tbuckley/cabot-search huggingface dataset:
Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia
Authors: Damiano Rondelli, Giovanni Barosi, Andrea Bacigalupo, Josef T. Prchal, Uday Popat, Emilio P. Alessandrino, Jerry L. Spivak, B. Douglas Smith, Hans G. Klingemann, Steven Fruchtman, Ronald Hoffman
Journal: Blood (2005)
Combination Bcl-2 Antisense and Radiation Therapy for Nasopharyngeal Cancer
Authors: Kenneth W. Yip, Joseph D. Mocanu, P.Y. Billie Au, Gillian T. Sleep, Dolly Huang, Pierre Busson, Wen-Chen Yeh, Ralph Gilbert, Brian O'Sullivan, Patrick Gullane, Carlo Bastianutto, Fei-Fei Liu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: A wide variety of tumors depend on the dysregulation of Bcl-2 family proteins for survival. The resulting apoptotic block can often provide a mechanism for resistance to anticancer treatments, such as chemotherapy and radiation. This current study evaluates the efficacy of combining systemically delivered Bcl-2 phosphorothioate antisense (Bcl-2 ASO) and radiation for nasopharyngeal cancer therapy. Results: Antisense uptake was unaffected by 0, 3, or 6 Gy radiation. Radiation decreased the fraction of viable C666-1 cells to 60%, with a further decrease to 40% in combination with Bcl-2 ASO. Despite a modest in vitro effect, Bcl-2 ASO alone caused the regression of established xenograft tumors in mice, extending survival by 15 days in a C666-1 and by 6 days in a C15 model. The survival times for mice treated with both Bcl-2 ASO and radiation increased by 52 days in C666-1 and by 20 days in C15 tumors. This combination resulted in a more-than-additive effect in C666-1 tumors. Less impressive gains observed in C15 tumors might be attributable to higher expression of antiapoptotic Bcl-2 family proteins and limited drug distribution in the tumor. Retreatment of C666-1 tumors with the Bcl-2 ASO-radiation combination, however, was effective, resulting in mice surviving for &amp;gt;80 days relative to untreated controls. Conclusions: Our results show that the Bcl-2 ASO and radiation combination is a highly potent therapy for nasopharyngeal cancer. Further examination of combination therapy with radiation and other Bcl-2 family–targeted anticancer agents in both preclinical and clinical settings is definitely warranted.
Short Gastric Veins as the Major Portal of Entry for Milk-Borne Murine Mammary Tumor Virus23
Authors: Jirayr R. Roubinian, Phyllis B. Blair
Journal: JNCI Journal of the National Cancer Institute (1980)

The flow pattern of the short gastric veins that drain the fundic portion of the stomach appeared to influence mammary tumorigenesis. In I and C57BL mice, strains that are highly resistant to murine mammary tumor virus (MuMTV)-induced mammary tumorigenesis, the short gastric veins empty directly into the splenic vein outside the spleen, connecting with the portal system. In (C57BL × I)F1 mice, which are highly susceptible to MuMTV-induced mammary tumorigenesis, the short gastric veins empty directly into the superior hilus of the spleen, connecting with the splenic parenchyma. Neonatal sple-nectomy or cauterization of the short gastric veins of (C57BL × I)F1 mice prior to the introduction of MuMTV by foster-nursing delayed the onset and reduced the final incidence of mammary tumors. When neonatal splenectomy was performed after milk-borne MuMTV introduction, it caused premature appearance of mammary tumors without affecting the final tumor incidence. In A, BALB/c, C3H, DBA/2, GR, and RIII mice, strains that are susceptible to MuMTV-induced mammary tumorigenesis, the short gastric veins also empty into the superior hilus of the spleen. Our findings suggest that susceptibility to mammary tumorigenesis may depend on the direct entry of milk-borne MuMTV into the splenic environment through the short gastric veins that drain the fundus of the stomach.
Issues in training the female player
Authors: Donald T Kirkendall
Journal: British Journal of Sports Medicine (2007)

