tbuckley/cabot-search huggingface dataset:
Androgens stimulate early stages of follicular growth in the primate ovary.
Authors: K A Vendola, J Zhou, O O Adesanya, S J Weil, C A Bondy
Journal: Journal of Clinical Investigation (1998)

The concept that androgens are atretogenic, derived from murine ovary studies, is difficult to reconcile with the fact that hyperandrogenic women have more developing follicles than normal-cycling women. To evaluate androgen's effects on primate follicular growth and survival, normal-cycling rhesus monkeys were treated with placebo-, testosterone-(T), or dihydrotestosterone-sustained release implants, and ovaries were taken for histological analysis after 3-10 d of treatment. Growing preantral and small antral follicles up to 1 mm in diameter were significantly and progressively increased in number and thecal layer thickness in T-treated monkeys from 3-10 d. Granulosa and thecal cell proliferation, as determined by immunodetection of the Ki67 antigen, were significantly increased in these follicles. Preovulatory follicles (> 1 mm), however, were not increased in number in androgen-treated animals. Follicular atresia was not increased and there were actually significantly fewer apoptotic granulosa cells in the T-treated groups. Dihydrotestosterone treatment had identical effects, indicating that these growth-promoting actions are mediated by the androgen receptor. These findings show that, over the short term at least, androgens are not atretogenic and actually enhance follicular growth and survival in the primate. These new data provide a plausible explanation for the pathogenesis of "polycystic" ovaries in hyperandrogenism.
Randomized Trial of the Combination of Lomeguatrib and Temozolomide Compared With Temozolomide Alone in Chemotherapy Naive Patients With Metastatic Cutaneous Melanoma
Authors: Malcolm Ranson, Peter Hersey, Damien Thompson, Jane Beith, Grant A. McArthur, Andrew Haydon, Ian D. Davis, Richard F. Kefford, Peter Mortimer, Peter A. Harris, Sofia Baka, Augustus Seebaran, Ami Sabharwal, Amanda J. Watson, Geoffrey P. Margison, Mark R. Middleton
Journal: Journal of Clinical Oncology (2007)

To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma.Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m2 TMZ or 200 mg/m2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment.One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm.The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.
Abstract 1608: Silibinin synergizes with histone deacetylase (HDAC) inhibitors in upregulating E-cadherin expression in non-small lung cancer (NSCLC) cells
Authors: Samiha Mateen, Komal Raina, Chapla Agarwal, Daniel Chan, Rajesh Agarwal
Journal: Cancer Research (2012)

Abstract Lung cancer is the leading cause of cancer-related mortalities, and the 5-year survival rate of this malignancy remains at 15%. This feature is attributed primarily to the early metastasis of the disease within the organ and to distant sites that involves the epithelial-to-mesenchymal transition (EMT) of lung cancer cells. Aggressive cancer cells with EMT are characterized by loss of cell adhesion, repression of E-cadherin expression and increased cell mobility. NSCLC cells widely differ in their basal level of E-cadherin expression, which is epigenetically silenced in most of them due to deacetylation by histone deactylases. This suggests that inhibitors of HDACs would be useful in NSCLC control. Several HDAC inhibitors (HDACi) have shown potential in this regard, and are in clinical trials; however, their toxicity and cancer cell resistance are the limiting factors. Silibinin (Sb), a non-toxic chemopreventive agent, has shown strong efficacy against epithelial cancers including NSCLC, and previously, we have demonstrated that Sb alters HDAC enzymatic activity and protein levels in a total cellular extract of H1299 cells. Herein, we sought to determine the putative role of Silibinin, either alone or in combination with other HDACi in modulating E-cadherin levels in NSCLC cell lines including H1299 cells (epigenetically silent E-cadherin levels). Treatment with HDAC inhibitors, Trichostatin A [TSA] (0.33-1 µM) or SAHA (0.5-5 µM) led to a dose-dependent induction of E-cadherin expression levels. Furthermore, the combinations of TSA (0.5 µM) with low doses of Sb (3.75-25 µM) in H1299 cells, significantly increased E-cadherin protein levels (24h), which remained sustained at later time points (48-72h) longer than with TSA alone treatments. Also, at these time points, Zeb1, a major transcriptional repressor of E-cadherin, was inversely down-modulated with the combination treatments. Substantial inhibition of invasion/migration of H1299 cells with similar treatment conditions further emphasized the biological significance of E-cadherin restoration. Unlike H1299 cells, treatment of H322 and H358 cells (with detectable E-cadherin level) with Sb (3.75-25 µM) alone was sufficient to consistently increase the basal levels of E-cadherin, with concomitant reduction of Zeb1 levels, which also led to inhibition of migratory potential of these cells. Overall these findings demonstrate that Sb alone or in combination with HDAC inhibitors upregulates E-cadherin expression levels in NSCLC cell lines, and this consequently leads to inhibition of invasion/migratory phenotype of these cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1608. doi:1538-7445.AM2012-1608
Circulating cancer cells in division in an early breast cancer patient
Authors: M.J. Serrano, R. Nadal, J.A. Lorente, M. Salido, R. Rodríguez, M. Rodríguez, M. Macià, P. Sánchez-Rovira, J.M. Corominas, L. González, L. Vera, J. Albanell, F. Solé
Journal: Annals of Oncology (2011)
How does the law recognize and deal with medical errors?
Authors: Alan F Merry
Journal: Journal of the Royal Society of Medicine (2009)

