Overexpression of CDT1 Is a Predictor of Poor Survival in Patients with Hepatocellular Carcinoma

Background

Genomic instability is a common feature in hepatocellular carcinoma. Deregulation of replication licensing factors has been shown to trigger DNA damage response contributing to genomic instability. Overexpression of DNA replication licensing factors chromatin licensing and DNA replication factor 1 (CDT1) and minichromosome maintenance complex component 7 (MCM7) has been previously reported in several human cancers. The aim of the present study was to evaluate the expression and prognostic significance of CDT1 and MCM7 in association with DNA damage response markers and p53 in patients with hepatocellular carcinoma.

Methods

Expression of CDT1, MCM7, p-H2A histone family member X (H2AX), phospho-ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia rad3-related (ATR) substrate, and p53 was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded surgical specimens from 111 patients who underwent hepatectomy for hepatocellular carcinoma. Statistical analysis was performed to evaluate associations between the studied proteins, clinicopathological parameters, and patient survival.

Results

CDT1 expression correlated with p-H2AX (p?=?0.038), while MCM7 correlated with p-H2AX and phospho-ATM/ATR substrate (p?<?0.001). Increased CDT1 expression was associated with higher tumor grade (p?=?0.006) and tumor-node-metastasis (TNM) stage (p?=?0.033). High CDT1 expression correlated significantly with reduced overall survival (60.8 and 26.5 % vs 82.8 and 53.0 %, for low CDT1 expression, at 2 and 5 years, respectively, p?=?0.012) and was identified by multivariate analysis as an independent predictor of poor overall survival (p?=?0.049).

Conclusions

Overexpression of CDT1 and MCM7 in hepatocellular carcinoma correlates with DNA damage response, and CDT1 overexpression is a significant prognostic biomarker in hepatocellular carcinoma.

     

Investigating Transitional Care to Decrease Post-pancreatectomy 30-Day Hospital Readmissions for Dehydration or Failure to Thrive

Background

Current literature emphasizes post-operative complications as a leading cause of post-pancreatectomy readmissions. Transitional care factors associated with potentially preventable conditions such as dehydration and failure to thrive (FTT) may play a significant role in readmission after pancreatectomy and have not been studied.

Methods

Thirty-one post-pancreatectomy patients, who were readmitted for dehydration or FTT between 2009 and 2014, were compared to 141 nonreadmitted patients. Medical record review and a questionnaire-based survey, specifically designed to assess transitional care, were used to identify predictors of readmissions for dehydration or FTT. Logistic regression models were used to evaluate outcomes.

Results

On multivariable analysis, the strongest predictors of readmission for dehydration and FTT were the patient’s lower educational level (P?=?0.0233), the absence of family during the delivery of discharge instructions (P?=?0.0098), episodic intermittent nausea at discharge (P?=?0.0019), uncertainty about quantity, quality, or frequency of fluid intake (P?=?0.0137), and the inability or failure to adhere to the clinician’s instructions in the outpatient setting (P?=?0.0048).

Conclusion

Transitional-care-related factors are found to be associated with post-pancreatectomy readmission for dehydration and FTT. Using these results to identify high-risk patients and implement focused preventive measures combining efficient communication and optimal inpatient and outpatient management could potentially decrease readmission rates.

     

Managing Small Ureteral Stones: A Retrospective Study on Follow-Up,Clinical Outcomes and Cost-Effectiveness of Conservative Management vs. Early Surgery

Introduction

The management of ureteral calculi has evolved over the past decades with the advent of new surgical and medical treatments. The current guidelines support conservative management as a possible approach for ureteral stones sized = 10 mm.

Objectives

We purport to follow the natural history of ureteral stones managed conservatively in this retrospective study, and attempt to ascribe an estimated health-care and cost-effectiveness, from presentation to time of being stone-free.

Materials and methods

192 male and female patients with a single ureteral stone sized = 10 mm were included in this study. The clinical and cost-related outcome was analyzed for different stone sizes (0-4, 4-6 and 6-10 mm). The effectiveness of selected follow-up (FU) scans was also analyzed.

Results

Stone size was found to be related to the degree of hydronephrosis and to the likelihood of need for a surgical management. Conservative management was found to be clinically effective, as 88% of the patients did not require surgery for their stone. 96.1% of the patients with a stone 0-4mm managed to expel their ureteral stone. Bigger ureteral stones were found to be more costly. The cost-effectiveness of the single FU scans was found to be related to their efficiency, while the global cost-effectiveness of conservative management vs. early surgery was higher for smaller stones (26.8 vs. 17.32% for stones 0-4 vs. 6-10 mm).