On the surface, the women’s game appears to be similar to the men’s game. On closer examination, there are subtle differences in the nature of how each gender plays the game, which are evident in the disparity between skills, tactics and fitness. The technical weaknesses of women include the first touch, dribbling, long passing and goal keeping. These skill limitations have dictated specific tactical approaches towards both attack and defence. Specific biological limitations inherent in the female player affect the pace and total work output in the women’s game. Although it is unrealistic to expect the women’s game to approach the work output of the men’s game, specific training of skills and fitness will influence the tactical approach to the game.
Effects of Rapamycin on Ryanodine Receptor/Ca <sup>2+</sup> -Release Channels From Cardiac Muscle
Authors: Edward Kaftan, Andrew R. Marks, Barbara E. Ehrlich
Journal: Circulation Research (1996)

Abstract Ryanodine receptors (RyRs) are intracellular channels that regulate the release of Ca 2+ from the endoplasmic reticulum of many cell types. The RyRs are physically associated with FK506-binding proteins (FKBPs); immunophilins, with cis - trans peptidyl-prolyl isomerase activity. FKBP12 copurifies with RyR1 (skeletal isoform) and modulates its gating. A different form of FKBP with a slightly higher molecular weight copurifies with RyR2 (cardiac isoform). Previous studies have demonstrated that FKBP stabilizes gating of the skeletal Ca 2+ -release channel. In the present study, we measured the activity of cardiac RyRs incorporated into planar lipid bilayers to show that rapamycin, a drug that inhibits the prolyl isomerase activity of FKBP and dissociates FKBP from the RyR, increases the open probability and reduces the current amplitude of cardiac muscle Ca 2+ -release channels. These experiments show for the first time that submicromolar concentrations of rapamycin can alter channel function. Our results provide support for the hypotheses that FKBP functionally associates with the RyR and that the immunosuppressant drug, rapamycin, alters the function of both cardiac and skeletal muscle isoforms of the Ca 2+ -release channel. Our findings suggest that FKBP-dependent modulation of channel function may be generally applicable to all members of the intracellular Ca 2+ -release channel family and that FKBPs may play important regulatory roles in many cell processes, ranging from long-term depression in neurons to contractility in cardiomyocytes.
The Dictyostelium genome encodes numerous RasGEFs with multiple biological roles.
Authors: Andrew Wilkins, Karol Szafranski, Derek J Fraser, Deenadayalan Bakthavatsalam, Rolf Müller, Paul R Fisher, Gernot Glöckner, Ludwig Eichinger, Angelika A Noegel, Robert H Insall
Journal: Genome biology (2005)

Dictyostelium discoideum is a eukaryote with a simple lifestyle and a relatively small genome whose sequence has been fully determined. It is widely used for studies on cell signaling, movement and multicellular development. Ras guanine-nucleotide exchange factors (RasGEFs) are the proteins that activate Ras and thus lie near the top of many signaling pathways. They are particularly important for signaling in development and chemotaxis in many organisms, including Dictyostelium.We have searched the genome for sequences encoding RasGEFs. Despite its relative simplicity, we find that the Dictyostelium genome encodes at least 25 RasGEFs, with a few other genes encoding only parts of the RasGEF consensus domains. All appear to be expressed at some point in development. The 25 genes include a wide variety of domain structures, most of which have not been seen in other organisms. The LisH domain, which is associated with microtubule binding, is seen particularly frequently; other domains that confer interactions with the cytoskeleton are also common. Disruption of a sample of the novel genes reveals that many have clear phenotypes, including altered morphology and defects in chemotaxis, slug phototaxis and thermotaxis.These results suggest that the unexpectedly large number of RasGEF genes reflects an evolutionary expansion of the range of Ras signaling rather than functional redundancy or the presence of multiple pseudogenes.
Baseline Cytology, Human Papillomavirus Testing, and Risk for Cervical Neoplasia: A 10-Year Cohort Analysis
Authors: M. E. Sherman, A. T. Lorincz, D. R. Scott, S. Wacholder, P. E. Castle, A. G. Glass, I. Mielzynska-Lohnas, B. B. Rush, M. Schiffman
Journal: JNCI Journal of the National Cancer Institute (2003)

