Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake.

A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose.

A simple and rapid liquid chromatography-mass spectrometry method to assay cabozantinib in plasma: Application to therapeutic drug monitoring in patients with renal cell carcinoma.

Cabozantinib is a novel multi-target tyrosine kinase inhibitor recently approved in metastatic renal cell carcinoma (mRCC) leading to frequent severe toxicities requiring empirical dose reduction. Therapeutic drug monitoring (TDM) could help to predict the risk for severe toxicities by quickly detecting overexposed patients followed by prospective adaptive dosing strategy. To achieve this goal, a simple and rapid assay to monitor cabozantinib plasma concentration was developed and validated.

The nuclear pore complex prevents sister chromatid recombination during replicative senescence.

The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage. Here, we uncover that fusing a DNA binding domain to the NPC basket protein Nup1 reduces telomere relocalization to nuclear pores early after telomerase inactivation. This Nup1 modification also impairs the relocalization to the NPC of expanded CAG/CTG triplet repeats.

Non-canonical Roles of Telomerase: Unraveling the Imbroglio.

Telomerase plays a critical role in stem cell function and tissue regeneration that depends on its ability to elongate telomeres. For nearly two decades, it turned out that TERT regulates a broad spectrum of functions including signal transduction, gene expression regulation, and protection against oxidative damage that are independent of its telomere elongation activity. These conclusions that were mainly obtained in cell lines overexpressing telomerase were further strengthened by models of ectopic expression of telomerase or models of G1 knockout mice without detectable telomere dysfunction.

[Next generation of anti-immune checkpoints antibodies].

Immune checkpoints balance initial antigen-driven T cell stimulation by enhancing or dampening activation, allowing co-existence of efficient immune responses and maintenance of self-tolerance. In oncology, checkpoints currently targeted by inhibitors to amplify activity of T cell, NK cells or myeloid cells responses comprise CTLA-4 (cytolytic T-lymphocyte-associated antigen 4 or CD152), PD-1 (programmed cell death 1, or CD279), PD-L1 ( programmed cell death-ligand 1, or CD274), LAG-3 (Lymphocyte-activation gene 3, or CD223), TIM3 (T-cell immunoglobulin and mucin-domain containing-3), TIGIT (T cell immunoreceptor with Ig and ITIM domains ), VISTA (V-domain Ig suppressor of T cell activation), B7/H3 (or CD276), KIR (killer-cell immunoglobulin-like receptor), NKG2A, CD39, CD73, CSF1R (colony-stimulating factor 1 receptor), CD47 or CD172a. Other "checkpoints" are being pharmacologically triggered in order to directly amplify T cell co-stimulation.

Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection.

In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear.

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs.

Recent advances in the understanding and therapeutic management of mastocytosis.

Mastocytosis is a rare disease due to the abnormal accumulation of mast cells in various tissues. Its clinical presentation is heterogeneous depending on mast cell infiltration and mediators release. In some cases, it is associated with hematological malignancies.

Combined Targeting of G9a and Checkpoint Kinase 1 Synergistically Inhibits Pancreatic Cancer Cell Growth by Replication Fork Collapse.

Because of its dismal outcome, pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge making the testing of new pharmacologic tools a goal of paramount importance. Here, we developed a rational approach for inhibiting PDAC growth based on leveraging cell-cycle arrest of malignant cells at a phase that shows increased sensitivity to distinct epigenomic inhibitors. Specifically, we simultaneously inhibited checkpoint kinase 1 (Chk1) by prexasertib and the G9a histone methyltransferase with BRD4770, thereby targeting two key pathways for replication fork stability.

Selecting machine-learning scoring functions for structure-based virtual screening.

Interest in docking technologies has grown parallel to the ever increasing number and diversity of 3D models for macromolecular therapeutic targets. Structure-Based Virtual Screening (SBVS) aims at leveraging these experimental structures to discover the necessary starting points for the drug discovery process. It is now established that Machine Learning (ML) can strongly enhance the predictive accuracy of scoring functions for SBVS by exploiting large datasets from targets, molecules and their associations.

