Hedgehog pathway as a drug target: Smoothened inhibitors in development

Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms

Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression.

While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression

Evaluation of Long-Term Cloud-Resolving Model Simulations Using Satellite Radiance Observations and Multi-Frequency Satellite Simulators

This paper proposes a methodology known as the Tropical Rainfall Measuring Mission (TRMM) Triple-Sensor Three-step Evaluation Framework (T3EF) for the systematic evaluation of precipitating cloud types and microphysics in a cloud-resolving model (CRM). T3EF utilizes multi-frequency satellite simulators and novel statistics of multi-frequency radiance and backscattering signals observed from the TRMM satellite. Specifically, T3EF compares CRM and satellite observations in the form of combined probability distributions of precipitation radar (PR) reflectivity, polarization-corrected microwave brightness temperature (Tb), and infrared Tb to evaluate the candidate CRM. T3EF is used to evaluate the Goddard Cumulus Ensemble (GCE) model for cases involving the South China Sea Monsoon Experiment (SCSMEX) and Kwajalein Experiment (KWAJEX). This evaluation reveals that the GCE properly captures the satellite-measured frequencies of different precipitating cloud types in the SCSMEX case but underestimates the frequencies of deep convective and deep stratiform types in the KWAJEX case. Moreover, the GCE tends to simulate excessively large and abundant frozen condensates in deep convective clouds as inferred from the overestimated GCE-simulated radar reflectivities and microwave Tb depressions. Unveiling the detailed errors in the GCE s performance provides the best direction for model improvements

High-Resolution Modeling of the Predictability of Convective Systems, and Influences by Absorbing Aerosols Over Northern India and the Himalayas Foothills During Boreal Summer

The Himalayas foothills region (HFR) is an important component of the South Asian monsoon. To the south, the HFR borders the fertile, populous, and heavily polluted Indo-Gangetic Plain (IGP). To the north, it rises to great height (approx. 4-5 km) to the Tibetan Plateau over a distance of less than 100 km. The HFR itself consists of complex mountainous terrain, with strong orographic forcing for precipitation. During the late spring and early summer, dust aerosol from the Thar and Middle East deserts , as well as moisture from the Arabian Sea were transported to the western part of the western part of the IGP and foothills spurs pre-monsoon severe thunderstorm over the region. During the monsoon season (mid June -August) convection from the Bay of Bengal, spread along the foothills northwestward to northern Pakistan. Recent climate model studies and preliminary observations have indicted not only the importance of dynamical forcing of precipitation in the HFR, but also possible strong impacts by the dense aerosols, from both local sources, and remote transport, that blanket the IGP from late spring up to the onset of the monsoon in June, and during monsoon breaks in July. In this work, we use the NASA Unified Weather Research and Forecasting (Nu-WRF) model to study the predictability ( 1-7 days) South Asian monsoon rainfall system. Results of 7 -day forecast experiments using an embedded domain of 27 km and 9 km resolution were conducted for the period June 11- July 15, 2008, with and without aerosol forcing are carried out to assess the intrinsic predictability of rainfall over the HFR, and possible impacts by aerosol direct effect, and possible connection of large-scale South Asian monsoon system

Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes

Maternal, pregnancy and fetal outcomes in de novo anti-glomerular basement membrane antibody disease in pregnancy: A systematic review

Background Outside of pregnancy, anti-glomerular basement membrane (GBM) antibody disease is associated with significant morbidity and mortality. However, there is limited knowledge regarding de novo anti-GBM disease in pregnancy. Methods A systematic review was performed to identify maternal, pregnancy and fetal outcomes in de novo anti-GBM disease in pregnancy. Studies were selected from PubMed, EMBASE, Cochrane Library databases and conference proceedings, without language restriction. Results Data from eight patients were derived from seven case reports and one unpublished case. Most (6/8) patients presented after the first trimester. During pregnancy, acute kidney injury (5/8), anemia (5/8), hematuria (8/8) and proteinuria (8/8) were common. When hemodialysis was required antepartum (5/8), renal function recovery to independence of renal replacement was unlikely (2/5). While pulmonary involvement was common (5/8), no permanent damage was reported (0/8). The majority of cases ended in live births (6/8) although prematurity (6/6), intrauterine growth restriction (2/6), small for gestational age (4/6) and complications of prematurity (1/6) were common. When anti-GBM levels were tested in the living newborn, they were detectable (2/5), but no newborn renal or lung disease was reported (0/6). Complications in pregnancy included gestational diabetes (3/8), hyperemesis gravidarum (2/8) and preeclampsia (2/8). Conclusions Live births can be achieved in de novo anti-GBM disease in pregnancy, but are commonly associated with adverse maternal, pregnancy and fetal outcomes. Only with awareness of common presentations, and management strategies can outcomes be optimized