tbuckley/cabot-search huggingface dataset:
Abstract 13113: Dipeptidyl Peptidase 4 Inhibition Ameliorates Hypertensive Heart Failure via Suppression of Angiotensin-ii-mediated Cardiac Na+/h+ Exchanger1 Pathway
Authors: Haruya Kawase, Yasuko K Bando, Morihiko Aoyama, Akio Monji, Toko Mitsui, Toyoaki Murohara
Journal: Circulation (2014)

Introduction: Hypertension is primary cause of heart failure (HF). Several reports demonstrated the blood-pressure (BP)-lowering property of dipeptidyl peptidase 4 (DPP4) inhibitors. Hypothesis: We tested the effect of a new DPP4 inhibitor teneligliptin on BP and HF using preclinical models. Methods: Spontaneously hypertensive rats (SHR; 10 week-old male) and normotensive counterpart (WKY) were treated with TEN (10mg/kg/day) for 4 weeks. Hypertensive HF was evaluated in terms of BP, cardiac function, histological remodeling, and pulmonary congestion. Results: Cardiac catheterization revealed that TEN ameliorated hypertension of SHR-CON (Fig.1). The maximum dP/dt of SHR-CON was elevated (10452±539 for SHR-CON and 5739±599 for WKY-CON), which was reduced by TEN (8033±656 in SHR-TEN) without affecting heart rate. Diastolic indices (minimum dP/dt and tau) were ameliorated by TEN. SHR-CON exhibited increase in heart and body weight (BW) ratio, left ventricular (LV) wall thickness, cardiomyocyte hypertrophy and fibrosis, which were attenuated by TEN. Elevated lung weight and BW ratio and circulating BNP level of SHR-CON were ameliorated by TEN. Cardiac and circulating DPP4 activities of SHR-CON were elevated, which was suppressed by TEN. Vasorelaxant signaling (Akt/eNOS) of each aorta and heart remained unaffected by TEN. Circulating angiotensin-2 (AT-II) was elevated in SHR-CON, which was suppressed by TEN without affecting ACE activity (Fig1). Because DPP4 interacts with Na+/H+ exchanger (NHE)-1 and -3, and NHE1 is related to hypertension and cardiac hypertrophy. In SHR-CON heart, NHE1 expression was elevated (Fig1), which was decreased by TEN. NHE-1 of cultured cardiomyocytes was upregulated by AT-II. Conclusions: TEN ameliorates hypertensive HF via normalizing elevated AT-II through an ACE-independent pathway, leading to reversal of hypertensive cardiac remodeling modulated by pathological AT-II/NHE-1 axis.
Evolutionary Paths That Expand Plasmid Host-Range: Implications for Spread of Antibiotic Resistance
Authors: Wesley Loftie-Eaton, Hirokazu Yano, Stephen Burleigh, Ryan S. Simmons, Julie M. Hughes, Linda M. Rogers, Samuel S. Hunter, Matthew L. Settles, Larry J. Forney, José M. Ponciano, Eva M. Top
Journal: Molecular Biology and Evolution (2015)

The World Health Organization has declared the emergence of antibiotic resistance to be a global threat to human health. Broad-host-range plasmids have a key role in causing this health crisis because they transfer multiple resistance genes to a wide range of bacteria. To limit the spread of antibiotic resistance, we need to gain insight into the mechanisms by which the host range of plasmids evolves. Although initially unstable plasmids have been shown to improve their persistence through evolution of the plasmid, the host, or both, the means by which this occurs are poorly understood. Here, we sought to identify the underlying genetic basis of expanded plasmid host-range and increased persistence of an antibiotic resistance plasmid using a combined experimental-modeling approach that included whole-genome resequencing, molecular genetics and a plasmid population dynamics model. In nine of the ten previously evolved clones, changes in host and plasmid each slightly improved plasmid persistence, but their combination resulted in a much larger improvement, which indicated positive epistasis. The only genetic change in the plasmid was the acquisition of a transposable element from a plasmid native to the Pseudomonas host used in these studies. The analysis of genetic deletions showed that the critical genes on this transposon encode a putative toxin–antitoxin (TA) and a cointegrate resolution system. As evolved plasmids were able to persist longer in multiple naïve hosts, acquisition of this transposon also expanded the plasmid’s host range, which has important implications for the spread of antibiotic resistance.
Vermont adopts Tarasoff: a real barn-burner
Authors: A A Stone
Journal: American Journal of Psychiatry (1986)

