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.

Emerging bone tissue engineering via Polyhydroxyalkanoate (PHA)-based scaffolds.

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers derived from microorganisms. On top of their biodegradability and biocompatibility, different PHA types can contribute to varying mechanical and chemical properties. This has led to increasing attention to the use of PHAs in numerous biomedical applications over the past few decades. Bone tissue engineering refers to the regeneration of new bone through providing mechanical support while inducing cell growth on the PHA scaffolds having a porous structure for tissue regeneration. This review first introduces the various properties PHA scaffold that make them suitable for bone tissue engineering such as biocompatibility, biodegradability, mechanical properties as well as vascularization. The typical fabrication techniques of PHA scaffolds including electrospinning, salt-leaching and solution casting are further discussed, followed by the relatively new technology of using 3D printing in PHA scaffold fabrication. Finally, the recent progress of using different types of PHAs scaffold in bone tissue engineering applications are summarized in intrinsic PHA/blends forms or as composites with other polymeric or inorganic hybrid materials.

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.

Stromally expressed ß-catenin modulates Wnt9b signaling in the ureteric epithelium.

The mammalian kidney undergoes cell interactions between the epithelium and mesenchyme to form the essential filtration unit of the kidney, termed the nephron. A third cell type, the kidney stroma, is a population of fibroblasts located in the kidney capsule, cortex and medulla and is ideally located to affect kidney formation. We found ß-catenin, a transcriptional co-activator, is strongly expressed in distinctive intracellular patterns in the capsular, cortical, and medullary renal stroma. We investigated ß-catenin function in the renal stroma using a conditional knockout strategy that genetically deleted ß-catenin specifically in the renal stroma cell lineage (ß-cats-/-). ß-cats-/- mutant mice demonstrate marked kidney abnormalities, and surprisingly we show ß-catenin in the renal stroma is essential for regulating the condensing mesenchyme cell population. We show that the population of induced mesenchyme cells is significantly reduced in ß-cats-/- mutants and exhibited decreased cell proliferation and a specific loss of Cited 1, while maintaining the expression of other essential nephron progenitor proteins. Wnt9b, the key signal for the induction of nephron progenitors, was markedly reduced in adjacent ureteric epithelial cells in ß-cats-/-. Analysis of Wnt9b-dependent genes in the neighboring nephron progenitors was significantly reduced while Wnt9b-independent genes remained unchanged. In contrast mice overexpressing ß-catenin exclusively in the renal stroma demonstrated massive increases in the condensing mesenchyme population and Wnt9b was markedly elevated. We propose that ß-catenin in the renal stroma modulates a genetic program in ureteric epithelium that is required for the induction of nephron progenitors.

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.

Early anatomy ultrasound in women at increased risk of fetal anomalies.

OBJECTIVE: This study was designed to assess the accuracy of ultrasound anatomy screening before 17 weeks gestation in a population at high risk of fetal anomalies. METHODS: Retrospective review of anatomy ultrasound examinations carried out between 12-17 weeks gestation in a high-risk population. Early sonographic findings were compared with the 18-22 week anatomy ultrasound, karyotype, echocardiogram and postnatal/postmortem results. RESULTS: A complete anatomical survey was achieved in 68 of 101 screened fetuses (67%), with cardiac anatomy having the lowest completion rate (78/101; 77%). Anomalies were suspected on ultrasound in 23 fetuses. Four of these did not undergo pathologic examination but had clearly abnormal findings on ultrasound. Eighteen fetuses had a confirmed abnormal outcome. Sensitivity of early anatomy ultrasound was 83.3% (n = 15/18) and specificity 94.9% (n = 75/79). There were 3 false negative ultrasounds (16.6%: trisomy 21 with short humerus, choanal atresia and ventriculomegaly, and a ventricular septal defect). False positive rate was 4.0% (4 ventricular septal defects). CONCLUSION: The high rate of visualization of anatomic structures between 12-17 weeks gestation allows for either early detection of fetal anomalies or parental reassurance in many cases. Subtle anomalies of the heart remain difficult to diagnose.

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.

Wavefront-guided laser in situ keratomileusis in the treatment of high myopia by using the CustomVue wavefront platform.

PURPOSE: To assess the efficacy, predictability, and safety of wavefront-guided laser in situ keratomileusis (LASIK) in the treatment of high myopia by using the Visx S4 CustomVue wavefront platform. METHODS: A retrospective analysis of consecutive cases of eyes with high myopia (manifest refraction spherical equivalent >or= -6.00 D) that underwent non-physician-adjusted wavefront-guided LASIK by using the Visx S4 CustomVue wavefront platform. Forty-three eyes of 29 patients were included. Preoperative best spectacle-corrected visual acuity (BSCVA), manifest refraction, WaveScan refraction, postoperative uncorrected visual acuity (UCVA) and BSCVA, and manifest refraction were determined. The clinical outcomes were evaluated on the basis of standard formats and criteria. Data at 3 months postoperatively are presented. RESULTS: Preoperatively, we found mean sphere was -6.89 +/- 1.08 D, mean cylinder was -0.97 +/- 0.75 D, and mean spherical equivalent (SE) was -7.38 +/- 1.20 D. Postoperatively, mean sphere was 0.02 +/- 0.40 D, mean cylinder was -0.40 +/- 0.40 D, and mean SE was -0.18 +/- 0.43 D. UCVA was 20/15 or better in 27.9% and cumulatively 20/20 or better in 58% of eyes. All eyes treated had at least 20/50 UCVA. Efficacy index was 0.94. Eighty-two percent of eyes were within 0.50 D and 97.6% were within 1.00 D of emmetropia at the 3-month follow-up visit. Ninety-one percent of eyes either maintained or gained 1 line of BSCVA. No eye lost >1 line of BSCVA. The safety index was 1.1. CONCLUSIONS: The 3-month follow-up results of our study indicate that wavefront-guided LASIK by using the Visx S4 CustomVue wavefront platform is an effective, predictable, and safe treatment of high myopia.