Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial.

Purpose: The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies.

Methods: The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group.

The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia.

Observation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily.

The Randomized AMBORA Trial: Impact of Pharmacological/Pharmaceutical Care on Medication Safety and Patient-Reported Outcomes During Treatment With New Oral Anticancer Agents.

Purpose: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking.

A Bacterial Toxin Perturbs Intracellular Amino Acid Balance To Induce Persistence.

Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of the toxin is often coupled to the induction of cellular response pathways, such as the stringent response, in response to multiple stress conditions. Under these conditions, the cell enters a quiescent state referred to as dormancy or persistence.

Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death.

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown.

A Localized Complex of Two Protein Oligomers Controls the Orientation of Cell Polarity.

Signaling hubs at bacterial cell poles establish cell polarity in the absence of membrane-bound compartments. In the asymmetrically dividing bacterium , cell polarity stems from the cell cycle-regulated localization and turnover of signaling protein complexes in these hubs, and yet the mechanisms that establish the identity of the two cell poles have not been established. Here, we recapitulate the tripartite assembly of a cell fate signaling complex that forms during the G-S transition.

A cell cycle kinase with tandem sensory PAS domains integrates cell fate cues.

All cells must integrate sensory information to coordinate developmental events in space and time. The bacterium Caulobacter crescentus uses two-component phospho-signalling to regulate spatially distinct cell cycle events through the master regulator CtrA. Here, we report that CckA, the histidine kinase upstream of CtrA, employs a tandem-PAS domain sensor to integrate two distinct spatiotemporal signals.

Congo Red Interactions with Curli-Producing E. coli and Native Curli Amyloid Fibers.

Microorganisms produce functional amyloids that can be examined and manipulated in vivo and in vitro. Escherichia coli assemble extracellular adhesive amyloid fibers termed curli that mediate adhesion and promote biofilm formation. We have characterized the dye binding properties of the hallmark amyloid dye, Congo red, with curliated E.

Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients.

Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126.

GPR126 is an orphan heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) that is essential for the development of diverse organs. We found that type IV collagen, a major constituent of the basement membrane, binds to Gpr126 and activates its signaling function. Type IV collagen stimulated the production of cyclic adenosine monophosphate in rodent Schwann cells, which require Gpr126 activity to differentiate, and in human embryonic kidney (HEK) 293 cells expressing exogenous Gpr126.

CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs.

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults.

Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.

In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index.

Bacterial scaffold directs pole-specific centromere segregation.

Bacteria use partitioning systems based on the ParA ATPase to actively mobilize and spatially organize molecular cargoes throughout the cytoplasm. The bacterium Caulobacter crescentus uses a ParA-based partitioning system to segregate newly replicated chromosomal centromeres to opposite cell poles. Here we demonstrate that the Caulobacter PopZ scaffold creates an organizing center at the cell pole that actively regulates polar centromere transport by the ParA partition system.

Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia.

Alterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area.

Branched signal wiring of an essential bacterial cell-cycle phosphotransfer protein.

Vital to bacterial survival is the faithful propagation of cellular signals, and in Caulobacter crescentus, ChpT is an essential mediator within the cell-cycle circuit. ChpT functions as a histidine-containing phosphotransfer protein (HPt) that shuttles a phosphoryl group from the receiver domain of CckA, the upstream hybrid histidine kinase (HK), to one of two downstream response regulators (CtrA or CpdR) that controls cell-cycle progression. To understand how ChpT interacts with multiple signaling partners, we solved the crystal structure of ChpT at 2.

Structural map of a microRNA-122: hepatitis C virus complex.

MicroRNA-122 (miR-122) enhances hepatitis C virus (HCV) fitness via targeting two sites in the 5'-untranslated region (UTR) of HCV. We used selective 2'-hydroxyl acylation analyzed by primer extension to resolve the HCV 5'-UTR's RNA secondary structure in the presence of miR-122. Nearly all nucleotides in miR-122 are involved in targeting the second site, beyond classic seed base pairings.

Affinity maturation to improve human monoclonal antibody neutralization potency and breadth against hepatitis C virus.

A potent neutralizing antibody to a conserved hepatitis C virus (HCV) epitope might overcome its extreme variability, allowing immunotherapy. The human monoclonal antibody HC-1 recognizes a conformational epitope on the HCV E2 glycoprotein. Previous studies showed that HC-1 neutralizes most HCV genotypes but has modest potency.

Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.

Purpose: The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL).

Patients And Methods: Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma.

Asthma is considered a Th2 cell–associated disorder. Despite this, both the Th1 cell–associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ.

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.

Background: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial.

Methods: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer.

A spindle-like apparatus guides bacterial chromosome segregation.

Until recently, a dedicated mitotic apparatus that segregates newly replicated chromosomes into daughter cells was believed to be unique to eukaryotic cells. Here we demonstrate that the bacterium Caulobacter crescentus segregates its chromosome using a partitioning (Par) apparatus that has surprising similarities to eukaryotic spindles. We show that the C.

Design, biologic evaluation, and SAR of novel pseudo-peptide incorporating benzheterocycles as HIV-1 protease inhibitors.

A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P(2) ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P(1)-P(2) linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain.

Transient expression of an IL-23R extracellular domain Fc fusion protein in CHO vs. HEK cells results in improved plasma exposure.

Transient transfection of mammalian cells in suspension culture has recently emerged as a very useful method for production of research-scale quantities of recombinant proteins. The most commonly used cell lines for this purpose are suspension-adapted HEK and CHO cells. We report here that the plasma exposure in mice of an IL-23R extracellular domain Fc fusion protein (IL23R-Fc) differed dramatically depending on whether the protein was prepared by transient transfection of HEK or CHO cells.

A novel and critical role for Oct4 as a regulator of the maternal-embryonic transition.

Background: Compared to the emerging embryonic stem cell (ESC) gene network, little is known about the dynamic gene network that directs reprogramming in the early embryo. We hypothesized that Oct4, an ESC pluripotency regulator that is also highly expressed at the 1- to 2-cell stages in embryos, may be a critical regulator of the earliest gene network in the embryo.

Methodology/principal Findings: Using antisense morpholino oligonucleotide (MO)-mediated gene knockdown, we show that Oct4 is required for development prior to the blastocyst stage.