A recent Vermont Supreme Court decision adopts and extends the Tarasoff precedent. This paper emphasizes three aspects of the new precedent that are of possible consequence to providers of mental health care. First, the decision imposes the Tarasoff duty on all "mental health professionals". Second, it demonstrates a legal scenario that in effect permits a single standard of care to be applied to all mental health professionals. Third, it creates liability for property damage as well as for personal injury.
Ig class-specific targeting of the B-cell receptor complex.
Authors: S. Welt, D. Kostyal
Journal: Journal of Clinical Oncology (2010)

e18553 Background: The B-cell receptor complex (BCRC) comprises an assembly of membrane-associated proteins in a lipid raft. Included in this complex is membrane Ig (mIg), which is associated with phosphotyrosine kinase signal transduction proteins CD79 a and b and spleen tyrosine kinase. The membrane B-cell receptors are constructed of homologues of their circulating immunoglobulin counterparts with an additional extracellular domain in proximity to the trans-membrane peptide. There are 8 specific sequences in the human genome for these domains: one each for mIgM, mIgG, mIgD, two variants for mIgE and three sequences for mIgA. We investigated whether these domains contain sequence homology to known proteins in order to gain insight into their function and evaluate their specificity. Methods: Using the Blast (Basic Local Alignment Search Tool) homology search engine we compared all 8 sequences to data in the human genome bank (UniProtKB/Swiss-Prot). In addition, specificity of sequences was confirmed by PCR analysis of cell lines of B-cell lineage compared to non-B-cell lines or epithelial derived cancer cell lines. Results: In each case, based on possible amino acid alignments, no homologies could be identified. In one case, mIgM, the intracellular peptide may be a single amino acid suggesting that trans-membrane signaling may be mediated through these unique (extracellular) sequences or by the hydrophobic trans-membrane peptide. PCR results confirmed the restricted expression of these unique peptide sequences. Non B-cell derived malignant cell lines do not express these unique sequences aberrantly. Conclusions: As a consequence of the uniqueness and specificity of these mIg sequences, we hypothesize that mIg trans-membrane signaling functions may reside in these domains. Thus these peptide sequences are relevant Ig-class specific targets for B-cell modulating drugs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Welt Bio-Molecular Pharmaceutical, LLC Welt Bio-Molecular Pharmaceutical, LLC Welt Bio-Molecular Pharmaceutical, LLC Welt Bio-Molecular Pharmaceutical, LLC
Abstract P182: Gender Difference in Response to Lifestyle Therapy in Obese Children with Combined Dyslipidemia
Authors: Rebecca Pratt, Donna Quinzi, Rae-Ellen W Kavey
Journal: Circulation (2012)

Combined dyslipidemia(CDL) [moderate to severe elevation in triglyceride (TG), decreased HDL-cholesterol (HDL), mild elevation in total (TC) and LDL-cholesterol (LDL)] is common in obese children. Primary treatment is lifestyle change. We reviewed the response to a standard staged approach in consecutive children with CDL referred to a pediatric cardiology prevention clinic who returned for follow-up(F/U). The clinical protocol uses the same physician/ registered dietitian team to prescribe a change in diet composition (fat free milk; no sugar-sweetened beverages; simple carbohydrates replaced with complex carbohydrates) and daily exercise (1/2 hr/d of moderate exercise beyond current activity). Patients return at 3 m intervals and are discharged when TG and LDL have normalized; calorie control and/or medication are not introduced until the primary approach has been unsuccessful at second F/U. Over the last 21 mos, 53 pts(52 % male) have been managed with this approach. At baseline (B/L), mean age was 12.9+3y with no significant difference between males(Ms) and females(Fs). In 94%, B/L BMI was &gt; 95 th %ile. RESULTS (mean + SD): ALL F/U 1 F/U 2 MALE F/U 1 F/U 2 FEMALE F/U 1 F/U 2 B/L B/L B/L TC 213+38 194+42 190+41 208+33 187+39 186+40 220+42 202+44 195+42 TG 282+136 205+110 193+98 283+131 182+78 173+89 279+141 230+133 215+105 HDL 40+12 39+10 40+10 39+8 38+7 39+7 41+15 41+13 41+12 LDL 127+41 118+39 114+41 123+40 115+40 110+43 132+44 121+39 119+38 For all pts, there was a significant mean decrease in TC (p=.007) and TG (p=.001) at the first F/U visit, sustained at second F/U with no significant change in LDL or HDL. The mean decrease in TC was similar in Ms(p=.028) and Fs(p=.022) but decrease in TG was greater in Ms(39%)(p=.0003) than in Fs (23%)(p=.036) (p=.059 between Ms and Fs). At F/U 2, 50% of Ms vs 20% of Fs had normalized TC and TG levels (p=.043). Although there was no specific approach to weight loss, mean BMI decreased by 0.4 kg/m 2 , with no difference between Ms and Fs. CONCLUSIONS: (1) A simple lifestyle change focused on change in diet composition and daily exercise can significantly improve CDL in obese children on short term F/U, without weight loss; (2) Normalization of the lipid profile is significantly more common in Ms than Fs. If confirmed in a prospective trial, these are potentially important findings for this large and growing patient group.
Senior citizens were routinely tested for “angel dust” in scam that led to $256m settlement
Authors: Owen Dyer
Journal: BMJ (2015)

