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To summarize the most recent publications highlighting the trends and disparities among patients diagnosed with high-risk endometrial cancer.Endometrial cancer mortality continues to rise, driven by the increasing incidence of high-risk histologic subtypes that accounts for a disproportionate number of endometrial cancer deaths. The lack of progress made in endometrial cancer treatment, particularly of high-risk histologic subtypes, disproportionately affects black women who are more likely to be diagnosed with these aggressive tumor types. Even when accounting for high-risk histology, various factors across the spectrum of care may influence the survival disparities between black and white women, including timely access to guideline-concordant care, clinical trial enrollment, and systemic racism that impacts cancer outcomes.In this review, we highlight the disproportionate impact of worsening endometrial cancer mortality and healthcare inequalities contributing to the endometrial cancer survival disparity between black and white women.

Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Supplementary Methods

Supplementary Figures S1-S13

Purpose:Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental Design:Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).Results:Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).Conclusions:An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Supplementary Tables S1-S11

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

Congenital cataracts are one of the major causes of childhood-onset blindness around the world. Genetic diagnosis provides benefits through avoidance of unnecessary tests, surveillance of extraocular features, and genetic family information. In this study, we demonstrate the value of genome sequencing in improving diagnostic yield in congenital cataract patients and families. We applied genome sequencing to investigate 20 probands with congenital cataracts. We examined the added value of genome sequencing across a total cohort of 52 probands, including 14 unable to be diagnosed using previous microarray and exome or panel-based approaches. Although exome or genome sequencing would have detected the variants in 35/52 (67%) of the cases, specific advantages of genome sequencing led to additional diagnoses in 10% (5/52) of the overall cohort, and we achieved an overall diagnostic rate of 77% (40/52). Specific benefits of genome sequencing were due to detection of small copy number variants (2), indels in repetitive regions (2) or single-nucleotide variants (SNVs) in GC-rich regions (1), not detectable on the previous microarray, exome sequencing, or panel-based approaches. In other cases, SNVs were identified in cataract disease genes, including those newly identified since our previous study. This study highlights the additional yield of genome sequencing in congenital cataracts.

Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte‒HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of human anagen scalp HFs. Quantitative immunohistomorphometry, X-ray microcomputed tomography, and transmission electron microscopy showed that the number and size of perifollicular adipocytes declined during anagen‒catagen transition, whereas fluorescence-lifetime imaging revealed increased lipid oxidation in adipocytes surrounding the bulge and/or sub-bulge region. Ex vivo, dWAT tendentially promoted hair shaft production, and significantly stimulated hair matrix keratinocyte proliferation and HF pigmentation. Both dWAT pericytes and PREF1/DLK1+ adipocyte progenitors secreted HGF during human HF‒dWAT co-culture, for which the c-Met receptor was expressed in the hair matrix and dermal papilla. These effects were reproduced using recombinant HGF and abrogated by an HGF-neutralizing antibody. Laser-capture microdissection‒based microarray analysis of the hair matrix showed that dWAT-derived HGF upregulated keratin (K) genes (K27, K73, K75, K84, K86) and TCHH. Mechanistically, HGF stimulated Wnt/β-catenin activity in the human hair matrix (increased AXIN2, LEF1) by upregulating WNT6 and WNT10B, and inhibiting SFRP1 in the dermal papilla. Our study demonstrates that dWAT regulates human hair growth and pigmentation through HGF secretion, and thus identifies dWAT and HGF as important novel molecular and cellular targets for therapeutic intervention in human hair growth and pigmentation disorders.

Purpose Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. Methods We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. Results We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld–Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. Conclusions We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously “hidden” heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

The solid-state properties of new chemical entities are critical to the stability and bioavailability of pharmaceutical drug products. The stability of the solid-state packing is described by the packing energy and an accurate prediction of this property for drug molecules would therefore be desirable. However, this has been difficult to achieve because of the lack of fundamental thermodynamic data on drug molecules. A potential solution would be to use calculated lattice energies to build a model and design molecules with desired physicochemical properties from an early stage, aligning with a “design by first intent” strategy for physicochemical properties. We first demonstrate the high correlation and interchangeability between QSPR models built using calculated lattice energies and experimental sublimation enthalpies for small organic molecules. We then present a QSPR model trained on in-house molecules using lattice energies calculated from crystal structures. The result is a model that enables fast prediction of the lattice energies of in-house molecules from 2-D molecular structure with reasonable accuracy (R2 = 0.92, root mean square error = 3.58 kcal/mol). We explore the model elements to improve our understanding of the molecular properties that contribute to lattice energy and then suggest potential cross-industry aspects that may enhance the application of the concept.

Ageing impacts multiple host mechanisms involved in cancer progression. Here we show that poorly metastatic Lewis lung carcinoma (LLC) cells form less bulky metastatic deposits in aged mice (>52 weeks) relative to their young (4–6 weeks) counterparts. Serial selection of LLC cells for increased metastatic capability in either young or old mice led in both cases to exaggerated growth of pulmonary nodules after only 5 cycles of in vivo passage. The respective metastatic cellular variants established in young (Y-series) or old (O-series) mice differed in cell morphology and constitutive activity of growth factor receptors, especially phospho-PDGFRa and phospho-EPHA7. These cell lines also exhibited marked differences in their time dependent profiles of cellular impedance (CI), which reflects their physical properties, such as cell shape, adhesion and interactions with substrata. In confluent monolayer culture Y-series cell lines generated high and increasing CI values, while these values remained low and constant in the O-series of cell lines. These observations suggest that the selective pressure of the metastatic microenvironment in young versus old hosts is sufficiently different to results in the enrichment of distinct, age-related metastatic phenotypes of cancer cells. Thus, age could inform therapeutic approaches to metastatic cancers.

e17073Background: ARID1a is thought to function as a tumor suppressor; mutations in this gene have been associated with many cancers. Recent studies have found ARID1a mutations in atypical endometr...

Auxiliary-directed biocatalysis is a powerful and relatively benign tool for chemical synthesis. We recently reported the use of theobromine as a chemical auxiliary for directing CYP3A4-catalyzed oxidations with predictable regio-, chemo- and stereo-selectivity (J. Am. Chem. Soc., 2011, 133, 7853). This highly successful strategy enabled the direct, regio- and stereo-selective hydroxylation of unactivated C–H bonds. However, recovering the products and starting materials from the resulting biocatalytic mixtures has proven challenging. To address this issue, we capitalized on the chemical auxiliary present on the starting material and enzymatic reaction products. The chemical auxiliary was used as a template to generate molecularly imprinted polymers (MIPs). When used in solid-phase extractions, the MIPs reported here allow for the recovery (>90%) of theobromine-containing products and starting materials from complex mixtures such as cellular membrane extracts. This strategy, which avoids the use of large amounts of organic solvents, represents an effective, easily-tailored, and reusable way to improve the recovered yield of biocatalytic transformations while extending the usefulness of a chemical auxiliary.