Two percent of patients admitted to acute care hospitals suffer serious harm from healthcare errors. These errors come to the attention of the law through complaints from patients harmed by them but only a minority of people who suffer harm complain, and most complaints are resolved by local healthcare mechanisms. So the vast majority of medical errors are not dealt with (or even recognized by) the law.

The legal response to medical errors that do gain legal consideration is typically dominated by one or more of three goals: compensation, accountability and retribution. These each feature, with greater or lesser emphasis, in different national, legal and regulatory regimes ( Figure 1; Table 1). Legislation related to medical registration and professional discipline is often the major mechanism by which the law deals with errors. In practice, policy may be of greater importance than the law itself. In the UK, for example, the likelihood that a fatal hospital error will result in prosecution for manslaughter may have increased in recent years ( Figure 2) even though the relevant law has remained unchanged over this period. This probably reflects a change in prosecution policy.1



Figure 1

Dealing with accidental harm in health care: the elements of an appropriate response and some mechanisms by which these are usually provided (reproduced with permission from: Runciman B, Merry A, Walton M. Safety and Ethics in Healthcare: A Guide to Getting ...





Table 1

Some of the organizations and processes through which the law recognizes and deals with medical errors





Figure 2

Number of doctors prosecuted for manslaughter in the UK in 5-year periods from 1945 to 2004 (data provided by RE Ferner and SE McDowell)




The law, science, moral philosophy and medicine
The law, considered as a system of rules that govern the way people live together, is made effective in part by threat of punishment. From religious or deontological viewpoints, punishment may be seen as justified in its own right; but a consequentialist justification for punishing doctors who, through their medical errors, cause harm to patients, holds that this deters other doctors from making the same mistakes in the future. This argument depends on the questionable prior premise that it is actually possible to deter error. Empirical and theoretical considerations suggest that this notion is unsustainable, and that to punish those in error is unjust.
p21&lt;sup&gt;WAF&amp;ndash;1&amp;sol;CIP&amp;ndash;1&lt;/sup&gt;, a Downstream Regulator of Functional p53 Loss, in Transitional Cell Carcinoma of Urothelium
Authors: E. &Ouml;zdemir, Y. Kakehi, O. Yoshida
Journal: European Urology (2000)
Ergonovine echocardiography as a screening test for diagnosis of vasospastic angina before coronary angiography
Authors: Jae-Kwan Song, Simon Jong-Koo Lee, Duk-Hyun Kang, None Sang Sig Cheong, None Myeong Ki Hong, Jae-Joong Kim, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (1996)
UNC5B Receptor Deletion Exacerbates Tissue Injury in Response to AKI
Authors: Punithavathi Ranganathan, Calpurnia Jayakumar, Sutip Navankasattusas, Dean Y. Li, Il-man Kim, Ganesan Ramesh
Journal: Journal of the American Society of Nephrology (2013)

Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. We investigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B−/flox) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B−/flox/GGT-cre). Mice were subjected to two different models of organ injury: ischemia reperfusion injury of the kidney and cisplatin-induced nephrotoxicity. Both mouse models of UNC5B depletion had normal organ function and histology under basal conditions. After AKI, however, UNC5B−/flox/GGT-cre mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B−/flox and wild-type mice. shRNA-mediated suppression of UNC5B expression in cultured tubular epithelial cells exacerbated cisplatin-induced cell death in a p53-dependent manner and blunted Akt phosphorylation. Inhibition of PI3 kinase similarly exacerbated cisplatin-induced apoptosis; in contrast, overexpression of UNC5B reduced cisplatin-induced apoptosis in these cells. Taken together, these results show that the netrin-1 receptor UNC5B plays a critical role in cell survival and kidney injury through Akt-mediated inactivation of p53 in response to stress.
More Light Shed on Structure and Destruction of Plaque as Laser Angioplasty Research Heats Up
Authors: Marsha F. Goldsmith
Journal: JAMA (1987)