One of the United States’ largest urine drug testing companies, Millennium Health, has agreed to pay $256m (£167m; €232m) to settle allegations that it fraudulently billed Medicare for hundreds of thousands of unnecessary drug tests on senior citizens and ran a kickback scheme designed to induce doctors to order the tests.

The agreement with the Department of Justice will resolve eight whistleblower suits filed by former company employees and clinics that did business with Millennium. The eight unnamed plaintiffs, whose suits were joined by the government under a provision of the False Claims Act, will share about $31m of the settlement.

In court filings, federal prosecutors described a company dominated by a “culture of greed, intimidation and intense sales pressure.” The core business was urine testing of patients on opioid therapy, normally done …
Induction of Lymphosarcoma in Sheep by Bovine Leukemia Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: S J Kenyon, J F Ferrer, R A McFeely, D C Graves
Journal: JNCI Journal of the National Cancer Institute (1981)

Newborn sheep inoculated with phytohemagglutinin (PHA)-treated short-term, cultures of lymphocytes from cattle infected with bovine leukemia virus (BLV) or with a BLV- infected long-term culture of bovine leukemic lymphocytes became persistently infected with BLV. Fifty percent or more of the sheep died with histologically confirmed lymphosarcomas. Cytogenetic studies of representative cases demonstrated that the tumors did not result from the progressive growth of neoplastic lymphocytes in the inoculum but rather from the neoplastic transformation of the recipients lymphoid cells. Neither BLV infection nor lymphosarcoma was observed in control uninoculated sheep or in sheep given injections of PHA-treated cultures of lymphocytes from BLV-free cows. The virus recovered from the tumorous sheep was indistinguishable from BLV morphologically, antigenically, and biologically, and its reverse transcriptase had the same cation preference and immunologic properties as the BLV enzyme. Persistent BLV infection and lymphosarcoma were also observed in a group of sheep inoculated neonatally with BLV-containing cell-free culture supernatants. These results extend previous observations on the high susceptibility of sheep to BLV infection and provide definitive evidence that BLV is a tumor-inducing virus.
구연 : 간세포암으로 간이식을 받은 환자에서 Milan 기준과 UCSF 기준에 대한 전산화단층검사의 정확성과 예후와의 연관성
Authors: 유찬란, 장정원, 김진동, 송명준, 배시현, 윤승규, 조세현, 한준열, 한남익, 이영석
Journal: Clinical and Molecular Hepatology (2009)
Computationally Efficient Composite Likelihood Statistics for Demographic Inference
Authors: Alec J. Coffman, Ping Hsun Hsieh, Simon Gravel, Ryan N. Gutenkunst
Journal: Molecular Biology and Evolution (2015)

