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Background: Complicated appendicitis (appendicitis with abscess, perforation, or generalized peritonitis) poses a significant burden on healthcare systems, with incidence up to 28–29%. Current management options include antibiotic therapy and up-front surgery, antibiotic therapy and percutaneous drainage, or antibiotic therapy alone. There is no consensus on treatment guidelines in current literature. This study aims to better define treatment algorithms for patients presenting with acute complicated appendicitis by evaluating clinical outcomes in those treated with or without surgery. Methods: We performed a single-institution, retrospective review of 220 adult patients (≥ 18 years old) treated for acute complicated appendicitis from January 2017 to June 2022. Demographic and clinicopathologic variables were collected and analyzed. We compared patients who were managed non-operatively versus operatively. Regression modeling was used to determine factors associated with non-operative management (NOM) and those predictive of failure of NOM. Results: Our analysis showed 26.3% patients with acute complicated appendicitis underwent NOM (n = 58), versus 73.6% underwent operative management at index admission (n = 162). Within the NOM group, 55.1% patients were treated with antibiotics alone (n = 32) versus 44.8% with percutaneous drainage (n = 26). Within the operative cohort, 88.7% of patients underwent appendectomy (n = 142). Age, body mass index, comorbidities, vital signs and laboratory values on admission were similar between both groups. Clinical factors predictive of initial NOM were perforation (OR 7.9, 95% CI 3.7–16.5) and phlegmon (OR 6.3, 95% CI 2.8–14.1) at presentation. Clinical factors predictive of failure of NOM requiring surgery on index admission or within 30 days was larger abscess and/or phlegmon size (OR 1.76, 95% CI 1.0–3.0). Conclusion: There may be a role in identifying clinical factors in patients with complicated appendicitis that favor non operative versus operative management. Larger abscess and/or phlegmon size could be a predictor of failure of NOM. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The complications of benign prostatic hyperplasia (BPH) among others include bladder stones. The prevalence of vesical calculus is eight times higher in men having BPH (3.4%) as compared with men without BPH (0.4%). The guidelines suggest that BPH obstruction should be managed along with removal of bladder stones. The objective of the study was to study the outcome of surgery in patients with BPH and bladder calculi. MATERIALS AND METHODS: This prospective study included all patients undergoing surgical treatment for BPH with vesical calculi. Outcomes were measured in terms of blood loss, operating time, days of hospitalization, postoperative urinary flow, postvoid residual, and complications. RESULTS: Five (13.51%) patients underwent perurethral cystolitholapaxy, 17 (45.94%) underwent percutaneous suprapubic cystolitholapaxy, and the remaining 15 (40.54%) underwent open cystolithotomy for bladder stones. The prostate (BPH) was managed by monopolar transurethral resection of prostate (TURP) in 14 (37.83%), bipolar TURP in 12 (32.43%), and laser prostatectomy (Holmium enucleation) in the remaining 11 (29.72%). At the time of discharge, all patients were free of bladder stones and voided well. At 3-month follow-up, the mean Q-max was 18.65 mL/s. CONCLUSIONS: Simultaneous management of BPH and bladder stones is safe and effective. The procedure chosen for managing bladder stones depends on the size, number, and experience of the surgeon. Smaller stones can be easily managed by minimally invasive procedures such as perurethral cystolitholapaxy and percutaneous cystolitholapaxy. [ABSTRACT FROM AUTHOR]

Background: More than 85% of young people around the world suffer from acne vulgaris, which is the most prevalent chronic inflammatory skin illness. The study's objective was to develop a herbal patch formulation contained quercetin, curcuminoids, and berberine HCl for the treatment of acne that utilizing ethyl cellulose and HPMC K4M as polymers and propylene glycol as a plasticizer. Materials and Methods: Drug excipient compatibility study was performed using FT-IR. Preliminary trial was done for screening of polymers and plasticizer concentrations. The combined influence of the two independent variables, namely the concentration of HPMC K4M and ethyl cellulose, on the dependent variables, tensile strength and cumulative % drug release at 24 hr, was examined using a 32 full factorial design. Patches were evaluated for physicochemical parameters. Results: Drug excipient compatibility study revealed that drug and excipients are compatible with each other. The optimized formulation (C0) showed tensile strength 2.56 kg/cm2, cumulative percentage drug release of quercetin, berberine HCl, and curcuminoids at 24 hr were 94.02%, 64.66%, and 94.21%, respectively. Tensile strength increased with an amount of HPMC K4M and Ethyl cellulose increases, the cumulative percentage of drug release decreased as HPMC K4M and ethyl cellulose concentrations were raised. Conclusion: Optimized herbal patch formulation had shown good physico-chemical and mechanical properties. The research shows that the developed formulation has the potential to be a useful replacement for the present medications in the market. [ABSTRACT FROM AUTHOR]

An organization's success depends on its employees, and an employee's performance decides whether the organization is successful. Employee performance enhances the productivity and output of organizations, i.e., the performance of an employee paves the way for the organization's success. Hence, analyzing employee performance and giving performance ratings to employees is essential for companies nowadays. It is evident that different people have different skill sets and behavior, so data should be gathered from all parts of an employee's life. This paper aims to provide the performance rating of an employee based on various factors. First, we compare various AI-based algorithms, such as random forest, artificial neural network, decision tree, and XGBoost. Then, we propose an ensemble approach, RanKer, combining all the above approaches. The empirical results illustrate that the efficacy of the proposed model compared to traditional models such as random forest, artificial neural network, decision tree, and XGBoost is high in terms of precision, recall, F1-score, and accuracy. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17) and the resulting gene PML-RARA, used for measurable residual disease (MRD) monitoring. Despite highly effective therapy for APL, MRD monitoring practices are not fully established. We aimed to assess the value of MRD monitoring by RT-qPCR in patients with APL treated with ATRA and arsenic trioxide +/– GO. We reviewed 223 patients with APL treated with this regimen. RT-qPCR for PML-RARA was measured every 3 months, and at 12, 18, and 24 months after therapy. Seven patients relapsed. Time to relapse was 7.9–12.4 months in 6 patients, and one patient relapsed after 79.5 months. These data show that MRD monitoring may be important for the detection of relapse in patients treated with this regimen within one year after completing therapy, however, since late molecular relapse is rare, our data suggest a low value of MRD monitoring beyond that first year. [ABSTRACT FROM AUTHOR]

