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Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim–sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. The antimicrobial activity of iclaprim was tested in vitro using an efficient axenic culture system, and in vivo using P. carinii endotracheally inoculated corticosteroid-treated rats. Animals were orally administered iclaprim (5, 25, 50 mg/kg/day), iclaprim/SMX (5/25, 25/125, 50/250 mg/kg/day), TMP (50 mg/kg/day), or TMP/SMX (50/250 mg/kg/day) once a day for ten consecutive days. The in vitro maximum effect (Emax) and the drug concentrations needed to reach 50% of Emax (EC50) were determined, and the slope of the dose–response curve was estimated by the Hill equation (Emax sigmoid model). The iclaprim EC50 value was 20.3 μg/mL. This effect was enhanced when iclaprim was combined with SMX (EC50: 13.2/66 μg/mL) (p = 0.002). The TMP/SMX EC50 value was 51.4/257 μg/mL. In vivo, the iclaprim/SMX combination resulted in 98.1% of inhibition compared to TMP/SMX, which resulted in 86.6% of inhibition (p = 0.048). Thus, overall, the iclaprim/SMX combination was more effective than TMP/SMX both in vitro and in vivo, suggesting that it could be an alternative therapy to the TMP/SMX combination for the treatment of Pneumocystis pneumonia. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B ( CHB) is one of the major public health challenges in the world. Due to a strong interplay between specific T-cell immunity and elimination of hepatitis B virus ( HBV), efforts to develop novel immunotherapeutics are gaining attention. TG1050, a novel immunotherapy, has shown efficacy in an animal study. To support the clinical development of TG1050 in China, specific immunity to the fusion antigens of TG1050 was assessed in Chinese patients. One hundred and thirty subjects were divided into three groups as CHB patients, HBV spontaneous resolvers, and CHB patients with HBsAg loss after antiviral treatment. HBV-specific T-cell responses to pools of HBV Core or Polymerase genotype D peptides included in TG1050 were evaluated. HBV Core- or Polymerase-specific cells were detected in peripheral blood mononuclear cells ( PBMCs) from the different cohorts. The frequencies and intensities of HBV Core-specific immune responses were significantly lower in CHB patients than in HBsAg loss subjects. In CHB patients, a dominant pool derived from Polymerase (Pol1) was the most immunogenic. CHB patients with low viral loads (<106 IU/ mL) were more likely to have a positive response specific to the Core peptide pool. Overall, genotype D-derived peptides included in TG1050 could raise broad and functional T-cell responses in PBMCs from Chinese CHB patients infected with genotype B/C isolates. Core-specific immunogenic domains appeared as 'hot spots' with the capacity to differentiate between CHB vs HBsAg loss subjects. These observations support the extended application and associated immune monitoring of TG1050 in China. [ABSTRACT FROM AUTHOR]