Conclusion

Conservative management is clinically effective with a significant cost-benefit, particularly for the subgroup of stones sized 0-4 mm, where a need for FU scans is in dispute.Key Words: Conservative management, Cost-effective, Tamsulosin, Ureteral calculus, Urolithiasis     

Process Development and Robust Control of Physical Attributes of an Amorphous Drug Substance

Control of physical attributes of amorphous active pharmaceutical ingredients (APIs) can be challenging due to processability issues, their wide variation during processing and the requirement to control them to specific ranges. In this article, we report our efforts to develop a robust isolation process for boceprevir, which delivers specific surface areas between 3.0 and 9.4 m²/g. We developed mechanistic process understanding by utilizing a new method to measure glass transition temperature of API suspensions. Boceprevir processability and surface area are determined by the interplay between the suspension operating conditions and glass transition temperature. Processing time and thermal history also influence API surface area evolution, rendering a dynamic nature to it. A control strategy was developed consisting of 2 elements: a continuous tee mixer precipitation process, which delivers API in the 40-60 m²/g range and 1 of 2 annealing step variants. In the first, surface area was controlled in 4 batches to 6.7-7.5 m²/g by equilibrating the API suspension above its glass transition temperature and a subsequent vacuum distillation. The second annealing variant controlled surface area to 4.5-6.5 m²/g for over 70 commercial batches through a dynamic vacuum distillation step with prescribed temperature and % batch volume distilled profiles versus time.     

Preparation of New Risperidone Depot Microspheres Based on Novel Biocompatible Poly(Alkylene Adipate) Polyesters as Long-Acting Injectable Formulations

Risperidone (RIS)-loaded microspheres based on poly(alkylene adipate)s derived from dicarboxylic acids and different aliphatic diols were prepared by the oil in water emulsion and solvent evaporation method. Specifically, 3 polyesters, namely poly(ethylene adipate), poly(propylene adipate), and poly(butylene adipate), were prepared with the aid of a 2-stage melt-polycondensation method and characterized by gel permeation chromatography, proton nuclear magnetic resonance (¹H NMR), differential scanning calorimetry, and X-ray diffraction analysis. Results showed that the molecular weight of the polyesters increased as the diol molecular weight increased, while all polymers were of semi-crystalline nature and the melting temperature was varying from 49.1°C to 51.8°C and 65.9°C for poly(propylene adipate), poly(ethylene adipate), and poly(butylene adipate), respectively. The particle size of the RIS-loaded microspheres varied from 10 to 100 μm depending on the polyester type and the drug loading, while X-ray diffraction analysis revealed amorphous active pharmaceutical ingredient in the cases of high drug-loaded microspheres. In vitro drug release studies along with scanning electron microscopy images of microspheres after the completion of dissolution process showed that in all cases RIS release was controlled by the glass transition temperature of polyesters and physical state of active pharmaceutical ingredients via diffusion.     

Analytical and electrochemical evaluation of the in vitro corrosion behavior of nickel-chrome and cobalt-chrome casting alloys for metal-ceramic restorations

In this study we examined the hypothesis based on relevant literature survey that the in vitro corrosion behavior of a Cobalt-chrome dental casting alloy for metal-ceramic restorations is better than that of a Nickel-chrome dental casting alloy. The corrosion released metal ions were analysed by Inductively Coupled Plasma-Atomic Emission Spectroscopy. Moreover, the specimens were electrochemically tested by linear polarization. The statistical analysis of the results showed statistically significant differences in corrosion rates of Nickel-chrome alloy and Cobalt-chrome alloy calculated by analytical and electrochemical measurements. The hypothesis was confirmed and the results showed that the corrosion rates of the Cobalt-chrome alloy were lower than that of the Nickel-chrome alloy.     

The role of adipocytokines in insulin resistance in normal pregnancy: visfatin concentrations in early pregnancy predict insulin sensitivity

BACKGROUND: Throughout pregnancy maternal adipose tissue is metabolically active, producing adipocytokines involved in the process of insulin resistance. We explored the role of serum adipocytokines, including the newly identified adipocytokine visfatin, in the process of insulin resistance in normal pregnancy. METHODS: We examined 80 pregnant nonobese, nondiabetic white women during the 3 trimesters of pregnancy. All study participants underwent anthropometric measurements, adipocytokine evaluation, and a 75-g oral glucose tolerance test. Homeostasis mathematical model assessment (HOMA-R), insulin sensitivity index (ISI), and indices of beta-cell secretion were calculated. RESULTS: Maternal weight, percentage total body fat, hip circumference, and indices of beta-cell secretion increased significantly during the 3 trimesters, and HOMA-R and ISI increased and decreased, respectively, in the 3rd trimester. During early pregnancy, insulin resistance, beta-cell secretion, and weight correlated positively with leptin. During the 1st trimester, visfatin correlated negatively with percentage body fat and was the best positive predictor of 2nd trimester ISI. In the 2nd trimester, serum visfatin was the best negative predictor of percentage body fat. CONCLUSIONS: During normal pregnancy of nonobese, nondiabetic women, adipose tissue increases, accompanied by a significant progressive increase of insulin resistance. Visfatin concentrations in the 1st trimester positively predict insulin sensitivity during the 2nd trimester. Body fat mass during 1st trimester of pregnancy is negatively associated with insulin sensitivity during the 2nd trimester and perhaps should be kept under control.