Fusarium species are generally appropriated pathogens in roots, plant debris and soil causing major disease as primary, secondary invader and co-invader with other pathogens. Fusarium chlamydosporum is the second most important pathogen, followed by F. solani to cause root rot disease in soybean (Glycine max) crop. The present study explores mycoparasitic activity of Pseudomonas aeruginosa (OG101) and Pseudomonas putida (PP) for the management of Fusarium infection in soybean crop. Investigation of glucanase production, chitinase production as well as effect on spore germination was assessed for in vitro biocontrol activity of Pseudomonas sp. and obtained that P. aeruginosa (OG101) produced 13% higher glucanase, 12% higher chitinase and 15% more spore inhibition as compared to P. putida (PP). Disease index of 1.73 and 2 was observed in plants treated with P. aeruginosa (OG101) and P. putida (PP) in presence of pathogen F. chlamydosporum, respectively. Both strains exhibited mycoparasitic activity which helps in management of fusarial infection in Glycine max. [ABSTRACT FROM AUTHOR]

* Context.--RNA-based next-generation sequencing (NGS) assays are being used with increasing frequency for comprehensive molecular profiling of solid tumors. Objective.--To evaluate factors that might impact clinical assay performance. Design.--A 4-month retrospective review of cases analyzed by a targeted RNA-based NGS assay to detect fusions was performed. RNA extraction was performed from formalin-fixed, paraffin-embedded tissue sections and/or cytology smears of 767 cases, including 493 inhouse and 274 outside referral cases. The types of samples included 422 core needle biopsy specimens (55%), 268 resection specimens (35%), and 77 cytology samples (10%). Results.--Successful NGS fusion testing was achieved in 697 specimens (90.9%) and correlated positively with RNA yield (P < .001) and negatively with specimen necrosis (P = .002), decalcification (P < .001), and paraffin block age of more than 2 years (P = .001). Of the 697 cases that were successfully sequenced, 50 (7.2%) had clinically relevant fusions. The testing success rates and fusion detection rates were similar between core needle biopsy and cytology samples. In contrast, RNA fusion testing was often less successful using resection specimens (P = .007). Testing success was independent of the tumor percentage in the specimen, given that at least 20% tumor cellularity was present. Conclusions.--The success of RNA-based NGS testing is multifactorial and is influenced by RNA quality and quantity. Identification of preanalytical factors affecting RNA quality and yield can improve NGS testing success rates. [ABSTRACT FROM AUTHOR]

Chickpea is produced as well as consumed highest in India amongst the whole world but, production is seriously curtailed by Fusarium wilt, caused by Fusarium oxysporum f.sp. ciceris (FOC). In stressful conditions, the reactive oxygen species (ROS) production increases in plants which cause significant damage. To reduce this ROS, plants have inbuilt antioxidants that can detoxify ROS and protect cells of plants. The present study aimed to investigate the effect of Micrococcus luteus on the induction of defense enzymes in the presence and absence of Fusarium in chickpea. Talc-based bio-formulation of marine M. luteus was employed under pot trials to scrutinize mechanism of induced resistance against Fusarium by the improvement of defense enzymes like SOD, POX as well as accumulation of L-proline, total phenolic and pigments like chlorophyll and carotenoids. Pot trials were done using four different conditions- T1 (control), T2 (M. luteus treated), T3 (FOC treated), and T4 (M. luteus + FOC treated). Defense enzymes were studied and a maximum increase in M. luteus treated plants as compared to control and pathogen treated plants were noted. The chlorophyll and carotenoid content were improved in M. luteus treated plants to pathogen treated plants. This study indicated that M. luteus helps the plant to protect itself from free radicals as it showed significant induction of enhanced plant defense response against soil-borne pathogen to protect chickpea plant. [ABSTRACT FROM AUTHOR]

Background: Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT).Methods: Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis.Results: MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2).Conclusions: Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials. [ABSTRACT FROM AUTHOR]

Plants require essential elements like C, H, O, N, P, K, considered as a macro elements and Zn as a micro element. This elemental approach can be done either by naturally or organic/inorganic fertilizers, conventionally. Considering the sustainable approach towards plant growth and development, usage of organic and inorganic fertilizers reduced by using biofertilizer with mineral weathering efficiency. Such a strain belong to family Actinomycetes, Streptomyces nanhaiensis strain YM4 was isolated from rhizosphere of rajagra plant of Khambhat region helps to plant growth promotion and mineral solubilisation efficiency. Present report suggest that it produces 73 µg ml-1 of indolic compounds and 4.48 µmol ml-1 ammonia production. Along with that it has an efficiency to solubilize 232 mg ml-1 of phosphate, 41.6 mg ml-1 of potassium and 41.16 ppm of zinc in laboratory conditions. The pot trial of liquid bioformulation of strain YM4 on millet crop enhance the plant growth with enhanced leaf biomass and pigment production, significantly. Effect of strain helps to mineralize and accumulate minerals in rhizospheric region of the millet crop. [ABSTRACT FROM AUTHOR]

