Citations

Nuclear translocation of mothers against decapentaplegic homolog 2/3 (SMAD2/3), core transcription factors of transforming growth factor β (TGF‐β) signaling, is critical for hepatic stellate cell (HSC) differentiation into metastasis‐promoting myofibroblasts. SMAD2/3 have multiple coactivators, including WW domain‐containing transcription regulator protein 1 (WWTR1 or TAZ) and p300 acetyltransferase. In the nucleus, TAZ binds to SMAD2/3 to prevent SMAD2/3 nuclear export. However, how TAZ and SMAD2/3 enter the nucleus remains poorly understood because neither contains a nuclear localization signal (NLS), an amino acid sequence tagging proteins for nuclear transport. p300 is an NLS‐containing large scaffold protein, so we hypothesized that SMAD2/3 and TAZ may undergo nuclear import through complexing with p300. Coimmunoprecipitation, immunofluorescence, and nuclear fractionation assays revealed that TGF‐β1 promoted binding of SMAD2/3 and TAZ to p300 and that p300 inactivation disrupted TGF‐β1‐mediated SMAD2/3 and TAZ nuclear accumulation. Deleting the p300 NLS blocked TGF‐β1‐induced SMAD2/3 and TAZ nuclear transport. Consistently, p300 inactivation suppressed TGF‐β1‐mediated HSC activation and transcription of genes encoding tumor‐promoting factors, such as connective tissue growth factor, Tenascin C, Periostin, platelet‐derived growth factor C, and fibroblast growth factor 2, as revealed by microarray analysis. Chromatin immunoprecipitation‐real‐time quantitative PCR showed that canonical p300‐mediated acetylation of histones also facilitated transcription in response to TGF‐β1 stimulation. Interestingly, although both TGF‐β1‐mediated and stiffness‐mediated HSC activation require p300, comparison of gene expression data sets revealed that transcriptional targets of TGF‐β1 were distinct from those of stiffness‐p300 mechanosignaling. Lastly, in tumor/HSC coinjection and intrasplenic tumor injection models, targeting p300 of activated‐HSC/myofibroblasts by C646, short hairpin RNA, or cre ‐mediated gene disruption reduced tumor and liver metastatic growth in mice. Conclusion: p300 facilitates TGF‐β1‐stimulated HSC activation by both noncanonical (cytoplasm‐to‐nucleus shuttle for SMAD2/3 and TAZ) and canonical (histone acetylation) mechanisms. p300 is an attractive target for inhibiting HSC activation and the prometastatic liver microenvironment.

ABSTRACT Acute acalculous cholecystitis (AAC) is an uncommon presentation of cholecystitis accounting for 10% of cases. AAC is caused by a localized ischemic event in the gallbladder usually in critically ill patients. Several cases of localized or systemic lymphoma have been described in the literature as causes of AAC. We present a patient with a rare case of AAC due to undiagnosed systemic Burkitt lymphoma. Pathology of the gallbladder revealed Burkitt lymphoma with analysis of his cerebral spinal fluid confirming Stage IV disease. This case report reviews acute acalculous cholecystitis, lymphomas of the gallbladder and extrahepatic duct, and adult Burkitt lymphoma.

Abstract Currier, BS, Harty, PS, Zabriskie, HA, Stecker, RA, Moon, JM, Jagim, AR, and Kerksick, CM. Fat-free mass index in a diverse sample of male collegiate athletes. J Strength Cond Res 33(6): 1474–1479, 2019—Fat-free mass index (FFMI) is a body composition metric that has been used to assess relative muscularity in athletes. Fat-free mass index is calculated by dividing FFM by height squared, although further height corrections through linear regression may be needed in taller individuals. This study reported height-adjusted FFMI (FFMI Adj ) data in 209 male collegiate athletes from 10 sports (baseball, cross country, football, golf, ice hockey, weightlifting, rugby, swimming, track and field, and water polo) and the FFMI Adj natural upper limit for sports with sufficient sample size. The body composition of all subjects (mean ± SD ; age: 20.7 ± 1.9 years, height: 182.9 ± 6.7 cm, body mass: 90.8 ± 16.8 kg, and percent body fat: 15.6 ± 5.3) was measured using dual-energy x-ray absorptiometry. Linear regression was used to adjust for height, and the FFMI Adj natural upper limit was determined by calculating the 97.5th percentile of all values. One-way analyses of variance with Games-Howell post hoc comparisons were used to determine between-sport differences. A paired-samples t -test revealed a significant difference ( p < 0.001) between unadjusted and adjusted mean FFMI values. The overall mean FFMI Adj was 22.8 ± 2.8 kg·m −2 . Significant between-sport differences ( p < 0.001) in FFMI Adj were identified. Average FFMI Adj was highest in football athletes (24.28 ± 2.39 kg·m −2 ) and lowest in water polo athletes (20.68 ± 3.56 kg·m −2 ). The FFMI Adj upper limit was calculated for all athletes (28.32 kg·m −2 ), rugby (29.1 kg·m −2 ), and baseball (25.5 kg·m −2 ). This study reported FFMI Adj values in a diverse cohort of male collegiate athletes, providing data for the first time in several sports. These values can be used to guide nutritional and exercise interventions, predict athletic performance, and provide coaches with standardized information regarding the potential for further FFM accretion in male athletes.

Abstract White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Pulmonary arterial hypertension (PAH) is a rare disease that carries a poor prognosis. For 45 years, the definition of pulmonary hypertension (PH) has been a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, based on expert opinion. Recent data indicate that the mortality risk starts in the mPAP range of 21–24 mmHg, which has recently been reflected in the World Symposium on PH consensus document defining PH as a mPAP > 20 mmHg. The mortality associated with these lower levels of pulmonary pressures suggests that these values reflect a more advanced disease stage than previously recognized. It is unknown whether interventions targeting patients with mPAP values in the range of 21–24 mmHg in the absence of left ventricular or hypoxic lung disease are of clinical benefit. Here we present historical perspective on the hemodynamic definition of PH, discuss recent epidemiologic data, and outline obstacles to enrolling and evaluating response to therapy in mild PAH patients, as well as potentially useful study designs.

PURPOSE Germline CDH1 pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of CDH1 PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for CDH1 variants in the multigene panel testing era. METHODS Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding CDH1 genetic testing experiences, medical management, and psychosocial adaptation. RESULTS Discordance existed in interpretations of CDH1 results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers’ knowledge and reported less CDH1 knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS. CONCLUSION Few individuals with CDH1 PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants’ CDH1 results, suggesting serious unmet informational needs.