Many population genetics tools employ composite likelihoods, because fully modeling genomic linkage is challenging. But traditional approaches to estimating parameter uncertainties and performing model selection require full likelihoods, so these tools have relied on computationally expensive maximum-likelihood estimation (MLE) on bootstrapped data. Here, we demonstrate that statistical theory can be applied to adjust composite likelihoods and perform robust computationally efficient statistical inference in two demographic inference tools: ∂a∂i and TRACTS. On both simulated and real data, the adjustments perform comparably to MLE bootstrapping while using orders of magnitude less computational time.
Rescue of a Transforming Virus From a Spontaneous Nonproducing Osteosarcoma in BALB/c Mice
Authors: P. Bentvelzen, K. Nooter, B. F. Deys
Journal: JNCI Journal of the National Cancer Institute (1978)

Cells from spontaneous osteosarcoma V793 that originated in a 19-month-old female BALB/c mouse were cultured. They did not produce a C-type oncovirus as determined by extracellular reverse transcriptase assay and cytoplasmic immunofluorescence. After cocultivation with Balb/3T3 cells chronically infected with a murine leukemia virus (MuLV), a focus-forming principle that transformed 3T3 cells, secondary BALB/c mouse embryo and WAG/Rij rat embryo fibroblasts were rescued. The transformation could be inhibited by antiserum to MuLV.
Lung transplantation in patients with COPD
Authors: A Benrajab
Journal: Thorax (2008)

Both unilateral and bilateral lung transplantation in chronic obstructive pulmonary disease (COPD) can improve pulmonary function, exercise capacity and quality of life; however, whether lung transplantation actually improves survival is debated.

In this study, survival after transplantation of one or two lungs in end-stage COPD …
Chancellor is attacked for proposed four year pay freeze
Authors: Gareth Iacobucci
Journal: BMJ (2015)

The chancellor, George Osborne, has displayed a “cynical disregard for NHS staff” by announcing an effective four year pay freeze in his annual budget, the BMA has said.

In his 2015 budget speech on 8 July1 Osborne announced plans to restrict annual salary increases across the public sector to 1% over the next four years, equating to a pay freeze at best for many NHS staff when inflation is taken into account. The BMA’s chairman, Mark Porter, said that NHS staff were paying the price for “the government’s failure to put NHS finances on a sustainable footing.”

Osborne’s budget2 confirmed that the government would honour its pre-election pledge of an extra £8bn (€11.2bn; $12.3bn) a year in NHS funding above inflation by the end of this parliament in 2020—alongside the £2bn already announced for 2015-16.

The extra £8bn by 2020 was the figure outlined by NHS England’s chief executive, Simon Stevens, as necessary …
Androgen Control of Cytosol Progesterone Receptor Levels in the MT-W9B Transplantable Mammary Tumor in the Rat&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: M M Ip, R J Milholland, U Kim, F Rosen
Journal: JNCI Journal of the National Cancer Institute (1982)

The effect of androgen on the levels of the cytosol progesterone receptor was examined in the transplantable rat mammary tumor MT-W9B and in the normal uteri of inbred WF rats. Progesterone receptor levels were barely detectable in tumors grown in male WF rats but were increased after castration or administration of 17 beta-estradiol. Both effects were blocked by testosterone. In tumors grown in intact female rats, both testosterone and dihydrotestosterone decreased progesterone receptor levels in a dose-dependent manner, and testosterone completely blocked the estradiol-induced increase in progesterone receptor levels in tumors from ovariectomized rats. The inhibitory effect of testosterone in female rats was blocked by the antiandrogen flutamide, suggesting an androgen receptor-dependent mechanism. Neither dihydrotestosterone nor testosterone had any effect on basal levels of progesterone receptor in tumors from ovariectomized rats. In uterus, up to 5 mg dihydrotestosterone/kg did not affect progesterone receptor levels, and a dose of 5 mg/kg was also uterotropic. This fact plus the finding that testosterone only partially blocked the estradiol-induced increase in uterine progesterone receptor levels suggested stimulation of different cell types by testosterone and estradiol. This did not appear to be the case in the tumor, however. Androgen is suggested to act as a negative modulator of progesterone receptor levels, which might have clinical relevance in terms of hormone therapy of breast cancer.
Campaigners demand right to generic version of breast cancer drug
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