Summary: This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL. [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukaemia (CLL) is a genetically heterogeneous disease characterised by genomic alterations and gene mutations that may portend worse survival or resistance to treatments. A total of 680 blood or bone marrow samples underwent targeted sequencing of 29 genes previously identified as being mutated in CLL, which were correlated to known prognostic clinical characteristics. Overall, 400 (59%) patients were treatment‐naïve (TN) and 280 (41%) were relapsed/refractory (R/R). Most patients (70%) had ≥1 mutation, with TP53 (22%), SF3B1 (18%), NOTCH1 (13%) and ATM (13%) being the most commonly mutated genes. A higher proportion of R/R patients had mutations in SF3B1 (P = 0·01) and TP53 (P < 0·001). Patients with mutated IGHVCLL more often had mutations in KLHL6 (P = 0·001) and MYD88 (P < 0·001). Pairwise associations showed mutational co‐occurrences in the TN group including SF3B1/ATM [false discovery rate (FDR) < 0·05] and NOTCH1/POT1 (FDR < 0·01). Recurrent mutations resulting in premature truncation prior to the ubiquitination domains of NOTCH1 in its PEST domain and BIRC3 in its RING domain can produce proteins that constitutively activate CLL. Frequent missense mutations, such as K700E in SF3B1 and E571K in XPO1, have unknown function but are most likely to be activating mutations. Future directions include using these mutations to identify pathways for therapeutic targeting and rational drug design. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms (MPNs) are clonal disorders divided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) or Ph chromosome-negative MPNs. Co-occurrence of these disease entities is very rare and typically involves presence of common p190 or p210 BCR/ABL fusion transcript (responsible for CML) along with JAK2V617F mutation (most common driver mutation in Ph-negative MPNs). Because of the rarity of such cases, it is not clear if the outcomes are any different in these patients. In this article, we report a unique patient with polycythemia vera driven by a rare complex in-frame deletion-insertion mutation in JAK2 exon 12, and CML driven by uncommon p210 e14a3 (b3a3) BCR/ABL fusion transcript. We describe clinical and laboratory features, bone marrow pathology, treatment, and overall outcome. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the effectiveness of highly sensitive allele-specific quantitative polymerase chain reaction (AS-qPCR) in the monitoring and early detection of relapsed Janus kinase 2 gene (JAK2 V617F) myelofibrosis (MF) following allogeneic hematopoietic stem cell transplantation (SCT). Based on the results, AS-qPCR is more sensitive than pyrosequencing in detecting relapse/refractory disease (R/R) in patients.

Internet of Things (IoT) has evolved many day-to-day objects into smart objects, which humans can control when they are connected via Internet. Its practical implementation came into existence a few years back. Since the advent of IoT, it has tackled many challenges such as management, tracking, observation, etc. It has contributed to various fields such as Healthcare 4.0, smart grid, smart agriculture, Intelligent Transportation Systems (ITS), smart cities, smart homes, smart cars, and many more. It has applications through almost all domains, but the question arises: the performance evaluating parameters about specific IoT applications to consider to detect flaws in it. As per literature, there exist no such article helps beginners in selecting performance evaluation parameters for IoT-enabled applications. Motivated from the aforementioned facts, this paper presents a survey on performance evaluation metrics' systematic study for various IoT applications. We then graphically present the comparison of multiple parameters of domains security, energy efficiency, data storage, and network performance. From the analysis, we can infer that, in the smart city, latency is the most usable parameter, i.e., 77%. In contrast, in Healthcare 4.0, equal importance is given to latency and network bandwidth, which is 50%. Also, in Industry 4.0, scalability is the most opted performance parameter by the researchers, which is 100%. The smart grid application uses latency and delay are the most valuable parameters, i.e., 60%. [ABSTRACT FROM AUTHOR]

The aim of this review is to provide updated information on the clinical use of non-invasive serum and imaging-based tests for fibrosis assessment in chronic hepatitis B (CHB) virus infection. In recent years, non-invasive tests (NIT) have been increasingly used to determine eligibility for treatment. Liver biopsy is still considered the gold standard for assessing inflammatory activity and fibrosis staging, but it is an invasive procedure with inherent limitations. Simple serum markers such as APRI and FIB-4 are limited by indeterminate results but remain useful initial tests for fibrosis severity if imaging elastography is not available. Point-of-care US-based elastography techniques, such as vibration-controlled transient elastography or 2D shear wave elastography, are increasingly available and have better accuracy than simple serum tests for advanced fibrosis or cirrhosis, although stiffness cut-offs are variable based on E-antigen status and inflammatory activity. Current NITs have poor diagnostic performance for following changes in fibrosis with antiviral therapy. However, NITs may have greater clinical utility for determining prognosis in patients with CHB that have advanced disease, especially for the development of hepatocellular carcinoma and/or liver decompensation. Algorithms combining serum and imaging NITs appear promising for advanced fibrosis and prognostic risk stratification. [ABSTRACT FROM AUTHOR]