CARDIOLOGISTS who have been struggling for six years with the promises and pitfalls inherent in laser angioplasty seem heartened by remembrance of the late Andreas Grüntzig, MD. Grüntzig, a pioneer in the process of using balloon-tipped catheters to unblock stenosed cardiac vessels, succeeded in gaining clinical acceptance of the procedure—120 000 of which were done in this country in 1986—only after seven years of experimental effort. Speakers at the recent American Heart Association meeting in Dallas suggested that current research employing laser probes may reach fruition within two years. Even two years ago, according to Jeffrey M. Isner, MD, Tufts University School of Medicine-New England Medical Center, Boston, serious questions existed about using lasers for angioplasty. Since then, the number of successful intraoperative and percutaneous procedures carried out in humans (in the United States and in Great Britain) on an experimental basis, first in peripheral arteries (about 100 procedures) and
Determination of the entire sequence of turtle CR1: the first open reading frame of the turtle CR1 element encodes a protein with a novel zinc finger motif
Authors: M. Kajikawa, K. Ohshima, N. Okada
Journal: Molecular Biology and Evolution (1997)

CR1 elements are a family of retroposons. They are classified as long interspersed elements (LINEs) or non-long-terminal-repeat (non-LTR) retrotransposons, and they have been found in the genomes of many vertebrates. However, they have been only partially characterized, and only a 2-kb region of the 3' end of chicken CR1 has been sequenced. In the present study, we determined the entire consensus sequence of CR1 elements in the turtle genome, designated PsCR1. The first open reading frame (ORF1) of PsCR1 has two unusual arrangements of Cys residues. One of them includes a zinc finger motif, CX2CX14CX2C. The putative zinc finger has cysteine residues with identical spacing and a similar amino acid composition to those found in the species-specific transcription initiation factors SL1 and TIF-IB. The 5' untranslated region (5' UTR) of PsCR1 contains a sequence similar to part of the human L1 promoter, L1 site A, and several cis elements of the type found in eukaryotic genes. Within a region of about 500 bp, there are nine "E boxes," cis elements that are recognized by the basic helix-loop-helix (bHLH) family of proteins. This observation raises the possibility that cellular transcription factors that bind to these sequences might act in concert to regulate the expression of PsCR1. The extent of the sequence divergence of the 3' UTR of CR1 between species was found to be lower than the rate of nonsynonymous substitutions per site in ORF2, suggesting that a strict functional constraint must exist for this region. This result strongly suggests that the conserved 3'-end sequence of CR1 is the recognition site for the reverse transcriptase of CR1. A discussion is presented of a possible mechanism for the integration of CR1 elements and also of the intriguing possible recruitment of the reverse transcriptase for the retroposition of SINEs.
A Comparative Analysis of Influenza Vaccination Programs
Authors: Shweta Bansal, Babak Pourbohloul, Lauren Ancel Meyers
Journal: PLoS Medicine (2006)

Background The threat of avian influenza and the 2004–2005 influenza vaccine supply shortage in the United States have sparked a debate about optimal vaccination strategies to reduce the burden of morbidity and mortality caused by the influenza virus. Methods and Findings We present a comparative analysis of two classes of suggested vaccination strategies: mortality-based strategies that target high-risk populations and morbidity-based strategies that target high-prevalence populations. Applying the methods of contact network epidemiology to a model of disease transmission in a large urban population, we assume that vaccine supplies are limited and then evaluate the efficacy of these strategies across a wide range of viral transmission rates and for two different age-specific mortality distributions. We find that the optimal strategy depends critically on the viral transmission level (reproductive rate) of the virus: morbidity-based strategies outperform mortality-based strategies for moderately transmissible strains, while the reverse is true for highly transmissible strains. These results hold for a range of mortality rates reported for prior influenza epidemics and pandemics. Furthermore, we show that vaccination delays and multiple introductions of disease into the community have a more detrimental impact on morbidity-based strategies than mortality-based strategies. Conclusions If public health officials have reasonable estimates of the viral transmission rate and the frequency of new introductions into the community prior to an outbreak, then these methods can guide the design of optimal vaccination priorities. When such information is unreliable or not available, as is often the case, this study recommends mortality-based vaccination priorities.
Biosimilars in IBD: hope or expectation?: Table 1
Authors: Krisztina B Gecse, Reena Khanna, Gijs R van den Brink, Cyriel Y Ponsioen, Mark Löwenberg, Vipul Jairath, Simon P L Travis, William J Sandborn, Brian G Feagan, Geert R A M D'Haens
Journal: Gut (2013)