Annual Pap smear screening has been favored over less frequent screening in the United States to minimize the risk of cervical cancer. We evaluated whether simultaneous screening with a Pap test and human papillomavirus (HPV) testing is useful for assessing the risk for cervical intraepithelial neoplasia (CIN) 3 or cervical cancer.We enrolled 23 702 subjects in a study of HPV infection at Kaiser Permanente, Northwest Division, Portland, OR. Data were analyzed for 20 810 volunteers who were at least 16 years old (mean = 35.9 years) with satisfactory baseline Pap tests and suitable samples for HPV testing. Women were followed for up to 122 months (from April 1, 1989, to June 30, 1999) to determine the risk for histopathologically confirmed CIN3 or cancer.Among 171 women with CIN3 or cancer diagnosed over 122 months, 123 (71.9%, 95% confidence interval [CI] = 65.2% to 78.7%) had baseline Pap results of atypical squamous cells or worse and/or a positive HPV test, including 102 (86.4%, 95% CI = 80.3% to 92.6%) of the 118 cases diagnosed within the first 45 months of follow-up. During this 45-month period, the cumulative incidence of CIN3 or cancer was 4.54% (95% CI = 3.61% to 5.46%) among women with a Pap test result of atypical squamous cells or worse, positive HPV tests, or both compared with 0.16% (95% CI = 0.08% to 0.24%) among women with negative Pap and HPV tests. Age, screening behavior, a history of cervical cancer precursors, and a history of treatment for CIN minimally affected results.Negative baseline Pap and HPV tests were associated with a low risk for CIN3 or cancer in the subsequent 45 months, largely because a negative HPV test was associated with a decreased risk of cervical neoplasia. Negative combined test results should provide added reassurance for lengthening the screening interval among low-risk women, whereas positive results identify a relatively small subgroup that requires more frequent surveillance.
Targeting the Phosphoinositide 3-Kinase Isoform p110δ Impairs Growth and Survival in Neuroblastoma Cells
Authors: Danielle Boller, Alexander Schramm, Kathrin T. Doepfner, Tarek Shalaby, André O. von Bueren, Angelika Eggert, Michael A. Grotzer, Alexandre Arcaro
Journal: Clinical Cancer Research (2008)

The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in neuroblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in neuroblastoma.The expression pattern and functions of class I(A) PI3K isoforms were investigated in tumor samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha or p110delta in SH-SY5Y and LA-N-1 cells by means of RNA interference.Overexpression of the catalytic p110delta and regulatory p85alpha isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110alpha or p110delta led to impaired cell growth, reduced expression of p110delta also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110delta were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110delta levels also displayed reduced activation of ribosomal protein S6 kinase in response to stimulation with epidermal growth factor and insulin-like growth factor-I.Together, our data reveal a novel function of p110delta in neuroblastoma growth and survival.
Regulation of autoimmunity and donor cell engraftment by recipient Lyt-2+ cells during the graft-versus-host reaction.
Authors: S E Harper, J R Roubinian, W E Seaman
Journal: The Journal of Experimental Medicine (1987)

