GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition.

The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.

Laparoscopic cholecystectomy for acute cholecystitis: an analysis of early versus delayed cholecystectomy and predictive factors for conversion.

BACKGROUND: There is an increasing preference for early laparoscopic cholecystectomy (ELC) as compared to delayed LC (DLC) in the management of acute cholecystitis (AC). Conversion to open cholecystectomy (LOC) remains an important outcome. We aim to compare ELC and DLC outcomes and identify LOC predictors. METHODS: Retrospective analysis of 466 patients who underwent LC for AC from June 2010 to June 2015 was performed. Patients were divided into ELC and DLC groups, defined as LC performed within 7 days and between 4 to 24 weeks of symptom onset, respectively. Peri-operative outcomes and predictors for LOC were analyzed. RESULTS: Conversion rates were comparable [ELC, 8.6% vs. DLC, 8.0%] (P=0.867). While median operative time was longer in ELC (101.5 min [83.0-130.1]) than DLC (88.0 min [62.3-118.8]) (P<0.001), intraoperative (ELC, 1.9% vs. DLC, 3.0%; P=0.541) and postoperative morbidity (ELC, 13.5% vs. DLC, 12.5%; P=0.688) was comparable. Median total length of stay (LOS) was shorter in ELC (4 days [3-6]) than DLC (5 days [4-9]) (P<0.001). Univariate analysis showed increased age (LC, 57 [45-66] vs. LOC, 60 [56-72]; P=0.016), presence of comorbidities (LC, 69.0% vs. LOC, 87.8%; P=0.009), previous abdominal surgery (LC, 6.1% vs. LOC, 17.1%; P=0.014), fever (P=0.001), Murphy's sign (P=0.005) and lower albumin (LC, 42.0 [39.0-45.0] vs. LOC, 40.0 [36.0-43.0]; P=0.003) to be predictors for LOC. CONCLUSIONS: ELC provides shorter LOS and eliminates the risk of gallstone-related morbidity while awaiting surgery. It should be advocated for patients with AC. The presence of comorbidities, increased age, previous abdominal surgery and low albumin are predictors for conversion.

Delayed Presentation of Acute Cholecystitis: Comparative Outcomes of Same-Admission Versus Delayed Laparoscopic Cholecystectomy.

INTRODUCTION: Studies have shown that same-admission laparoscopic cholecystectomy (SALC) is superior to delayed laparoscopic cholecystectomy (DLC) for acute cholecystitis (AC). However, no studies have compared both modalities in patients with delayed presentation. The aim of the study was to compare outcomes between SALC and DLC in AC patients with more than 7-day symptom duration. METHODS: A retrospective analysis of 83 AC patients who underwent LC after presenting with >7 days of symptoms from June 2010 to June 2015 was performed. Patients were divided into L-SALC and L-DLC, defined as LC performed within the same admission and between 4 and 24 weeks after discharge, respectively. Peri-operative outcomes were evaluated. RESULTS: In L-SALC patients, the intra-operative severity was higher (p < 0.001) and median operative time was longer (L-SALC, 107 min (46-220) vs L-DLC, 95 mins (25-186)) (p = 0.048). Conversion rates were also higher in L-SALC than that in L-DLC (L-SALC, 21.4% vs L-DLC, 4.9%) (p = 0.048). While post-operative morbidity was similar, L-SALC was associated with a longer post-operative length of stay as compared to L-DLC (L-SALC, 2 (1-17) vs L-DLC, 1 (1-6)) (p < 0.001). CONCLUSION: DLC provides lower conversion rates and shorter length of stay in AC patients presenting beyond 7 days of symptoms. This group of patients should be offered DLC.

Same admission laparoscopic cholecystectomy for acute cholecystitis: is the "golden 72 hours" rule still relevant?