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments.

Schwann cells support oncogenic potential of pancreatic cancer cells through TGFβ signaling.

Pancreatic ductal adenocarcinoma (PDAC) is one of the solid tumors with the poorest prognosis. The stroma of this tumor is abundant and composed of extracellular matrix and stromal cells (including cancer-associated fibroblasts and immune cells). Nerve fibers invading this stroma represent a hallmark of PDAC, involved in neural remodeling, which participates in neuropathic pain, cancer cell dissemination and tumor relapse after surgery.

Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma.

Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues.

HVEM has a broader expression than PD-L1 and constitutes a negative prognostic marker and potential treatment target for melanoma.

HVEM (Herpes Virus Entry Mediator) engagement of BTLA (B and T Lymphocyte Attenuator) triggers inhibitory signals in T cells and could play a role in evading antitumor immunity. Here, HVEM expression levels in melanoma metastases were analyzed by immunohistochemistry, correlated with overall survival (OS) in 116 patients, and validated by TCGA transcriptomic data. Coincident expression of HVEM and its ligand BTLA was studied in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry (n = 21) and immunofluorescence (n = 5).

Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy.

: The promotion of antitumor response by targeting co-stimulatory B7 superfamily members has become evident to create a new wave of cancer immunotherapy. Inducible Co-Stimulator (ICOS), which is expressed on activated T cells, gained interest in the translational medicine community.: We performed an extensive literature review using the keywords 'ICOS' and 'cancer', and the Clinicaltrials.

The necessity of a more aggressive initial surgical treatment in patients with mesothelioma of the testicular tunica vaginalis.

Mesothelioma of the tunica vaginalis of the testis (MTVM) is a rare tumor encountering for less than 1% of mesothelioma. Patients suffering from these tumors have poor survival due to local and distant metastasis despite treatment. Actually, no specific treatment recommendations exist for this tumor, yet radical orchidectomy is the gold standard in limited disease.

Targeting intrinsically disordered proteins involved in cancer.

Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in attractive therapeutic targets; however, targeting IDPs is challenging because of their dynamic nature. In the last years, different experimental and computational approaches, as well as the combination of both, have been explored to identify molecules to target either the hot-spots or the allosteric sites of IDPs.

Epigenetic down-regulation of the HIST1 locus predicts better prognosis in acute myeloid leukemia with NPM1 mutation.

Background: The epigenetic machinery is frequently altered in acute myeloid leukemia. Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22) in CN-AML patient blasts.

Pulmonary giant chondromatous hamartoma with multifocal evolution in an infant.

Hamartoma is the most common benign pulmonary tumor in adults, but is rarely described in the pediatric population. Giant chondromatous and progressive forms are even rarer. We report the novel case of a 13-month-old infant hospitalized for giant pulmonary chondromatous hamartoma discovered during a septic episode, rapidly progressive, with severe multifocal lesions, without clear response to several cytotoxic therapies.

[E-health and "Cancer outside the hospital walls", Big Data and artificial intelligence].

To heal otherwise in oncology has become an imperative of Public Health and an economic imperative in France. Patients can therefore receive live most of their care outside of hospital with more ambulatory care. This ambulatory shift will benefit from the digital revolution and the development of digital health or e-health.

Correction: NKp30 expression is a prognostic immune biomarker for stratification of patients with intermediate-risk acute myeloid leukemia.

[This corrects the article DOI: 10.18632/oncotarget.17747.

Diastereoselective Synthesis of Potent Antimalarial -β-lactam Agents.

Fifteen novel β-lactams bearing N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2- aminoethyl) β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction (Staudinger). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to theformation of -β-lactam derivatives. These newly synthesized β-lactams were evaluated for their antimalarial activity against K14 resistant strain and showed good to excellent EC50 values.