Nox1 is essential for TLR2-dependent production of ROS. We also found that Pam3CSK4 stimulated migration of MASMCs from wild-type mice in a Transwell system, but MASMCs from Nox1-deficient mice failed to show this response. Wild-type MASMCs produced matrix metalloprotease 2 in response to Pam3CSK4, whereas Nox1-deficient MASMCs failed to generate this protease. Moreover, stimulation of MASMCs with Pam3CSK4 resulted in increased expression of the pro-inflammatory cytokine macrophage inflammatory protein 2 in a Nox1-dependent manner, leading to enhanced monocyte-endothelial cell adhesion and trans-endothelial migration of U937 cells. These data suggest that Nox1 plays an important role in TLR2-mediated intracellular H2O2 generation, activation of matrix metalloprotease 2, and secretion of pro-inflammatory cytokines, which in turn stimulate MASMC migration and vascular remodelling.
Characterization of cardiac myocyte and tissue β-adrenergic signal transduction in rats with heart failure
Authors: Hiroyuki Yoshida, Kouichi Tanonaka, Yuki Miyamoto, Tsutomu Abe, Masaya Takahashi, Madhu B Anand-Srivastava, Satoshi Takeo
Journal: Cardiovascular Research (2001)

The cellular basis of alterations in beta-adrenergic signal transduction in rats with chronic heart failure (CHF) remains unclear. The aim of the present study was to examine this signal transduction system in isolated ventricular cardiomyocytes of rats with CHF. We focused on changes in the levels of stimulatory (Gs) and inhibitory G-proteins (Gi).CHF was induced in male Wistar rats by coronary artery ligation (CAL). Hemodynamic and biochemical parameters were measured 8 weeks after CAL. Alterations in contractile function and Ca(2+) transients via beta-adrenergic receptor signaling of cardiomyocytes isolated from rats with CHF were characterized by simultaneous measurements of cell shortening and fura-2 fluorescence intensity.Coronary artery-ligated rats showed symptoms of CHF, such as decreased contractile function, increased left ventricular volume, decreased chamber stiffness, and about 40% infarct formation of the left ventricle, by 8 weeks after surgery. The contractile function and Ca(2+) dynamics of cardiomyocytes from the rats with CHF remained normal under basal conditions. Only cardiac cell length was increased. The responses of peak shortening, fura-2 fluorescence ratio amplitude, and cAMP content to beta-adrenoceptor stimulation were reduced in cardiomyocytes of the rats with CHF, whereas direct stimulation of adenylate cyclase did not affect the response of these variables. Cardiomyocyte Gsalpha protein was decreased, whereas no changes in Gialpha proteins were seen in these cells. Increases in tissue Gsalpha and Gialpha proteins in the scar zone were detected. The results on tissue levels of collagen and G-proteins in the viable left ventricle appeared to depend on the presence of nonmyocytes.The results suggest that impaired contractile function of cardiomyocytes is unlikely to account for global LV contractile dysfunction, and that down-regulation of beta-adrenoceptors occurs in cardiomyocytes per se. The difference in changes of G-protein between the cardiomyocyte and myocardial tissue suggests an appreciable contribution of nonmyocytes to myocardial G-protein levels.
2007 Young Investigator Award
Authors: Michelle P. Winn
Journal: Journal of the American Society of Nephrology (2008)

FSGS is a pathologic lesion that frequently causes the nephrotic syndrome and ensuing renal failure. The cause remains unknown in the majority of individuals; however, in the past two decades, rare familial forms have been identified. It has been suggested that known genetic causes of the hereditary form of this disease account for upwards of 18% of cases. Mutations in five genes have been found to cause inherited nephrotic syndromes and FSGS. In this article, I discuss the phenotypic characteristics of hereditary FSGS and the transient receptor potential cation channel 6 (TRPC6) protein, which is the genetic impetus for an autosomal dominant form of FSGS. The TRP channels have been implicated in varied biologic functions such as mechanosensation, ion homeostasis, cell growth, and phospholipase C-dependent calcium entry into cells. The mutated ion channel causes an increase in calcium transients. Current evidence also suggests that blocking TRPC6 channels may be of therapeutic benefit in idiopathic FSGS, a disease with a generally poor prognosis. Preliminary experiments reveal that the commonly used immunosuppressive agent FK-506 can inhibit TRPC6 activity in vivo. This creates the intriguing possibility that blocking TRPC6 channels within the podocyte may translate into long-lasting clinical benefits in patients with FSGS.