Several noninvasive blood biomarkers have been established for the assessment of liver fibrosis in patients with chronic hepatitis B virus ( HBV) infection, but their clinical performance remains inconclusive. Here, we compared the diagnostic performance of these biomarkers and developed a novel algorithm for assessing liver fibrosis. Six hundred and sixteen chronically HBV-infected and treatment-naïve patients who underwent liver biopsy were enrolled and randomly divided into training (N=410) and internal validation cohorts (N=206). One hundred and fifty-nine patients from another centre were recruited as an external validation cohort. Receiver operating characteristic ( ROC) curves were used to analyse the performance of the gamma-glutamyltransferase-to-platelet ratio ( GPR), red cell volume distribution width-to-platelet ratio ( RPR), FIB-4 index, aspartate aminotransferase-to-platelet ratio index ( APRI) and HBV DNA level against liver histology, and a novel algorithm was developed using the recursive partitioning and regression tree ( RPART) method. In the training cohort, the area under the ROC curve of FIB-4 was significantly higher than that of APRI ( P=.038) but was comparable to those of GPR, RPR and HBV DNA; however, the performance of the biomarkers was similar among the validation cohort. The established RPR- HBV DNA algorithm performed better in the training cohort than any individual blood biomarker, and the corresponding sensitivity, specificity, positive predictive value and negative predictive value were 63%, 90%, 72% and 80%, respectively. In the internal and external validation cohorts, the performance of the algorithm in assessing liver fibrosis was also superior to that of other biomarkers. These results suggest that the established RPR- HBV DNA algorithm might improve the diagnostic accuracy of liver fibrosis in treatment-naïve patients with chronic HBV infection, although additional studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Radiation courses generally involve multiple visits over the course of weeks, depending on the disease site and treatment technique. Therefore, radiation therapy (RT) may be discontinued prior to planned treatment completion. The purpose of this analysis is to identify any clinical or socioeconomic factors that could serve as predictors of RT discontinuation.Materials/methods: Using the National Cancer Database (NCDB) data from 2017, we identified 7,561 cases treated with RT, chemoradiation (CRT), surgery with RT (S+RT), or surgery with CRT (S+CRT) that had information on radiation discontinuation. The variables that we assessed include age (18- < 50, 50- < 70, 70+), gender (male, female), race (White, Black, other), insurance status (private, Medicare, Medicaid/uninsured, other government), income level (< $30,000, $30,000- < $35,000, $35,000- < $46,000, $46,000+), Charlson-Deyo Comorbidity Score (0, 1, ≥2), treatment type (RT, CRT, S+RT or S+CRT), disease site, and distance from patient residence to treatment facility. RT discontinuation was compared to socioeconomic and clinicopathologic characteristics using chi-square analysis for categorical predictors and Wilcoxon-Mann-Whitney test for continuous predictors.Results: Of the 7,561 patients with information on RT discontinuation, 7,349 (97.2%) patients completed RT, whereas RT was discontinued in 212 (2.8%) patients. The reasons for discontinuation are shown in Table 1. Patients who are 70+ years old (3.7%, P = 0.008), male (3.4%, P = 0.014), Black (3.2%, P = 0.030), Medicaid/uninsured (3.9%, P < 0.0001), income < $30,000 (4.9%, P < 0.0001) and Charlson-Deyo Comorbidity Score ≥2 (3.9%, P = 0.005) had the highest percentages of RT discontinuation in their respective categories. By treatment type, CRT (5.94%) had the highest discontinuation rates, followed by RT (3.1%), S+CRT (2.1%), and S+RT (1.8%), P < 0.0001. Disease site correlated with RT discontinuation (P < 0.0001) with the highest rates of RT discontinuation for cancers of the urinary tract (8.8%), head and neck (6.2%), and respiratory tract (6.0%). The median distance between patient residence and treatment facility was 11.2 and 9.6 miles for patients in the RT completion and RT discontinuation groups, respectively (P = 0.294).Conclusion: In this NCDB analysis, both clinical and socioeconomic characteristics, including age, gender, race, insurance status, income level, comorbidities, treatment type, and disease site, correlated with RT discontinuation rates. While toxicity of treatment was reported, patient decision was the most common reason for RT discontinuation. Table 1. Reasons for RT discontinuation (N = 212). [ABSTRACT FROM AUTHOR]

Anti-inflammation strategy is one of the proposed therapeutic approaches to hepatic fibrosis. IL-17 is critical in inflammation, but the role of IL-17 in liver fibrosis has not yet been elucidated. In this study, we investigate the role of IL-17 on bile duct ligation-induced liver injury and fibrosis in C57BL/6 mice. Animals were sacrificed at designated times, and serum and liver tissues were collected for analysis of liver function and serum IL-6, IL-1β, tumour necrosis factor-alpha ( TNF-α) and transforming growth factor-β ( TGF-β) levels. IL-17 blockade with anti- IL-17A mAb significantly improved liver function and decreased hepatocellular necrosis, pro-inflammatory cytokines, neutrophils and macrophages influx. Furthermore, CD3 + and CD8 + lymphocytes, neutrophils and macrophages were found to express IL-17, and neutrophils are the principal IL-17-producing cells after BDL-induced liver injury. These data indicated that IL-17 signal contributes to the pathogenesis of cholestatic liver injury and blocked of IL-17 could potentially benefit patients with cholestatic liver disease. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) are small noncoding RNAs that are critical regulators of gene function. In the recent years, miRNAs have been increasingly noted for their capacity to regulate key malignant properties of tumor cells. MicroRNA-128 (miR-128) is a brain-enriched miRNA that is normally involved in the development of the nervous system and in the maintenance of neural physiological functions. In tumor cells, miR-128 expression is dysregulated through a variety of genetic and epigenetic events. Dysregulation of miR-128 has profound effects on tumorigenesis and maintenance of tumor cells through alterations in cellular proliferation, differentiation, metabolism, and apoptosis. This article will review the latest advances in our understanding of miR-128, specifically in the context of clinical and fundamental cancer biology. Further characterization of miR-128 will likely identify its new roles in cancer biology. The use of miR-128 as a diagnostic and/or therapeutic tool may result in improvements in diagnosis, prognosis, and treatment of numerous cancers. [ABSTRACT FROM AUTHOR]

Background:Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours.Methods:Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course.Results:Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile.Conclusions:These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) infection in healthcare personnel occurs mostly by mycobacteria inhalation and contact with infected material. Here, we report a case of primary inoculation TB in a surgeon resulting from an accidental scalpel injury. Standard anti-TB treatment produced a good result, and no relapses occurred in the 18-month follow-up period. Given the increased incidence of TB and the use of surgery to treat multidrug-resistant (MDR) strains, this report underscores the need to take special precautions during lesion excision in TB patients. [ABSTRACT FROM AUTHOR]

