α-Adrenergic inhibition of proliferation in HepG2 cells stably transfected with the α1B-adrenergic receptor through a p42MAP kinase/p21Cip1/WAF1-dependent pathway

AbstractActivation of α1B adrenergic receptors (α1BAR) promotes DNA synthesis in primary cultures of hepatocytes, yet expression of α1BAR in hepatocytes rapidly declines during proliferative events. HepG2 human hepatoma cells, which do not express α1BAR, were stably transfected with a rat α1BAR cDNA (TFG2 cells), in order to study the effects of maintained α1BAR expression on hepatoma cell proliferation. TFG2 cells had a decreased rate of growth compared to mock transfected HepG2 cells as revealed by a decrease in [3H]thymidine incorporation into DNA. Stimulation of α1BAR with phenylephrine caused a further large reduction in TFG2 cell growth, whereas no effect on growth was observed in mock transfected cells. Reduced cell growth correlated with increased percentages of cells found in G0/G1 and G2/M phases of the cell cycle. In TFG2 cells, phenylephrine increased p42MAP kinase activity by 1.5- to 2.0-fold for up to 24 h and increased expression of the cyclin dependent kinase inhibitor protein p21Cip1/WAF1. Treatment of TFG2 cells with the specific MEK1 inhibitor PD98059, or infection with a −/− MEK1 recombinant adenovirus permitted phenylephrine to increase rather than decrease [3H]thymidine incorporation. In addition, inhibition of MAP kinase signaling by PD98059 or MEK1 −/− blunted the ability of phenylephrine to increase p21Cip1/WAF1 expression. In agreement with a role for increased p21Cip1/WAF1 expression in causing growth arrest, infection of TFG2 cells with a recombinant adenovirus to express antisense p21Cip1/WAF1 mRNA blocked the ability of phenylephrine to increase p21Cip1/WAF1 expression and to inhibit DNA synthesis. Antisense p21Cip1/WAF1 permitted phenylephrine to stimulate DNA synthesis in TFG2 cells, and abrogated growth arrest. These results suggest that transformed hepatocytes may turn off the expression of α1BARs in order to prevent the activation of a growth inhibitory pathway. Activation of this inhibitory pathway via α1BAR appears to be p42MAP kinase and p21Cip1/WAF1 dependent

Assessing the Completeness of Reporting in Preclinical Oncolytic Virus Therapy Studies

Irreproducibility of preclinical findings could be a significant barrier to the “bench-to-bedside” development of oncolytic viruses (OVs). A contributing factor is the incomplete and non-transparent reporting of study methodology and design. Using the NIH Principles and Guidelines for Reporting Preclinical Research, a core set of seven recommendations, we evaluated the completeness of reporting of preclinical OV studies. We also developed an evidence map identifying the current trends in OV research. A systematic search of MEDLINE and Embase identified all relevant articles published over an 18 month period. We screened 1,554 articles, and 236 met our a priori-defined inclusion criteria. Adenovirus (43%) was the most commonly used viral platform. Frequently investigated cancers included colorectal (14%), skin (12%), and breast (11%). Xenograft implantation (61%) in mice (96%) was the most common animal model. The use of preclinical reporting guidelines was listed in 0.4% of articles. Biological and technical replicates were completely reported in 1% of studies, statistics in 49%, randomization in 1%, blinding in 2%, sample size estimation in 0%, and inclusion/exclusion criteria in 0%. Overall, completeness of reporting in the preclinical OV therapy literature is poor. This may hinder efforts to interpret, replicate, and ultimately translate promising preclinical OV findings