Despite significant improvements in the signs and symptoms of myelofibrosis (MF), and possible prolongation of patients' survival, some have disease that is refractory to ruxolitinib and many lose their response over time. Furthermore, patients with ≥3 mutations are less likely to respond to ruxolitinib. Here we describe outcomes after ruxolitinib discontinuation in MF patients enrolled in a phase 1/2 study at our center. After a median follow-up of 79 months, 86 patients had discontinued ruxolitinib (30 of whom died while on therapy). The median follow-up after ruxolitinib discontinuation for the remaining 56 patients was 32 months, with median survival after discontinuation of 14 months. Platelets <260 × 109/L at the start of therapy or <100 × 109/L at the time of discontinuation were associated with shorter survival after discontinuation. Of 62 patients with molecular data at baseline and follow-up, 22 (35%) acquired a new mutation while receiving ruxolitinib (14 [61%] in ASXL1). Patients showing clonal evolution had significantly shorter survival after discontinuation (6 vs 16 months). Transfusion dependency was the only clinical variable associated with clonal evolution. These findings underscore the need for novel therapies and suggest that clonal evolution or decreasing platelet counts while on ruxolitinib therapy may be markers of poor prognosis. [ABSTRACT FROM AUTHOR]

Treatment of cancer patients involves a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Traditionally, patients with metastatic disease are treated with combination chemotherapies or targeted agents. These cytotoxic agents have good response rates and achieve palliation; however, complete responses are rarely seen. The field of cancer immunology has made rapid advances in the past 20 years. Recently, a number of agents and vaccines, which modulate the immune system to allow it to detect and target cancer cells, are being developed. The benefit of these agents is twofold, it enhances the ability the body's own immune system to fight cancer, thus has a lower incidence of side effects compared to conventional cytotoxic chemotherapy. Secondly, a small but substantial number of patients with metastatic disease are cured by immunotherapy or achieve durable responses lasting for a number of years. In this article, we review the FDA-approved immunotherapy agents in the field of genitourinary malignancies. We also summarize new immunotherapy agents being evaluated in clinical studies either as single agents or as a combination. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) represents a significant global disease burden, with an estimated 130-150 million people worldwide living with chronic HCV infection. Within the six major clinical HCV genotypes, genotype 3 represents 22-30% of all infection and is described as a unique entity with higher rates of steatosis, faster progression to cirrhosis, and higher rates of hepatocellular carcinoma. Hepatic steatosis in the setting of hepatitis C genotype 3 (HCV-3) is driven by viral influence on three major pathways: microsomal triglyceride transfer protein, sterol regulatory element-binding protein-1c, and peroxisome proliferator-associated receptor-α. Historically with direct-acting antivirals, the rates of cure for HCV-3 therapies lagged behind the other genotypes. As current therapies for HCV-3 continue to close this gap, it is important to be cognizant of common drug interactions such as acid-suppressing medication and amiodarone. In this review, we discuss the rates of steatosis in HCV-3, the mechanisms behind HCV-3-specific steatosis, and current and future therapies. [ABSTRACT FROM AUTHOR]

Contamination of potentially carcinogenic hexavalent chromium (Cr(VI)) in the drinking water is a major public health concern worldwide. However, little information is available regarding the biological effects of a nanomoler amount of Cr(VI). Here, we investigated the genotoxic effects of Cr(VI) at nanomoler levels and their repair pathways. We found that DNA damage response analyzed based on differential toxicity of isogenic cells deficient in various DNA repair proteins is observed after a three-day incubation with K2CrO4 in REV1-deficient DT40 cells at 19.2 μg/L or higher as well as in TK6 cells deficient in polymerase delta subunit 3 (POLD3) at 9.8 μg/L or higher. The genotoxicity of Cr(VI) decreased ~3000 times when the incubation time was reduced from three days to ten minutes. TK mutation rate also significantly decreased from 6 day to 1 day exposure to Cr(VI). The DNA damage response analysis suggest that DNA repair pathways, including the homologous recombination and REV1- and POLD3-mediated error-prone translesion synthesis pathways, are critical for the cells to tolerate to DNA damage caused by trace amount of Cr(VI). [ABSTRACT FROM AUTHOR]

A sensitive and high throughput bioanalytical method has been developed for reliable determination of amodiaquine (AQ), N -desethylamodiaquine (DEAQ), artesunate (AS) and dihydroartemisinin (DHA) in human plasma by LC–MS/MS. The method employs a solid phase extraction procedure without an evaporation step and with optimum use of organic solvents to circumvent degradation of artemisinin derivatives. The analytes and their deuterated internal standards (ISs) were analyzed on Hypersil Gold (100 mm × 4.6 mm, 5 μm) column using acetonitrile and 2.0 mM ammonium formate (pH 2.50) in 80:20 ( v/v ) ratio as the mobile phase. A triple quadrupole mass spectrometer equipped with an electrospray ionization interface was used to detect and quantify the analytes. The method was established over the concentration range of 0.250–30.0 ng/mL, 1.50–180 ng/mL, 2.00–600 ng/mL and 5.00–1400 ng/mL for AQ, DEAQ, AS and DHA respectively using 250 μL human plasma. The intra-day and inter-day accuracy and precision (% CV) across quality controls varied from 93.3–105.0% and 1.7–8.3 respectively for all the analytes. The stability was assessed in whole blood as well as in plasma samples under different conditions. All four analytes were stable in whole blood up to 2 h on melting ice. The long term stability in plasma was ascertained up to 90 days. IS-normalized matrix factors ranged from 0.988–1.023 for all the analytes. The method was successfully applied to a bioequivalence study using 50 mg artesunate and 135 mg amodiaquine fixed dose formulation in 14 healthy subjects. [ABSTRACT FROM AUTHOR]