When lymphocytes from DBA/2 mice are transferred to (C57BL X DBA/2)F1 (BDF1) mice, the ensuing graft-vs.-host reaction (GVHR) causes an autoimmune illness resembling human SLE. To examine the role of recipient T cells in this process, BDF1 mice were depleted of L3T4+ or Lyt-2+ cells by thymectomy followed by treatment with mAbs to L3T4 or Lyt-2. This produced sustained depletion of these T cell subsets. Subsequent grafting with parental DBA/2 lymphocytes produced autoimmune disease in mice depleted of L3T4+ cells and controls but not in mice depleted of Lyt-2+ cells. Analysis of blood lymphocytes 4 wk after donor cell transfer demonstrated that BDF1 recipients depleted of Lyt-2+ cells were virtually repopulated with donor T lymphocytes, compared with less than or equal to 35% donor cell engraftment in all other groups. Thus, recipient Lyt-2+ cells influence both host cell engraftment and autoimmunity during the parent-into-F1 GVHR.
Avoiding axillary dissection in breast cancer surgery: a randomized trial to assess the role of axillary radiotherapy
Authors: U. Veronesi, R. Orecchia, S. Zurrida, V. Galimberti, A. Luini, P. Veronesi, G. Gatti, G. D'Aiuto, L. Cataliotti, R. Paolucci, P. Piccolo, N. Massaioli, P. Sismondi, A. Rulli, F. Lo Sardo, A. Recalcati, D. Terribile, A. Acerbi, N. Rotmensz, P. Maisonneuve
Journal: Annals of Oncology (2005)
Effect of Fine Mechanical Filter Air Cleaner on the Removal of House Dust Mite Allergens
Authors: S.R. Agrawal, Y.W. Lee, H.J. Kim, J.H. Sohn, J.Y. Kim, K.Y. Jeong, Y.J. Kim, S.H. Lee, C.S. Hong, J.W. Park
Journal: Journal of Allergy and Clinical Immunology (2009)
Insights into cancer mechanisms from genomic research on urological cancers
Authors: Wolfgang A Schulz, Teodora Ribarska
Journal: Genome Medicine (2011)

Molecular mechanisms driving cancer development and progression are rarely unique to one cancer type. Rather, recent genomic studies of urological cancers suggest that common mechanisms recur with variations. Examples include alterations in hypoxia response regulation, epigenetic regulator proteins, and signal transduction pathways in renal, prostatic and urothelial carcinomas. Consideration of these variations alongside the common basic cancer mechanisms might be important for the successful development of targeted therapies.
Ovarian reserve testing and the use of prognostic models in patients with subfertility
Authors: A. Bukman
Journal: Human Reproduction Update (2001)

The decline in fecundity with female age is a well-known phenomenon for clinicians dealing with subfertility patients. Diminishing ovarian reserve seems to be the reason for declining fecundity. Since age is only a rough estimate of ovarian reserve, many tests have been developed to predict ovarian reserve more precisely. This review focuses on these ovarian reserve tests and their clinical role in predicting response to ovarian stimulation and pregnancy chances. According to our analysis, the clomiphene citrate challenge test has the strongest correlation in predicting ovarian reserve, and is the only test that is validated in the general infertility population. The antral follicle count by ultrasound is promising and may offer clinical use. It is not known whether a combination of tests can provide more accurate information of ovarian reserve. It is not yet clear to which extent the results of ovarian reserve tests can be incorporated into the available prognostic models. There is a need for prospective cohort studies that focus on prognostic factors among which are the results of ovarian reserve tests. Only then can the qualitative and quantitative relevance of ovarian reserve testing in the context of the prognosis for couples with subfertility be established.
Proteome‐wide analyses of human hepatocytes during differentiation and dedifferentiation
Authors: Cliff Rowe, Dave T. Gerrard, Roz Jenkins, Andrew Berry, Kesta Durkin, Lars Sundstrom, Chris E. Goldring, B. Kevin Park, Neil R. Kitteringham, Karen Piper Hanley, Neil A. Hanley
Journal: Hepatology (2013)