Weather and our food supply

The steep rate of increase in yield of grain crops in the United States since the mid-1950\u27s has resulted in the use of the term explosion in technology. Surplus grains piled up to such proportions after the 1960 · harvest that acreage control appeared. to be in order. But despite substantial reductions in acreages after 1960 the increased output per acre has just about compensated for acreage reductions. During this period of rapid increase in output per acre there has been a growing tendency to believe that technology has reduced the influence of weather on grain production so that we no longer need to fear shortages due to unfavorable weather. There is also a popular belief that acreage control$ fail to achieve the objective of production control, and that public funds are being wasted in storing surplus grains which we don\u27t need. There is increasing evidence, however, that a period of favorable weather interacted with technology to produce our recent high yields, and that perhaps half of the increase in yield per acre since 1950 has been due to a change to more favorable weather for grain crops. These findings have important implications in continued support for research in production technology and in the way in which we look at our surplus stocks of feed and food grains. If a period of favorable weather has been responsible for half of the increase in yields since 19501 then what can we expect if the weather trend reverses itself for a few years? Do we have periodicity in weather, and have we just passed through a run of favorable years that might be followed by a run of unfavorable years? Should we treat our surplus grains as reserves? How does our rate of growth in grain output compare with the needs of a growing world population? And of course I in the background of these questions is one big question -- how much of our recent high yields is really due to weather? To answer these important questions the Center for Agriculture and Economic Development invited outstanding authorities to present their ideas under three main headings: (1) Techniques for Evaluation of Weather Variables in Agricultural Production I (2) Periodicity in Weather Patterns: Implications in Agriculture I and (3) Weather Considerations in Agricultural Policy. The papers have been assembled in the order of their presentation under the general outline above.https://lib.dr.iastate.edu/card_reports/1021/thumbnail.jp

Early lineage restriction in temporally distinct populations of Mesp1 progenitors during mammalian heart development.

Cardiac development arises from two sources of mesoderm progenitors, the first heart field (FHF) and the second (SHF). Mesp1 has been proposed to mark the most primitive multipotent cardiac progenitors common for both heart fields. Here, using clonal analysis of the earliest prospective cardiovascular progenitors in a temporally controlled manner during early gastrulation, we found that Mesp1 progenitors consist of two temporally distinct pools of progenitors restricted to either the FHF or the SHF. FHF progenitors were unipotent, whereas SHF progenitors were either unipotent or bipotent. Microarray and single-cell PCR with reverse transcription analysis of Mesp1 progenitors revealed the existence of molecularly distinct populations of Mesp1 progenitors, consistent with their lineage and regional contribution. Together, these results provide evidence that heart development arises from distinct populations of unipotent and bipotent cardiac progenitors that independently express Mesp1 at different time points during their specification, revealing that the regional segregation and lineage restriction of cardiac progenitors occur very early during gastrulation.This is the author's accepted manuscript and will be under embargo until the 24th of February 2015. The final version is published by NPG in Nature Cell Biology here: http://www.nature.com/ncb/journal/v16/n9/full/ncb3024.html

Highlights From the Annual Meeting of the American Epilepsy Society 2022

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia

Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis

The glutamatergic and dopaminergic systems are thought to be involved in the pathophysiology of schizophrenia. Their interaction has been widely documented and may have a role in the neurobiological basis of the disease. The aim of this study was to compare, using proton magnetic resonance spectroscopy (1H-MRS), glutamate levels in the precommissural dorsal-caudate (a dopamine-rich region) and the cerebellar cortex (negligible for dopamine) in the following: (1) 18 antipsychotic-naïve subjects with prodromal symptoms and considered to be at ultra high-risk for schizophrenia (UHR), (2) 18 antipsychotic-naïve first- episode psychosis patients (FEP), and (3) 40 age- and sex- matched healthy controls. All subjects underwent a 1H-MRS study using a 3Tesla scanner. Glutamate levels were quantified and corrected for the proportion of cerebrospinal fluid and percentage of gray matter in the voxel. The UHR and FEP groups showed higher levels of glutamate than controls, without differences between UHR and FEP. In the cerebellum, no differences were seen between the three groups. The higher glutamate level in the precommissural dorsal-caudate and not in the cerebellum of UHR and FEP suggests that a high glutamate level (a) precedes the onset of schizophrenia, and (b) is present in a dopamine-rich region previously implicated in the pathophysiology of schizophrenia.peer-reviewe

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Contemporary Management of Locally Advanced and Recurrent Rectal Cancer: Views from the PelvEx Collaborative

Pelvic exenteration is a complex operation performed for locally advanced and recurrent pelvic cancers. The goal of surgery is to achieve clear margins, therefore identifying adjacent or involved organs, bone, muscle, nerves and/or vascular structures that may need resection. While these extensive resections are potentially curative, they can be associated with substantial morbidity. Recently, there has been a move to centralize care to specialized units, as this facilitates better multi-disciplinary care input. Advancements in pelvic oncology and surgical innovation have redefined the boundaries of pelvic exenterative surgery. Combined with improved neoadjuvant therapies, advances in diagnostics, and better reconstructive techniques have provided quicker recovery and better quality of life outcomes, with improved survival This article provides highlights of the current management of advanced pelvic cancers in terms of surgical strategy and potential future developments

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700