Background The molecular events that drive the transformation from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) have yet to be fully characterized. We hypothesized that detection of these mutations at the time of transformation from MDS to AML may lead to poorer outcomes. Methods We analyzed 102 MDS patients who were admitted to our institution between 2004 and 2013, had wild-type (wt) FLT3-ITD and RAS at diagnosis, progressed to AML, and had serial mutation testing at both the MDS and AML stages. Results We detected FLT3-ITD and/or RAS mutations in twenty-seven (26%) patients at the time of transformation to AML. Twenty-two patients (81%) had RAS mutations and five (19%) had FLT3-ITD mutations. The median survival after leukemia transformation in patients who had detectable RAS and/or FLT3-ITD mutations was 2.4 months compared to 7.5 months in patients who retained wt RAS and FLT3-ITD (hazard ratio [HR]: 3.08, 95% confidence interval [CI]: 1.9–5.0, p < 0.0001). In multivariate analysis, FLT3-ITD and RAS mutations had independent prognostic significance for poor outcome. [ABSTRACT FROM AUTHOR]

Although most patients with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal response, or quickly lose their response. To identify genes that may predict response to ruxolitinib, we performed targeted next-generation sequencing (NGS) of a panel of 28 genes recurrently mutated in hematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study. We also tested for CALR deletions by standard polymerase chain reaction methods. Ninety-eight percent of patients had a mutation in ≥1 gene. Seventy-nine (82.1%) patients had the JAK2V617F mutation, 9 (9.5%) had CALR mutations (7 type 1, 2 type 2), 3 (3.1%) had MPL mutations, and 4 (4.2%) were negative for all 3. ASXL1/JAK2 and TET2/JAK2 were the most frequently comutated genes. Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 were found in <5% of patients. Spleen response (≥50% reduction in palpable spleen size) was inversely correlated with the number of mutations; patients with ≤2 mutations had ninefold higher odds of a spleen response than those with ≥3 mutations (odds ratio = 9.37; 95% confidence interval, 1.86-47.2). Patients with ≥3 mutations also had a shorter time to treatment discontinuation and shorter overall survival than those with fewer mutations. In multivariable analysis, only number of mutations and spleen response remained associated with time to treatment discontinuation. Patients with ≥3 mutations had the worst outcomes, suggesting that multigene profiling may be useful for therapeutic planning for MF. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis. However, double inv(3)(q21q26.2) is extremely rare in AML. We report here 3 cases analyzed by oligonucleotide microarray comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP). Clinicopathologic, cytogenetic and molecular findings were correlated with clinical outcome to better understand the entity. Results: The study group included one man and two women at 56-74 years of age. The AML arose from myelodysplastic syndrome in one patient and from chronic myelomonocytic leukemia in another patient. Monosomy 7 was found as additional cytogenetic finding in one patient. One patient had a single inv(3) in the initial clone and acquired double inv(3) as part of clonal evolution. EVI1 (MECOM) rearrangement was confirmed using metaphase/interphase fluorescence in situ hybridization (FISH). Microarray (aCGH + SNP) data analysis revealed that the double inv(3) was a result of acquiring copy neutral loss of heterozygosity of chromosome 3q: arr[hg19] 3q13.21q29(10,344,387-197,802,470)x2 hmz, spanning ~ 94.3 Mb in size. Mutational profiling showed a PTPN11 mutation at a low level (~10 %) in one patient and wild type FLT3 and RAS in all patients. No patients achieved cytogenetic remission and all died with an overall survival (OS) of 23, 12 and 5 months, respectively. Conclusions: Double inv(3) is a result of acquired copy neutral loss of heterozygosity, a somatic repair event occurring as a part of mitotic recombination of the partial chromosome 3q. The double inv(3) in AML patients is highly associated with a rapid disease progression. [ABSTRACT FROM AUTHOR]

The diagnostic assessment of liver fibrosis, amajor determinant of disease severity, is an important step in the management of patients with chronic liver diseases. Liver biopsy is still considered the gold standard for the assessment of necroinflammation and fibrosis; however, recent technical advances have resulted in the development of numerous serum biomarkers and imaging tools as noninvasive alternatives to biopsy. These tests include biological (serum biomarker algorithms), physical (imaging assessment of tissue stiffness), and physiological (breath test) methods. Accumulating evidence shows that noninvasive tests provide prognostic information of clinical relevance, which has led to their incorporation into clinical guidelines and everyday practice. Here, the authors review and compare invasive and noninvasive tests for the diagnosis of liver fibrosis. They discuss emerging functional genomic, microparticle, protein-profiling, and bio- imaging tools, focusing on novel sensitive tools that are able to assess the dynamic nature of fibrogenesis, a key requirement for the assessment of the efficacy of antifibrotic compounds in the future. [ABSTRACT FROM AUTHOR]

Background: TP53 mutation is more prevalent in therapy-related myeloid neoplasms (t-MN) than their de novo counterparts; however, the pattern of mutations involving TP53 gene in t-MN versus de novo diseases is largely unknown. Methods: We collected 108 consecutive patients with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML). Clinical, hematological, and cytogenetic data were collected by searching the electronic medical record. TP53 sequencing was performed in all patients using a clinically validated next-generation sequencing-based gene panel assay. A previously published patient cohort consisting of 428 patients with de novo MDS/AML was included for comparison. Results: We assessed 108 patients with t-MN, in which 40 patients (37%) had TP53 mutations. The mutation frequency was similar between t-MDS and t-AML; but significantly higher than de novo MDS/AML (62/428 patients, 14.5%) (p < 0.0001). TP53 mutations in t-MN were mainly clustered in DNA-binding domains, with an allelic frequency of 37.0% (range, 7.1 to 98.8). Most mutations involved single nucleotide changes, of which, transitions (65.9%) were more common than transversions (34.1%). Missense mutations were the most frequent, followed by frameshift and nonsense mutations. This TP53 mutation pattern was strikingly similar to that observed in de novo MDS/AML. TP53 mutations in t-MN were associated with a complex karyotype (p < 0.0001), a higher number of chromosomal abnormalities (p < 0.0001), and an inferior overall survival in affected patients (6.1 vs 14.1 months) by univariate (p < 0.0001) and multivariate analyses (p = 0.0020). Conclusions: Our findings support the recent notion that heterozygous TP53 mutation may be a function of normal aging and that mutated cells are subject to selection upon exposure to cytotoxic therapy. t-MN carrying TP53 mutation have an aggressive clinical course independent of other confounding factors. [ABSTRACT FROM AUTHOR]