Failure to predict hepatotoxic drugs in preclinical testing makes it imperative to develop better liver models with a stable phenotype in culture. Stem cell-derived models offer promise, with differentiated hepatocyte-like cells currently considered to be "fetal-like" in their maturity. However, this judgment is based on limited biomarkers or transcripts and lacks the required proteomic datasets that directly compare fetal and adult hepatocytes. Here, we quantitatively compare the proteomes of human fetal liver, adult hepatocytes, and the HepG2 cell line. In addition, we investigate the proteome changes in human fetal and adult hepatocytes when cultured in a new air-liquid interface format compared to conventional submerged extracellular matrix sandwich culture. From albumin and urea secretion, and luciferase-based cytochrome P450 activity, adult hepatocytes were viable in either culture model over 2 weeks. The function of fetal cells was better maintained in the air-liquid interface system. Strikingly, the proteome was qualitatively similar across all samples but hierarchical clustering showed that each sample type had a distinct quantitative profile. HepG2 cells more closely resembled fetal than adult hepatocytes. Furthermore, clustering showed that primary adult hepatocytes cultured at the air-liquid interface retained a proteome that more closely mimicked their fresh counterparts than conventional culture, which acquired myofibroblast features. Principal component analysis extended these findings and identified a simple set of proteins, including cytochrome P450 2A6, glutathione S transferase P, and alcohol dehydrogenases as specialized indicators of hepatocyte differentiation.Our quantitative datasets are the first that directly compare multiple human liver cells, define a model for enhanced maintenance of the hepatocyte proteome in culture, and provide a new protein "toolkit" for determining human hepatocyte maturity in cultured cells.
Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant <i>Mycobacterium tuberculosis</i> through Efflux
Authors: Gail E. Louw, Robin M. Warren, Nicolaas C. Gey van Pittius, Rosalba Leon, Adelina Jimenez, Rogelio Hernandez-Pando, Christopher R. E. McEvoy, Melanie Grobbelaar, Megan Murray, Paul D. van Helden, Thomas C. Victor
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.Objective: To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.Methods: Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.Measurements and Main Findings: Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).Conclusion: Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment.
Role of gastric atrophy in mediating negative association between Helicobacter pylori infection and reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma
Authors: K. E L McColl, H. Watabe, M. H Derakhshan
Journal: Gut (2008)

The incidence of oesophageal adenocarcinoma has increased markedly over the past three decades, particularly in the Western world.1 2 The cancer is considered to be a long-term complication of chronic oesophageal mucosal damage produced by acidic gastric refluxate. The gastric juice, which also contains pepsin and intermittently bile, produces ulceration of the oesophageal squamous mucosa, and in some individuals the mucosa undergoes columnar metaplasia to resemble that of the gastric antrum or small or large intestine. This metaplastic mucosa referred to as Barrett’s oesophagus is believed to be the precursor of oesophageal adenocarcinoma. Though the evidence for the increasing incidence of oesophageal adenocarcinoma is unequivocal and there is also some evidence of an increase in Barrett’s oesophagus,3 the evidence for an increase in the incidence of reflux oesophagitis is less robust. However, this may simply be due to the problem in obtaining reliable population incidence rates for reflux oesophagitis.

The rapid rise in incidence of oesophageal adenocarcinoma indicates a change in the environment, and there is considerable interest in identifying the responsible factor or factors. Increased body weight due to dietary and lifestyle factors is a strong candidate. Body mass index (BMI) has been progressively increasing over the past few decades in the Western world, and there is a strong positive association between BMI and oesophageal adenocarcinoma.4

Another environmental candidate for explaining the rising incidence of oesophageal adenocarcinoma is loss of a protective effect related to Helicobacter pylori infection. The prevalence of H pylori infection has been falling in the Western world over recent decades, thus showing the opposite trend to oesophageal adenocarcinoma.5 In addition, numerous studies have demonstrated a negative association between H pylori infection and reflux oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma.6–10 There is also a plausible, biological mechanism by which …
Do GPs deserve their pay rise?
Authors: Denis Colligan
Journal: BMJ (2005)

Editor—Many people (non-general practitioners) must surely be asking, “So, how much do GPs earn?” when considering whether general practitioners deserve their recent pay rise.1

The answer is quite a lot. Full time general practitioner principals in well organised practices would be disappointed to earn less than £100 000 a year for 2004-5. The range can be considerable, given the differing circumstances in which doctors work; for full time principals it is £80 000-£120 000. For 2006-7 the quality points will be worth on average (depending on practice size) £120 per point, compared with £70 this year.

Don't forget, general practitioners have dropped the 24 hour responsibility and so are now working something in the region of a 45-55 hour week.