The authors describe a patient who experienced two successive strokes in the right hemisphere. After the first stroke, she showed stimulus-centered left neglect confined to right space on a circle discrimination task, which resolved. After the second stroke, she showed body-centered left neglect on the same task. These observations of two types of left neglect in the same patient suggest there are at least two distinct spatial attentional systems in the brain: global and focal attentional systems.
Camptothecin poly[n-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-I tumor therapy: intratumor release and antitumor efficacy.
Authors: Jürgen Dittmer
Journal: Molecular Cancer (2003)

Soluble copolymers of camptothecin (CPT), based on poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA), were obtained by conjugation through the degradable spacers -Gly-Phe-Leu-Gly- or -Gly-6-aminohexanoyl-Gly-. We investigated to what extent passive accumulation and retention of hydroxypropyl methacrylamide copolymer of CPT (pHPMA-CPT) in tumors and modulation of the drug release influence efficacy. Release of CPT in vivo was detected by time-resolved phase-shift fluorescence imaging on tumor specimens, based on the evidence that free and bound drug had different fluorescence lifetimes in solution. HT-29 murine specimens, obtained at several times after treatment with (3)H-labeled free CPT, pHPMA-Gly-Phe-Leu-Gly-CPT, or pHPMA-Gly-6-aminohexanoyl-Gly-CPT, were either imaged for time-resolved phase-shift fluorescence or subjected to autoradiography. Phase shifts of CPT conjugates were equal or longer than those of free CPT, indicating the presence of both free and polymer-bound drug in the tumor, in agreement with autoradiograms. pHPMA-Gly-Phe-Leu-Gly-CPT underwent relevant intratumor hydrolysis during the first 24 h, whereas the hydrolysis of pHPMA-Gly-6-aminohexanoyl-Gly-CPT was slow. The latter showed antitumor activity at doses from 10 to 22.5 mg/kg/day against s.c. HT-29, A2780, M14, and A549 s.c. xenografts. Moreover, inhibition of tumor growth lasted for up to 73-88 days, and cures were observed on mice with orthotopic implanted HT-29; pHPMA-Gly-Phe-Leu-Gly-CPT was 2-fold more potent than pHPMA-Gly-6-aminohexanoyl-Gly-CPT but less tolerated. Our data suggest that the efficacy of pHPMA-CPT copolymers is related to their intratumor accumulation, and in vivo properties of releasing CPT by esterolytic and proteolytic degradation.
Bone marrow-sparing and prevention of alopecia by AS101 in non-small-cell lung cancer patients treated with carboplatin and etoposide.
Authors: B Sredni, M Albeck, T Tichler, A Shani, J Shapira, I Bruderman, R Catane, B Kaufman, Y Kalechman
Journal: Journal of Clinical Oncology (1995)

PURPOSE The aim of this study was to evaluate the ability of the immunomodulator AS101 to prevent chemotherapy-induced neutropenia and thrombocytopenia and thus allow patients to receive full-dose antineoplastic agents according to protocol design. We also aimed to determine the production level of various hematopoietic growth factors in treated patients. PATIENTS AND METHODS This study of 44 unresectable or metastatic non-small-cell lung cancer (NSCLC) patients was an open-label prospective randomized study of standard chemotherapy alone versus chemotherapy plus AS101. Each patient received carboplatin (300 mg/m2 intravenously [IV] on day 1 of a 28-day cycle, and etoposide (VP-16) (200 mg/m2 orally) on days 3, 5, and 7 of each cycle. AS101 was administered at 3 mg/m2 three times per week starting 2 weeks before chemotherapy. RESULTS AS101, which manifested no major toxicity, significantly reduced neutropenia and thrombocytopenia and thus allowed all treated patients to receive full-dose antineoplastic agents, in contrast to only 28.5% of the control group. Continuous treatment with AS101 significantly reduced the number of days per patient of thrombocytopenia and neutropenia and did not provide protection to tumor cells as reflected by the higher overall response rate compared with the chemotherapy-alone arm. Interestingly, AS101 treatment also significantly prevented chemotherapy-induced alopecia. These effects correlate with the ability of AS101-treated patients to increase significantly the production of colony-stimulating factors (CSFs) interleukin-1 alpha (IL-1 alpha) and IL-6. CONCLUSION AS101 has significant bone marrow (BM)-sparing effects and prevents hair loss in chemotherapy-treated patients, with minimal overall toxicity. These effects are probably due to increased production of IL-1 alpha, IL-6, and granulocyte-macrophage (GM)-CSF.