Zheng Q, Zhang L, Zhou X, Wang Q, Wang Y, Tang L, Song F, Huang D. C-shaped root canal system in mandibular second molars in a Chinese population evaluated by cone-beam computed tomography. International Endodontic Journal, 44, 857-862, 2011. Abstract Aim To evaluate the anatomical features of C-shaped canal systems in Chinese mandibular second molars by cone-beam computed tomography (CBCT). Methodology A total of 608 patients of Chinese descent with healthy, well-developed mandibular second molars were enrolled. These patients were referred to the West China Hospital of Stomatology and required radiographic examination by CBCT as part of their routine dental treatment. Of the 608 examined CBCT images, 528 showed unilateral intact molars and 80 showed bilateral intact molars. Bilateral molar data were only used to analyse the distribution of unilateral and bilateral occurrences of C-shaped canals. The following in vivo CBCT observations were made: (i) frequency and type of root; (ii) frequency of C-shaped canals by gender, age and tooth position (left versus right); (iii) the classification of cross-sectional canal images of C-shaped canals; and (iv) unilateral and bilateral occurrences of C-shaped canals. Results Fused roots were present in 39% of molars. A C-shaped canal system was present in 39% of the teeth. This prevalence did not differ with gender, age and tooth position. Most (81%) of the C-shaped canals in individuals with bilateral molars were symmetrical. Most of the canals with uninterrupted 'C'-shapes appeared to divide into two or more canals towards the canal terminus. Conclusion There was high prevalence of C-shaped canals in the mandibular second molars of Chinese population. The canal systems varied considerably in their anatomical configuration. [ABSTRACT FROM AUTHOR]

Therapy for hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients results in modest cure rates. Gene expression patterns in peripheral blood mononuclear cells from 29 patients coinfected with HIV and HCV were used to predict virological response to therapy for HCV infection. Prediction analysis using pretherapy samples identified 79 genes that correctly classified all 10 patients who did not respond to therapy, 8 of 10 patients with a response at the end of treatment, and 7 of 9 patients with sustained virological response (86% overall). Analysis of 17 posttreatment samples identified 105 genes that correctly classified all 9 patients with response at the end of treatment and 7 of 8 patients with sustained virological response (94% overall). Failure of anti-HCV therapy was associated with elevated expression of interferon-stimulated genes. Gene expression patterns may provide a tool to predict anti-HCV therapeutic response. [ABSTRACT FROM AUTHOR]

Discusses the role of the Bel-2 protein family in tumorigenesis and chemoresistance. Factions of interacting proteins including BH3-only proteins; Role of BH3-only proteins in transmission of specific death signals; Findings that highlight the therapeutic prospects for targeting the Bcl-2 family with small molecules.

Objective: To determine the effect of adding intravenous theophylline (administered as aminophylline) to nebulizations of albuterol and intravenous methylprednisolone in adults hospitalized for acute asthma.Design: Randomized, placebo-controlled, double-blind study.Setting: Inpatient service of a tertiary-care, university teaching hospital.Patients: 21 adults (22 to 48 years old)--10 in the aminophylline group and 11 in the placebo group.Interventions: Nebulized albuterol, 2.5 or 5.0 mg every 0.5 to 4 hours; intravenous methylprednisolone, 60 mg every 6 hours; and either individualized doses of aminophylline or placebo for 48 hours.Measurements: Forced expiratory volume in 1 second (FEV1), the number of "as needed" albuterol nebulizations and total dose, asthma symptom scores, and adverse effects.Results: At admission from the emergency department, the mean +/- SD baseline FEV1 was 49% +/- 19% of the predicted value in the aminophylline group and 43% +/- 13% of the predicted value in the placebo group. The improvement in FEV1 at 3 hours was greater in the aminophylline group (29% +/- 23% compared with 10% +/- 10% in the placebo group; mean difference, 19 percentage points; 95% CI, 3 to 35 percentage points; P = 0.023). At 48 hours, FEV1 was 75% +/- 19% of the predicted value in the aminophylline group and 58% +/- 15% of the predicted value in the placebo group (mean difference, 17 percentage points; CI, 0.2 to 34.8 percentage points; P = 0.048). Aminophylline-treated patients required fewer nebulizations of albuterol (10.3 +/- 3.8 compared with 16.4 +/- 5.3; mean difference, -6.1; CI, -10.3 to -1.8) and less total dosage (34 +/- 16 mg compared with 70 +/- 34 mg; mean difference, -36 mg; CI, -60.6 to -11.3 mg P = 0.02). No statistical differences were observed in asthma symptom scores or frequency of adverse effects.Conclusions: Individualized doses of intravenous theophylline added to frequent nebulizations of albuterol and intravenous methylprednisolone appear to benefit adults admitted to the hospital with acute asthma and are well tolerated when serum concentrations are maintained in the therapeutic range. [ABSTRACT FROM AUTHOR]