We evaluated the impact of antiretroviral-induced dyslipidemia on hepatitis C virus (HCV) biogenesis in human immunodeficiency virus (HIV)/HCV coinfected patients. This study used serum samples from antiretroviral-naive HIV/HCV patients initiating their first regimen as part of AIDS Clinical Trials Group study protocols (A5142, A5202). Initiation of antiretrovirals increased most lipoproteins and apolipoproteins. In the multivariable model, changes in apolipoproteins were associated with changes in log10 HCV RNA from baseline to week-24 of therapy. Off-target lipogenic changes need to be considered in the context of liver and other metabolic disease in HIV/HCV patients. [ABSTRACT FROM AUTHOR]

In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS ( p = 0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) ( p = 0.0410) and de novo AML (12.8%) ( p = 0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms. [ABSTRACT FROM AUTHOR]

Mottled-dappled ( Mo-dp ) is a mouse model of Menkes disease caused by a large, previously uncharacterized deletion in the 5′ region of Atp7a , the mouse ortholog of ATP7A . Affected mutants die in utero at embryonic day 17, and show bending and thickening of the ribs and distortion of the pectoral and pelvic girdles and limbs. To characterize this allele, we designed a custom 4x180K microarray on the mouse X chromosome and performed comparative genomic hybridization using extracted DNA from normal and carrier Mo-dp females, and identified an approximately 9 kb deletion. We used PCR to fine-map the breakpoints and amplify a junction fragment of 630 bp. Sequencing of the junction fragment disclosed the exact breakpoint locations and that the Mo-dp deletion is precisely 8990 bp, including approximately 2 kb in the promoter region of Atp7a . Western blot analysis of Mo-dp heterozygous brains showed diminished amounts of Atp7a protein, consistent with reduced expression due to the promoter region deletion on one allele. In heterozygous females, brain copper levels tended to be lower compared to wild type whereas neurochemical analyses revealed higher dihydroxyphenylacetic acid:dihydroxyphenylglycol (DOPAC:DHPG) and dopamine:norepinephrine (DA:NE) ratios compared to normal (P = 0.002 and 0.029, respectively), consistent with partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. Heterozygous females showed no significant differences in body weight compared to wild type females. Our results delineate the molecular details of the Mo-dp mutation for the first time and define novel biochemical findings in heterozygous female carriers of this allele. [ABSTRACT FROM AUTHOR]

The article reports on research which was conducted to evaluate the association of IDH1 , IDH2 and DNMT3A mutations with clinical outcome, in patients with acute myeloid leukemia (AML) over 60 years of age who were treated with front-line hypomethylating agent (HMA) therapy. Researchers evaluated 68 patients aged 60 and older betwen 2000 and 2010. They found that their study was unable identify a direct correlation between the presence of various epigenetic mutations and response, event-free or overall survival in their cohort of older patients treated with front-line HMA therapy.

Although new hepatitis B virus (HBV) infections are decreasing due to improving vaccination coverage, patients without vaccination coverage can still suffer from manifestation of acute hepatitis B with jaundice and (although rarely) liver failure. No treatment is indicated for mild acute hepatitis B; however, antiviral therapy should be initiated for patients showing signs of significant liver impairment as exemplified by deterioration of prothrombin time to an equivalent of 1.5 or 50% of the 'Quick test'. For fulminant hepatitis, there is no complete agreement on whether antiviral treatment would alter the course, but it should still be started, as it would reduce the risk of reinfection in case there is a need for liver transplantation. Patients in danger of progression towards acute liver failure should be referred to transplant centers as early as possible. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

It is estimated that there are 350-400 million individuals with chronic hepatitis B virus infection (HBV) worldwide. The natural course of HBV infection is variable with a number of individuals developing no or only mild disease, while others will die from liver-associated complications if left untreated. It is estimated that 25 % of individuals with HBV infection will eventually die from the complications of HBV-associated liver disease. Several viral and host variables including hepatitis B e antigen status, HBV genotype, viral load, hepatitis B surface antigen and transaminase levels, and viral mutations have been identified as determinants of disease outcomes. The personalized approach to the treatment of chronic hepatitis B might include mere monitoring of the disease in some patients but aggressive treatment in others. Individuals who require treatment should have close monitoring to help ensure maximum medication compliance, to watch for adverse events, and to monitor virologic and biochemical responses. Therefore, management of patients with chronic HBV infection requires a practical setting to demonstrate the relevance of personalized medicine, the roles and limitations of genetic and non-genetic factors, and the risks and benefits of individualized patient care. This article provides an overview of the viral and host genetics of chronic HBV and reviews the clinical utility of serum quantitative hepatitis B surface antigen in the management of patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]

