Sequential adjustment of cytotoxic T lymphocyte densities improves efficacy in controlling tumor growth.

Understanding the human cytotoxic T lymphocyte (CTL) biology is crucial to develop novel strategies aiming at maximizing their lytic capacity against cancer cells. Here we introduce an agent-based model, calibrated on population-scale experimental data that allows quantifying human CTL per capita killing. Our model highlights higher individual CTL killing capacity at lower CTL densities and fits experimental data of human melanoma cell killing.

Publisher Correction: Localization of RalB signaling at endomembrane compartments and its modulation by autophagy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens.

CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis.

Molecular Inverse Comorbidity between Alzheimer's Disease and Lung Cancer: New Insights from Matrix Factorization.

Matrix factorization (MF) is an established paradigm for large-scale biological data analysis with tremendous potential in computational biology. Here, we challenge MF in depicting the molecular bases of epidemiologically described disease-disease (DD) relationships. As a use case, we focus on the inverse comorbidity association between Alzheimer's disease (AD) and lung cancer (LC), described as a lower than expected probability of developing LC in AD patients.

Localization of RalB signaling at endomembrane compartments and its modulation by autophagy.

The monomeric GTPase RalB controls crucial physiological processes, including autophagy and invasion, but it still remains unclear how this multi-functionality is achieved. Previously, we reported that the RalGEF (Guanine nucleotide Exchange Factor) RGL2 binds and activates RalB to promote invasion. Here we show that RGL2, a major activator of RalB, is also required for autophagy.

ChiCMaxima: a robust and simple pipeline for detection and visualization of chromatin looping in Capture Hi-C.

Capture Hi-C (CHi-C) is a new technique for assessing genome organization based on chromosome conformation capture coupled to oligonucleotide capture of regions of interest, such as gene promoters. Chromatin loop detection is challenging because existing Hi-C/4C-like tools, which make different assumptions about the technical biases presented, are often unsuitable. We describe a new approach, ChiCMaxima, which uses local maxima combined with limited filtering to detect DNA looping interactions, integrating information from biological replicates.

Multiparametric analysis of CD8 T cell compartment phenotype in chronic lymphocytic leukemia reveals a signature associated with progression toward therapy.

CD8 T cells are frontline defenders against cancer and primary targets of current immunotherapies. In CLL, specific functional alterations have been described in circulating CD8 T cells, yet a global view of the CD8 T cell compartment phenotype and of its real impact on disease progression is presently elusive. We developed a multidimensional statistical analysis of CD8 T cell phenotypic marker expression based on whole blood multi-color flow-cytometry.

Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma.

Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and analyses we show that a subset of FL patients displays a 'high' immune escape phenotype.

Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors.

A series of simple -alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA).

PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice.

is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed to the coding sequence of elastin ().

Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites.

Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare  putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism.

Phenotypic and lipidomic characterization of primary human epidermal keratinocytes exposed to simulated solar UV radiation.

Background: Ultraviolet (UV) radiation is known to be one of the most important environmental hazards acting on the skin. The most part of UV radiation is absorbed in the epidermis, where keratinocytes are the most abundant and exposed cell type. Lipids have an important role in skin biology, not only for their important contribution to the maintenance of the permeability barrier but also for the production and storage of energy, membrane organization and cell signalling functions.

Effect of combined inhibition of p110 alpha PI3K isoform and STAT3 pathway in ovarian cancer platinum-based resistance.

Background: Ovarian cancer is associated with poor prognostic outcome due to late diagnosis and to intrinsic and acquired resistance to platinum-based chemotherapy in a large number of patients. This chemoresistance is acquired through the peritoneal and ascites microenvironment by several released factors, such as IL-6,. Preclinical studies have implicated the activation of PI3K pathway in chemoresistance, showing it to extend tumor cell survival and modulate multidrug resistance.

[F]FDG-PET/CT in Hodgkin Lymphoma: Current Usefulness and Perspectives.

Functional imaging using 18-fluorodeoxyglycose ([F]FDG) positron emission tomography combined with computed tomography (PET/CT) has become a major imaging modality in Hodgkin lymphoma. This imaging modality allows for a significant improvement in staging, increased sensitivity, which involves differentiating residual tumors from fibrosis during assessment, and highly impacts treatment decisions into new PET-driven strategies. This review presents the main scientific data concerning the current applications of [F]FDG-PET/CT in Hodgkin lymphoma at baseline, interim, and the end of treatment evaluation along with the main PET-driven trials for therapeutic decisions.

Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.

Antibody-Drug Conjugates for the Treatment of Hematological Malignancies: A Comprehensive Review.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutic agents that bring new opportunities for the treatment of hematological malignancies by meeting unmet medical needs. These drugs consist of a cytotoxic agent connected by a linker to a human, humanized, or chimeric antibody targeting a surface antigen specifically expressed by tumor cells. These ADCs are being developed to specifically deliver the cytotoxic agent into tumor cells.

Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.

BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling: Summary and Recommendations from the Organizing Committee.

The Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 1, 2016 at the American Society of Hematology meeting to discuss the emerging data and technologies for minimal residual disease assessment and immune profiling in myeloma. Particular emphasis was placed on developing strategies to incorporate these techniques into clinical trial design. This document reviews the literature, summarizes the topics discussed in the workshop, and provides recommendations for integration of these techniques into future clinical trial design.

Prospective Assessment of First-Year Quality of Life After Pelvic Exenteration for Gynecologic Malignancy: A French Multicentric Study.

Background: Pelvic exenteration remains one of the most mutilating procedures, with important postoperative morbidity, an altered body image, and long-term physical and psychosocial concerns. This study aimed to assess quality of life (QOL) during the first year after pelvic exenteration for gynecologic malignancy performed with curative intent.

Methods: A French multicentric prospective study was performed by including patients who underwent pelvic exenteration.

Oligomycins A and E, major bioactive secondary metabolites produced by Streptomyces sp. strain HG29 isolated from a Saharan soil.

An actinobacterial strain, HG29, with potent activity against pathogenic, toxigenic and phytopathogenic fungi was isolated from a Saharan soil sample of Algeria. On the basis of morphological and chemotaxonomic characteristics, the strain was classified in the genus Streptomyces. Analysis of the 16S rRNA gene sequence showed a similarity level of 99.

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer.

γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks.

Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS-driven Pancreatic Tumorigenesis.

Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive.

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy.

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone.