Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.

Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma.

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial.

COPD in HIV-Infected Patients: CD4 Cell Count Highly Correlated.

Background: COPD is a frequent and significant cause of respiratory morbidity in HIV-infected patients despite the control of HIV. We aimed to analyze the factors correlated with COPD in this population to evaluate the existence of specific indicators of vulnerability in this population.

Methods And Findings: 623 HIV-infected outpatients were enrolled during one year.

Virological response and resistance mutations to NS3/4A inhibitors in hepatitis C virus-human immunodeficiency virus coinfection.

Aim: To evaluate virological response to telaprevir or boceprevir in combination with pegylated interferon and ribavirin and resistance mutations to NS3/4A inhibitors in hepatitis C virus-human immunodeficiency virus (HCV-HIV) coinfected patients in a real life setting.

Methods: Patients with HCV genotype 1-HIV coinfection followed in Nice University Hospital internal medicine and infectious diseases departments who initiated treatment including pegylated interferon and ribavirin (PegIFN/RBV) + telaprevir or boceprevir, according to standard treatment protocols, between August 2011 and October 2013 entered this observational study. Patient data were extracted from an electronic database (Nadis(®)).

Incidences and risk factors of first-line HAART discontinuation: a limitation to the success of the "seek, test, treat, and retain" strategy?

To evaluate the incidence and risk factors of first-highly active antiretroviral therapy (HAART) modifications/interruptions and their causes in a cohort of newly-treated patients by using a competing risk model. In nine centers of the French cohort Dat'AIDS, in 1 year and 2 years of censorship, a competing risk analysis was implemented in HIV1 patients aged 18 years or older first-treated between September 2002 and March 2012. In 4669 patients, 3628 modifications (77.

Increased time exposure to tenofovir is associated with a greater decrease in estimated glomerular filtration rate in HIV patients with kidney function of less than 60 ml/min/1.73 m2.

Tenofovir (TDF), atazanovir (ATAZ) and indinavir (IND) have been reported as possible risk factors for incident chronic kidney disease (CKD) in HIV-infected patients. We investigated the relationship between the duration of antiretroviral exposure and estimated glomerular filtration rate (eGFR) evolution in CKD patients. In a cohort of 1,750 HIV-infected patients, we identified 121 CKD patients with a mean follow-up of 44 ± 35 months.

Intraspecific phylogenetic analysis of Siberian woolly mammoths using complete mitochondrial genomes.

We report five new complete mitochondrial DNA (mtDNA) genomes of Siberian woolly mammoth (Mammuthus primigenius), sequenced with up to 73-fold coverage from DNA extracted from hair shaft material. Three of the sequences present the first complete mtDNA genomes of mammoth clade II. Analysis of these and 13 recently published mtDNA genomes demonstrates the existence of two apparently sympatric mtDNA clades that exhibit high interclade divergence.

Prediction of HIV-1 protease inhibitor resistance by Molecular Modeling Protocols (MMPs) using GenMol software.

This paper investigates the contribution of Molecular Modeling to (i) predict and (ii) understand more fundamentally HIV drug resistance. Based on a new automated GenMol module, these goals are approached by Molecular Modeling Protocols (MMPs), respectively, (i) the Molecular Modeling Phenotype Protocol (MMPP) and (ii) the Molecular Modeling Phenotype-Genotype Protocol (MMGPP). Section 2 recalls clinical practice with a reference case study and Section 3 presents atomistic simulation tools.

A high quality draft consensus sequence of the genome of a heterozygous grapevine variety.

Background: Worldwide, grapes and their derived products have a large market. The cultivated grape species Vitis vinifera has potential to become a model for fruit trees genetics. Like many plant species, it is highly heterozygous, which is an additional challenge to modern whole genome shotgun sequencing.

Whole-genome shotgun sequencing of mitochondria from ancient hair shafts.

Although the application of sequencing-by-synthesis techniques to DNA extracted from bones has revolutionized the study of ancient DNA, it has been plagued by large fractions of contaminating environmental DNA. The genetic analyses of hair shafts could be a solution: We present 10 previously unexamined Siberian mammoth (Mammuthus primigenius) mitochondrial genomes, sequenced with up to 48-fold coverage. The observed levels of damage-derived sequencing errors were lower than those observed in previously published frozen bone samples, even though one of the specimens was >50,000 14C years old and another had been stored for 200 years at room temperature.

Frequency, determinants and consequences of delayed access to care for HIV infection in France.

Background And Objectives: We analysed the frequency and predictors of delayed access to care (DAC) for HIV infection, and its influence on survival.

Methods: We studied predictors of DAC among 18,721 patients enrolled between 1997 and 2002 in the French Hospital Database on HIV (FHDH), DAC being defined by a CD4* T-cell count below 200 copies/mm3 and/or AIDS at FHDH enrollment. The association of DAC with the initiation of combined antiretroviral therapy (cART) and of DAC with survival were analysed with Cox multivariable models.

Resistance of hepatitis C virus to NS3-4A protease inhibitors: mechanisms of drug resistance induced by R155Q, A156T, D168A and D168V mutations.

Background/aims: One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor).

Unique features of a highly pathogenic Campylobacter jejuni strain.

Campylobacter jejuni, a major human enteric pathogen, exhibits significant strain-to-strain differences which result in differences in pathogenic potential. C. jejuni 81-176 is a highly virulent strain that exhibits unique pathogenic features and is used by many research laboratories.

Multiplex sequencing of paired-end ditags (MS-PET): a strategy for the ultra-high-throughput analysis of transcriptomes and genomes.

The paired-end ditagging (PET) technique has been shown to be efficient and accurate for large-scale transcriptome and genome analysis. However, as with other DNA tag-based sequencing strategies, it is constrained by the current efficiency of Sanger technology. A recently developed multiplex sequencing method (454-sequencing) using picolitre-scale reactions has achieved a remarkable advance in efficiency, but suffers from short-read lengths, and a lack of paired-end information.

In the era of highly active antiretroviral therapy, why are HIV-infected patients still admitted to hospital for an inaugural opportunistic infection?

Objectives: To identify factors related to delayed testing, and delayed or interrupted care-seeking or treatment uptake, among HIV-infected patients.

Design: HIV-infected patients hospitalized for an opportunistic infection (OI) cases were included in a prospective study and compared with controls matched by age and sex who had regular follow-up and treatment. Patients were asked to complete a questionnaire about their therapeutic itinerary and their socioeconomic, psychological and medical characteristics.

Apoptosis of naive CD4+ T-cells from HIV-infected patients with poor immune response to HAART is enhanced in vitro by steroid.

Objective: Because the absence of immune restoration in HIV-infected patients efficiently treated by highly active antiretroviral therapy (HAART) may be due to excessive immune activation, we prospectively studied the effect of hydrocortisone on T-cell apoptosis in a cohort of patients with satisfactory virologic response.

Methods: Apoptosis of T-cell subsets including naïve CD45RA(+)CD4+ T-cells was determined at baseline and at months 1 and 3 after initiation of HAART. A satisfactory immune response was defined as an increase >100/microL CD4+ T-cells at month 3 compared to baseline.

Expression profiling using a hexamer-based universal microarray.

We describe a transcriptional analysis platform consisting of a universal micro-array system (UMAS) combined with an enzymatic manipulation step that is capable of generating expression profiles from any organism without requiring a priori species-specific knowledge of transcript sequences. The transcriptome is converted to cDNA and processed with restriction endonucleases to generate low-complexity pools (approximately 80-120) of equal length DNA fragments. The resulting material is amplified and detected with the UMAS system, comprising all possible 4,096 (4(6)) DNA hexamers.

Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships.

Background: There have been no published reports comparing the CYP450 GeneChip microarray assay with more standard methods of genetic testing.

Methods: We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay.

Efficacy and safety of vancomycin constant-rate infusion in the treatment of chronic Gram-positive bone and joint infections.

OBJECTIVE: To evaluate the efficacy and safety of vancomycin constant-rate infusion over 24 h in the treatment of Gram-positive bone infections, METHODS: Vancomycin (40 mg/kg/day) was administered without a loading dose to 15 patients (12 male, three female) aged 23--90 years, weighing 46--85 kg, with postoperative chronic bone and joint infections. The 24-h dose was adjusted to maintain plasma levels between 25 and 35 mg/L. Mean duration of therapy was 6.

Synthesis of Novel Nucleic Acid Mimics via the Stereoselective Intermolecular Radical Coupling of 3'-Iodo Nucleosides and Formaldoximes(1).

A highly convergent free radical coupling of alkyl iodides and oximes, mediated by bis(trimethylstannyl) benzopinacolate (8), has been utilized to prepare a series of dimeric nucleosides as mimics of natural nucleic acids. The systematic optimization of the reaction conditions allowed for the single-step conversion of the appropriate iodides and oximes into the 2'-deoxy dimers 9 in moderate to excellent yields. For example, the reaction of 3'-deoxy-3'-iodo-5'-(triphenylmethyl)thymidine (6a) with 3'-O-(tert-butyldiphenylsilyl)-5'-O-(methyleneimino)thymidine (7a) in the presence of 8 in degassed benzene gave an 81% yield of 3'-de(oxyphosphinico)-3'-(methyleneimino)-5'-O-(triphenylmethyl)thymidylyl-(3'-->5')-3'-O-(tert-butyldiphenylsilyl)thymidine (9a).

Sugar modified oligonucleotides. I. Carbo-oligodeoxynucleotides as potential antisense agents.

For the first time, carbo-oligodeoxynucleotides, namely c-dT4 and c-dT12, have been synthesized. As compared to the natural oligomers these carbo-oligodeoxynucleotides are at least 5 times more stable toward enzymatic degradation and bind more strongly to complementary DNA. These preliminary data indicate that such oligomers fulfill the requirements to be considered as potential antisense agents.