We report the case of a previously healthy 21-year-old woman who presented 6 days post-partum in acute fulminant hepatic failure. A liver ultrasound demonstrated normal echogenicity without discrete nodules while an enhanced computed tomography (CT) demonstrated innumerable 1- to 3-mm hypodense nodules throughout the liver with greater involvement of the left lobe. Liver biopsy confirmed herpes simplex virus infection. We believe this disease has a characteristic appearance on CT and prompt recognition can expedite diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Objectives: The objective of present study was to develop chitosan-based sustained release nicorandil microspheres to reduce the dosing frequency. Materials and Methods: The nicorandil-loaded chitosan microspheres were formulated by emulsion crosslinking method. A 32 factorial design was employed to study the infl uence of drug: Polymer ratio and volume of glutaraldehyde (GA) on percentage entrapment effi ciency, particle size, and % drug release at 8 h. Results: The entrapment effi ciency was found to be 41.67 ± 1.43-77.33 ± 1.97% and particle size range 65.67 ± 2.08-146.67 ± 2.18 μm. The batch CH5 showed 79.11 ± 2.23 and 96.21 ± 2.41% drug release at 8 and 12 h, respectively. Conclusions: Drug: Polymer ratio and volume of GA had signifi cant effect on % entrapment effi ciency, particle size, and % drug release. From the scanning electron microscopy (SEM) study observed that microspheres were spherical and fairly smooth surface. Fickian diffusion was the mode of drug release from nicorandil-loaded chitosan microspheres formulations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop and optimize formulations of mucoadhesive patches of Ropinirole. The Ropinirole is a non-ergoline dopamine agonist with high relative specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes. This action in humans correlates with treatment for Parkinson's disease. Ropinirole after oral administration undergoes hepatic metabolism and shows a lesser bioavailability up to 55% and biological half life of 6 hrs. Ropinirole buccal patches are prepared using different mucoadhesive polymers by solvent casting technique. The prepared buccal patches were characterized for number of parameters. Ex-vivo permeation study was also conducted for optimized formulations. All the patches were of smooth surface and elegant texture. All the prepared patches are weighing in between 12.00-15.33 mg and thickness ranges from 0.104-0.135 mm. The swelling index of all formulations was found in the range of 31.33- 40.72. Ex-vivo mucoadhesion force values of all the prepared patches lies in between 22.723 and 27.063 gm. The release of Ropinirole from all the formulations was in the range of 77.18 to 90.64% at the end of 8 hrs. The permeation of the drug through the buccal mucosa was found to be release in the range of 78.39-71.33 % after 8 hrs. FT-IR studies revealed that, there was no incompatibility of the drug with the excipients used. The swelling index was found to be more with the PVP K30 content and inversely proportional to the Carbopol 940 content. From among all the designed formations, the formulation F2, F8 and F11 containing HPMC K4M and carbopol 940 retarded the drug release in a controlled manner for prolonged period of more than 8 hrs, gave satisfactory in-vitro resident time maximum duration of 6.26 and 6.58 hrs, so it was selected as the best formulations. Release of Ropinirole from all films followed zero order and mechanism was diffusion rate limited. The stability study conducted as per the ICH guidelines and the formulations were found to be stable. From this study, it can be concluded that, these formulations of Ropinirole mucoadhesive buccal patches promising one as the controlled drug delivery, shows moderate swelling, convenient resident time will lead to may improve the bioavailability and greater therapeutic efficacy. Addition of hydrophilic polymer carbopol 940P significantly improved the bioadhesion of the films but decreased the drug release. [ABSTRACT FROM AUTHOR]

Bi-clonality is a rare phenomenon seen in approximately 5% of chronic B-cell lymphoproliferative disorders. Both true bi-clonality and somatic hypermutation resulting in intraclonal evolution have been described. We present the case of a 37-year-old female who developed extranodal marginal zone B-cell lymphoma with immunohistochemical studies showing monotypic immunostaining of plasma cells for immunoglobulin lambda light chain on her right arm in 2008. Three years later, she developed a second focus of extranodal marginal zone B-cell lymphoma on her left arm, but immunohistochemical studies demonstrated monotypic immunostaining of plasma cells for immunoglobulin kappa light chain confirmed after repeat analysis. Evaluation for systemic lymphoma with laboratory and imaging studies was negative. Together, the findings were consistent with bi-clonal, multifocal extranodal primary cutaneous marginal zone B-cell lymphoma. We present this case to highlight a rare phenomenon within primary cutaneous marginal zone lymphomas. [ABSTRACT FROM AUTHOR]

BACKGROUND: IDH1 and IDH2 gene mutations are novel, recurring molecular aberrations among patients with normal karyotype acute myeloid leukemia (AML). METHODS: Among 358 patients with AML treated on 4 protocols using high-dose ara-C plus idarubicin induction, pretreatment samples were available for 170 (median age 53 years, [range, 17-73]; 96% ≤65) and were evaluated for IDH1R132, IDH2R172, and IDH2R140 mutations or the codon 105 single nucleotide polymorphism (SNP) in IDH1. RESULTS: IDH1 and IDH2 mutations were present in 12 (7%) and 24 (14%) of patients, and IDH1 G105 SNP in 24 (14%). Overall, 52 (30%) patients had IDH gene alterations. There was no association with complete response (CR), remission duration, overall survival, and event-free survival and any of the IDH alterations, and no association with a higher CR rate or survival with the 4 regimens for the 52 patients with aberrant IDH. Among the patients with diploid karyotype and NPM1mut FLT3WTgenotype, those with IDH1 or IDH2 mutations had an inferior outcome. CONCLUSIONS: IDH aberrations and IDH1 codon 105 SNP occur in about 30% of younger patients with AML, mostly with diploid karyotype. Using high-dose ara-C-based induction regimens, we did not detect an association with outcome for any of the aberrations. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

The simple, accurate, precise, reproducible and economical procedure for simultaneous estimation of Levofloxacin hemihydrate and Ornidazole in tablet dosage form as well as in bulk drugs have been developed using double beam UV Spectrophotometer. The method based on solving of simultaneous equation using 289 nm (λmax of LEV) and 320 nm (λmax of ORN) as two analytical wavelengths for both drugs. The solution of both drugs was prepared using Distilled water as a solvent. The proposed method is suitable for simultaneous determination of Levofloxacin hemihydrate and Ornidazolein pharmaceutical dosage form. [ABSTRACT FROM AUTHOR]