BACKGROUND: Studies have shown that same admission laparoscopic cholecystectomy (SALC) is superior to delayed laparoscopic cholecystectomy for acute cholecystitis (AC). While some proposed a"golden 72-hour" for SALC, the optimal timing remains controversial. The aim of the study was to compare the outcomes of SALC in AC patients with different time intervals from symptom onset. METHODS: A retrospective analysis of 311 patients who underwent SALC for AC from June 2010-June 2015 was performed. Patients were divided into three groups based on the time interval between symptom onset and surgery: <4 days (E-SALC), 4-7 days (M-SALC), >7 (L-SALC). RESULTS: The mean duration of symptoms was 2(1-3), 5(4-7) and 9 (8-13) days for E-SALC, M-SALC and L-SALC, respectively (p < 0.001). Conversion rates were higher in the L-SALC group [E-SALC, 8.2% vs M-SALC, 9.6% vs L-SALC, 21.4%] (p = 0.048). The total length of stay was longer in patients with longer symptom duration [E-SALC, 4 (2-33) vs M-SALC, 2 (2-23) vs L-SALC, 7 (2-49)] (p < 0.001). CONCLUSION: Patients with AC presenting beyond 7 days of symptoms have higher conversion rates and longer length of stay associated with SALC. However, patients with less than a week of symptoms should be offered SALC.

ß-Catenin overexpression in the metanephric mesenchyme leads to renal dysplasia genesis via cell-autonomous and non-cell-autonomous mechanisms.

Renal dysplasia, a developmental disorder characterized by defective ureteric branching morphogenesis and nephrogenesis, ranks as one of the major causes of renal failure among the pediatric population. Herein, we demonstrate that the levels of activated ß-catenin are elevated in the nuclei of ureteric, stromal, and mesenchymal cells within dysplastic human kidney tissue. By using a conditional mouse model of mesenchymal ß-catenin overexpression, we identify two novel signaling pathways mediated by ß-catenin in the development of renal dysplasia. First, the overexpression of ß-catenin within the metanephric mesenchyme leads to ectopic and disorganized branching morphogenesis caused by ß-catenin directly binding Tcf/lef consensus binding sites in the Gdnf promoter and up-regulating Gdnf transcription. Second, ß-catenin overexpression in the metanephric mesenchyme leads to elevated levels of transcriptionally active ß-catenin in the ureteric epithelium. Interestingly, this increase of ß-catenin-mediated transcription results from a novel Ret/ß-catenin signaling pathway. Consistent with these findings, analysis of human dysplastic renal tissue demonstrates that undifferentiated mesenchymal cells expressing high levels of ß-catenin also express increased GDNF. Furthermore, dysplastic ureteric tubules that were surrounded by high levels of GDNF also exhibited increased levels of activated ß-catenin. Together, these data support a model in which the elevation of ß-catenin in the metanephric mesenchyme results in cell-autonomous and non-cell-autonomous events that lead to the genesis of renal dysplasia.

Visual outcomes after wavefront-guided laser in situ keratomileusis with and without iris registration.

PURPOSE: To compare the clinical outcomes of wavefront-guided laser in situ keratomileusis in eyes in which iris registration was used (IR group) and eyes in which iris registration would not engage (no-IR group). SETTING: Shiley Eye Center, University of California San Diego, La Jolla, California, USA. METHODS: This retrospective analysis comprised 112 eyes of 64 patients who had wavefront-guided LASIK using the Visx CustomVue S4 IR platform (Advanced Medical Optics) for myopia or myopic astigmatism. The safety, efficacy, predictability, and need for enhancement at the 3-month follow-up were evaluated and compared between the IR group and the no-IR group. RESULTS: By 3 months postoperatively, all eyes in the IR group and 93% of eyes in the no-IR group had the same best spectacle-corrected visual acuity (BSCVA) as preoperatively or had gained 1 to 2 lines of BSCVA. No eye in either group lost more than 1 line of BSCVA (P = 0.12). Ninety-six percent of eyes in the IR group and 93% in the no-IR group were within +/-0.50 diopter (D) of the postoperative manifest refraction spherical equivalent (P = 0.24), and all eyes were within +/-1.00 D of emmetropia. Four eyes in the IR group and 11 in the no-IR group required retreatment during the follow-up period (P = 0.1). CONCLUSION: The results in the IR group and the no-IR group were comparable, with no statistically significant differences in measured outcomes.