Artificial intelligence for quality assurance in radiotherapy.

In radiotherapy, patient-specific quality assurance is very time-consuming and causes machine downtime. It consists of testing (using measurement with a phantom and detector) if a modulated plan is correctly delivered by a treatment unit. Artificial intelligence and in particular machine learning algorithms were mentioned in recent reports as promising solutions to reduce or eliminate the patient-specific quality assurance workload.

Automation in radiotherapy treatment planning: Examples of use in clinical practice and future trends for a complete automated workflow.

Modern radiotherapy treatment planning is a complex and time-consuming process that requires the skills of experienced users to obtain quality plans. Since the early 2000s, the automation of this planning process has become an important research topic in radiotherapy. Today, the first commercial automated treatment planning solutions are available and implemented in a growing number of clinical radiotherapy departments.

A study of the interplay effect in radiation therapy using a Monte-Carlo model.

Purpose: In modulated radiotherapy, breathing motion can lead to Interplay (IE) and Blurring (BE) effects that can modify the delivered dose. The aim of this work is to present the implementation, the validation and the use of an open-source Monte-Carlo (MC) model that computes the delivered dose including these motion effects.

Methods: The MC model of the Varian TrueBeam was implemented using GATE.

PI3K functions as a hub in mechanotransduction.

Mammalian cells integrate different types of stimuli that govern their fate. These stimuli encompass biochemical as well as biomechanical cues (shear, tensile, and compressive stresses) that are usually studied separately. The phosphatidylinositol 3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways.

Low Replicative Stress Triggers Cell-Type Specific Inheritable Advanced Replication Timing.

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin.

Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas.

Nanobody-Based Quantification of GTP-Bound RHO Conformation Reveals RHOA and RHOC Activation Independent from Their Total Expression in Breast Cancer.

As key regulators of the actin cytoskeleton, RHO GTPase expression and/or activity are deregulated in tumorigenesis and metastatic progression. Nevertheless, the vast majority of experiments supporting this conclusion was conducted on cell lines but not on human tumor samples that were mostly studied at the expression level only. Up to now, the activity of RHO proteins remains poorly investigated in human tumors.

3D Model Characterization by 2D and 3D Imaging in t(14;18)-Positive B-NHL: Perspectives for In Vitro Drug Screens in Follicular Lymphoma.

Follicular lymphoma (FL) is an indolent B cell lymphoproliferative disorder of transformed follicular center B cells, which accounts for 20-30 percent of all non-Hodgkin lymphoma (NHL) cases. Great advances have been made to identify the most relevant targets for precision therapy. However, no relevant models for in vitro studies have been developed or characterized in depth.

Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features.

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.).

Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells.

Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry.

Hepatocellular carcinoma (HCC) usually afflicts individuals in their maturity after a protracted liver disease. Contrasting with this pattern, the age structure of HCC in Andean people displays a bimodal distribution with half of the patients developing HCC in adolescence and early adulthood. To deepen our understanding of the molecular determinants of the disease in this population, we conducted an integrative analysis of gene expression and DNA methylation in HCC developed by 74 Peruvian patients, including 39 adolescents and young adults.

Lymphoma Heterogeneity Unraveled by Single-Cell Transcriptomics.

High-definition transcriptomic studies through single-cell RNA sequencing (scRNA-Seq) have revealed the heterogeneity and functionality of the various microenvironments across numerous solid tumors. Those pioneer studies have highlighted different cellular signatures correlated with clinical response to immune checkpoint inhibitors. scRNA-Seq offers also a unique opportunity to unravel the intimate heterogeneity of the ecosystems across different lymphoma entities.

Clinical Implications of Inflammation in Acute Myeloid Leukemia.

Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as , , or transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity.

Design and Mechanism of Action of a New Prototype of Combi-Molecule "Programed" to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment.

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a "combi-molecule" to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model.

Effector and stem-like memory cell fates are imprinted in distinct lymph node niches directed by CXCR3 ligands.

T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8 effector T cell differentiation is associated with positioning at the lymph node periphery.

Phosphorylation of the MNK1 substrate eIF4E is not required for response to acute pancreatitis.

Background: The MNK1 protein kinase is directly activated by the MAPK pathway and is specifically expressed in pancreatic acinar cells. Both the MNK1 kinase and the MAPK pathway are required for response to pancreatitis, suggesting that their pharmacological targeting would be of therapeutic interest. Because the mRNA cap-binding protein and translation initiation factor eIF4E is the major known MNK1 substrate, one could anticipate that the protective function of MNK1 in pancreatitis is mediated by eIF4E phosphorylation.

Identification of novel, clonally stable, somatic mutations targeting transcription factors PAX5 and NKX2-3, the epigenetic regulator LRIF1, and BRAF in a case of atypical B-cell chronic lymphocytic leukemia harboring a t(14;18)(q32;q21).

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g.

Severe toxicity of capecitabine in a patient with DPD deficiency after a safe FEC-100 experience: why we should test DPD deficiency in all patients before high-dose fluoropyrimidines.

We report the case of a 44-year-old patient who experienced severe toxicity while being treated with capecitabine at standard dose for metastatic breast cancer. As the patient had already received 5-FU within the FEC protocol (5-FU 500 mg/m, epirubicin 100 mg/m, and cyclophosphamide 500 mg/m) 10 years ago without experiencing any severe adverse event, no DPD deficiency testing was performed before capecitabine treatment. Nevertheless, she experienced severe diarrhea and grade 2 hand-foot syndrome from the first cycle, forcing her to stop the treatment.

Single-Cell Virtual Cytometer allows user-friendly and versatile analysis and visualization of multimodal single cell RNAseq datasets.

The development of single-cell transcriptomic technologies yields large datasets comprising multimodal informations, such as transcriptomes and immunophenotypes. Despite the current explosion of methods for pre-processing and integrating multimodal single-cell data, there is currently no user-friendly software to display easily and simultaneously both immunophenotype and transcriptome-based UMAP/t-SNE plots from the pre-processed data. Here, we introduce Single-Cell Virtual Cytometer, an open-source software for flow cytometry-like visualization and exploration of pre-processed multi-omics single cell datasets.

Why Target Innate Immune Cells in Cancers?

The immune system is a smart way to fight cancer, with its precise targeting of cancer cells sparing healthy cells [...

Nuclear upregulation of class I phosphoinositide 3-kinase p110β correlates with high 47S rRNA levels in cancer cells.

The class I phosphoinositide 3-kinase (PI3K) catalytic subunits p110α and p110β are ubiquitously expressed but differently targeted in tumours. In cancer, (encoding p110β) is seldom mutated compared with (encoding p110α) but can contribute to tumorigenesis in certain PTEN-deficient tumours. The underlying molecular mechanisms are, however, unclear.