Objectives Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. Methods 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. Results Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. Conclusions SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication. [ABSTRACT FROM AUTHOR]

Background & Aims: IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC. Methods: Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. Results: CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p =0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p =0.001) of CC patients in the Duke cohort. Conclusions: IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection. [ABSTRACT FROM AUTHOR]

The role of insulin resistance (IR) and hepatic steatosis in fibrogenesis in chronic hepatitis C infection (CHC) has yielded conflicting data and few studies have been performed in Asian-region populations. We retrospectively investigated the relationship between host metabolic variables, including IR and hepatic steatosis, to hepatic fibrosis in Asian-region CHC genotype 2/3 patients. A total of 303 treatment-naïve Asian-region patients with CHC genotype 2/3 were enrolled in a multicenter phase 3 study of albinterferon alfa-2b plus ribavirin for 24 weeks. IR was defined as Homeostasis Model for Assessment of IR (HOMA-IR) > 2. Baseline liver biopsy was evaluated by a single expert histopathologist. Post hoc subgroup logistic regression modeling selected for independent variables associated with significant fibrosis (METAVIR stage F2-F4). Insulin resistance was available in 263 non-diabetic Asian-region patients (hepatitis C virus-2 [HCV-2] = 171, HCV-3 = 92), and 433 non-Asian region patients (407 'Caucasian'); METAVIR fibrosis prevalence F0-F1 (minimal fibrosis) = 201 (77%) and F2-F4 (significant fibrosis) = 59 (23%), and steatosis prevalence of grade 0 = 169 (65%), grade 1 = 64 (25%), grade 2/3 = 27 (10%). Median HOMA-IR was 1.8 (interquartile range: 1.2-2.7); 100 (38%) patients had HOMA-IR > 2. Factors independently associated with significant fibrosis included HOMA-IR (odds ratio [OR] = 8.42), necro-inflammatory grade (OR = 3.17), age (OR = 1.07) and serum total cholesterol levels (OR = 0.008). This was similar to non-Asian region patients, but steatosis was not associated with significant fibrosis in either cohort. In this subgroup study of Asian-region HCV genotype 2 or 3 patients, insulin resistance, along with age, cholesterol levels and necro-inflammation, but not steatosis may be associated with significant hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are reported in acute myeloid leukemia (AML). We studied the frequency and the clinicopathologic features of IDH1 and IDH2 mutations in AML. Mutations in IDH1 (IDH1(R)¹³²) and IDH2 (IDH2(R)¹⁷²) were assessed by Sanger sequencing in 199 AML cases. Point mutations in IDH1(R)¹³² were detected in 12 (6.0%) of 199 cases and in IDH2(R)¹⁷² in 4 (2.0%) of 196 cases. Of the 16 mutated cases, 15 (94%) were cytogenetically normal, for an overall frequency in this group of 11.8%. IDH1(R)¹³² and IDH2(R)¹⁷² mutations were mutually exclusive. Concurrent mutations in NPM1, FLT3, CEBPA, and NRAS were detected only in AML with the IDH1(R)¹³² mutation. The clinical and laboratory variables of patients with AML with IDH mutations showed no significant differences compared with patients with wild-type IDH. We conclude that IDH1(R)¹³² and IDH2(R)¹⁷² mutations occur most often in cytogenetically normal AML cases with an overall frequency of approximately 11.8%. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection is a global health problem, but the current therapy is effective in <50% of patients infected with genotype 1. With advances in cell culture systems over the past decade, the development of directly acting antivirals (DAAs) for HCV has become possible. There are currently >50 active clinical trials in this therapeutic area and NS3/4A protease inhibitors are now entering Phase III study. To date, we have learned that DAAs are potent inhibitors of HCV replication, resulting in rapid declines in serum HCV RNA levels, and have the potential to allow shortening of therapy. However, these agents drive selective pressure for mutant viruses that can develop rapidly and have reduced susceptibility to the drug. Therefore, for now, the current standard of care including pegylated interferon α (pegIFN) and ribavirin remains a crucial part of new drug development. Furthermore, the adverse event profile for the early DAAs has added to the concerns of tolerability that are so common for the current standard of care. Ongoing issues include the optimal duration of therapy, how and when to combine DAAs, and the long-term role of pegIFN and ribavirin. Here, we summarize the current information regarding the effectiveness of protease inhibitors in treating chronic HCV and discuss the key challenges now facing the field. [ABSTRACT FROM PUBLISHER]

Abstract: Dawn launched on 27 September 2007 on a mission to orbit main belt asteroids (4) Vesta in 2011–2012 and (1) Ceres in 2015. The operations team conducted an extensive set of assessments of the engineering subsystems and science instruments during the first 80 days of the mission. A major objective of this period was to thrust for one week with the ion propulsion system to verify flight and ground systems readiness for typical interplanetary operations. Upon successful conclusion of the checkout phase, the interplanetary cruise phase began, most of which will be devoted to thrusting. The flexibility afforded by the use of ion propulsion enabled the project to accommodate a launch postponement of more than three months caused by a combination of launch vehicle and tracking system readiness, unfavorable weather, and then conflicts with other launches. Even with the shift in the launch date, all of the science objectives are retained with the same schedule and greater technical margins. This paper describes the conclusion of the development phase of the project, launch operations, and the progress of mission operations through the conclusion of deterministic thrusting in October 2008. [Copyright &y& Elsevier]