A biosimilar is a biological medicine that enters the market subsequent to expiration of the patent of an original reference product and its similarity to the reference medicine exhibits ‘no clinically meaningful differences in terms of quality, safety and efficacy’.1 In practice, patents protect a reference product for 10 years after its approval before registration for a similar biological medicine can be applied for.1 The term ‘biosimilar’ is recognised by all regulators, but synonyms include ‘similar biotherapeutic product’ (WHO) and ‘subsequent-entry biologic’ (Canada).2 Biopharmaceutical agents are derived from living cells or organisms and are usually complex proteins. Therefore, regulators are establishing novel specific approval pathways for biosimilars that differ from those for chemical generics. Since the first approval in 2005, several biosimilars of somatropin (human growth hormone), filgrastim (granulocyte colony-stimulating factor, G-CSF) and epoetin (erythropoietin) have become available in Europe. Currently, 12 biosimilars are authorised in the European market, and numerous others, including monoclonal antibodies (mAbs), have applied for authorisation.3 ,4 This subject has received increasing attention in gastroenterology, because the patent on infliximab is due to expire and regulatory approval for two biosimilar infliximabs have already been filed for to the European Medicines Agency (EMA). One of these molecules is already available for patient care in South Korea.4 ,5 

Biological agents are currently in widespread use for the treatment of chronic inflammatory diseases. As recently as in 2000, only two of the world's top 10 grossing drugs were biological agents. In 2012, estimates are that seven are biological agents, of which adalimumab and infliximab lead the list.6 The long duration of development and high manufacturing costs are cited as the main contributors to the high cost of biological agents. For example, the average yearly cost of infliximab treatment for Crohn's disease in …
Cytomegalovirus Infection and Abnormal T-Lymphocyte Subset Ratios in Homosexual Men
Authors: W. LAWRENCE DREW
Journal: Annals of Internal Medicine (1985)

T-helper:T-suppressor cell ratios of 1 or less were found in 2 of 42 homosexual men without antibodies to cytomegalovirus but in 33 of 67 homosexual men with antibodies (p < 0.001). Of 34 men without antibody who were followed prospectively, 12 became seropositive for cytomegalovirus and all 12 developed helper: suppressor ratios of less than 1.0. These ratios remained at 1 or less for an average of 9.6 months but persisted for 15 months or more in 3 men. None of the men in the prospective study developed antibodies to the acquired-immunodeficiency-syndrome-associated retrovirus. These results indicate that in the homosexual men studied, abnormally low T-lymphocyte helper: suppressor ratios occurred almost exclusively in those who were infected with cytomegalovirus, and in those prospectively followed low ratios did not reflect contact with the syndrome-associated retrovirus. Abnormal ratios were rarely seen in men who had never been exposed to cytomegalovirus. Thus, cytomegalovirus infection may be an important cofactor in the immunologic disorders leading to the acquired immunodeficiency syndrome.
Potential Drugs Against Cervical Cancer: Zinc-Ejecting Inhibitors of the Human Papillomavirus Type 16 E6 Oncoprotein
Authors: W. Beerheide, H.-U. Bernard, Y.-J. Tan, A. Ganesan, W. G. Rice, A. E. Ting
Journal: JNCI Journal of the National Cancer Institute (1999)

The principal agent in the etiology of cervical cancer, i.e., human papillomavirus (HPV) type 16, encodes three oncoproteins, E5, E6, and E7. Structural and mutational studies have identified two potential zinc-finger domains as critical for E6 protein function. We investigated several assays to identify and characterize compounds that interfere with the binding of zinc to E6.Thirty-six compounds were selected on the basis of their structure, which would facilitate their participation in sulfhydryl residue-specific redox reactions, and were tested for their ability to release zinc from E6 protein. The zinc-ejecting compounds were then tested for their ability to inhibit E6 binding to E6-associated protein (E6AP) and E6-binding protein (E6BP), two coactivators of E6-mediated cellular transformation. The binding of E6 to E6BP and E6AP was measured by use of surface plasmon resonance (a technique that monitors molecular interactions by measuring changes in refractive index) and by use of in vitro translation assays. The compounds were also tested for their effects on the viability of HPV-containing cell lines.Nine of the 36 tested compounds ejected zinc from E6. Two of the nine compounds inhibited the interaction of E6 with E6AP and E6BP, and one of these two, 4, 4'-dithiodimorpholine, selectively inhibited cell viability and induced higher levels of p53 protein (associated with the induction of apoptosis [programmed cell death]) in tumorigenic HPV-containing cells.We have described assay systems to identify compounds, such as 4,4'-dithiodimorpholine, that can potentially interfere with the biology and pathology of HPV. These assay systems may be useful in the development of drugs against cervical cancer, genital warts, and asymptomatic infections by genital HPVs.