Identification of predictive models including polymorphisms in cytokines genes and clinical variables associated with post-transplant complications after identical HLA-allogeneic stem cell transplantation.

Backgrounds: Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies, it can be associated with relevant post-transplant complications. Several reports have shown that polymorphisms in immune system genes are correlated with the development of post-transplant complications. Within this context, this work focuses on identifying novel polymorphisms in cytokine genes and developing predictive models to anticipate the risk of developing graft-versus-host disease (GVHD), transplantation-related mortality (TRM), relapse and overall survival (OS).

Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood-Brain Barrier and Assess Target Site Disposition.

The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood-brain barrier (BBB) permeability evaluation tools are needed to explore drugs' ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution.

Digital PCR Improves Sensitivity and Quantification in Monitoring CAR-T Cells in B Cell Lymphoma Patients.

Chimeric antigen receptor T cells (CAR-T) has emerged as a promising therapy, over 60% of patients fail to sustain a long-term response. The underlying factors that leads to the effectiveness of this therapy are not completely understood, CAR-T cell persistence and monitoring seems to be pivotal for ensuring a successful response. Various monitoring methods such as multiparametric flow cytometry (MFC) or quantitative PCR (qPCR) have been applied.

Cell-Free DNA Dynamic Concentration and Other Variables Are Predictors of Early Progression after Chimeric Antigen Receptor T Cell Therapy in Patients with Diffuse Large B Cell Lymphoma.

We propose a novel biomarker that can identify patients at high risk of early progression after chimeric antigen receptor (CAR) T cell therapy. Calculation of cell-free DNA (cfDNA) with a pre-apheresis (PA) and pre-lymphodepletion (PL) sample allows monitoring of tumor dynamics (∆cfDNA). In the present study, ∆cfDNA and other biomarkers and clinical variables were evaluated in 58 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL).

Leveraging Physiologically Based Modelling to Provide Insights on the Absorption of Paliperidone Extended-Release Formulation under Fed and Fasting Conditions.

Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing frequency. The administration of the ER after a high-fat/high-calorie meal leads to increased maximum plasma concentration and area under the curve values by 60% and 54%, respectively.

Novel Candidate and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing.

The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals.

'No-one knows how to care for LGBT community like LGBT do': LGBTQIA+ experiences of COVID-19 in the United Kingdom and Brazil.

The coronavirus pandemic and responses to it have had uneven impacts on different segments of societies. This study analysed the experiences of LGBTQIA+ people during the COVID-19 emergency, based on interviews in the United Kingdom and Brazil in 2020. The two countries are instructive cases, given the different social, cultural, economic, and political contexts.

Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLA-matched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT.

-ITD Expression as a Potential Biomarker for the Assessment of Treatment Response in Patients with Acute Myeloid Leukemia.

-internal tandem duplication (ITD) analysis is not typically performed in cDNA samples and is not considered an appropriate marker for monitoring measurable residual disease (MRD). The aims of this study were to compare -ITD mutation analysis in DNA and cDNA samples at diagnosis and to demonstrate the usefulness of its expression measurement as an MRD marker after allogeneic stem cell transplantation (allo-HSCT) or FLT3 inhibitor (FLT3i) administration. A total of 46 DNA and cDNA diagnosis samples, 102 DNA and cDNA post-allo-HSCT samples from 34 patients and 37 cDNA samples from 7 patients with refractory/relapse AML treated with FLT3i were assessed for the -ITD mutation through fragment analysis.

Risk prediction of CMV reactivation after allogeneic stem cell transplantation using five non-HLA immunogenetic polymorphisms.

Despite advances in the understanding of the pathophysiology of cytomegalovirus (CMV) infection, it remains as one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of this study was to determine the genotype of cytokines and chemokines in donor and recipient and their association with CMV reactivation. Eighty-five patients receiving an allo-HSCT from an HLA-identical sibling donor were included in the study.

Incorporation of next-generation sequencing in clinical practice using solid and liquid biopsy for patients with non-Hodgkin's lymphoma.

Although next-generation sequencing (NGS) data on lymphomas require further validation before being implemented in daily practice, the clinical application of NGS can be considered right around the corner. The aim of our study was to validate an NGS lymphoid panel for tissue and liquid biopsy with the most common types of non-Hodgkin's lymphoma [follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)]. In this series, 372 somatic alterations were detected in 93.

Next Generation Cytogenetics in Myeloid Hematological Neoplasms: Detection of CNVs and Translocations.

Conventional cytogenetics are the gold standard for the identification of chromosomal alterations recurrent in myeloid neoplasms. Some next-generation sequencing (NGS) panels are designed for the detection of copy number variations (CNV) or translocations; however, their use is far from being widespread. Here we report on the results of a commercial panel including frequent mutations, CNVs and translocations in myeloid neoplasms.

Clinical Utility of the Detection of the Loss of the Mismatched HLA in Relapsed Hematological Patients After Haploidentical Stem Cell Transplantation With High-Dose Cyclophosphamide.

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients.

Elafin as a Predictive Biomarker of Acute Skin Graft--Host Disease After Haploidentical Stem Cell Transplantation Using Post-Transplant High-Dose Cyclophosphamide.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients.

Clinical utility of targeted next-generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition.

Myeloid neoplasms (MN) with germline predisposition (MNGP) are likely to be more common than currently appreciated. Many of the genes involved in MNGP are also recurrently mutated in sporadic MN. Therefore, routine analysis of gene panels by next-generation sequencing provides an effective approach to detect germline variants with clinical significance in patients with hematological malignancies.

Genetic biomarkers identify a subgroup of high-risk patients within low-risk -mutated acute myeloid leukemia.

Although acute myeloid leukemia (AML) with -ITD is a low-risk entity, its relapse rate remains high. Out of 333 AML patients, 27 were , and were analyzed in greater detail in order to find associations between clinical and molecular features and cumulative incidence of relapse. Next-generation sequencing (NGS) was performed on diagnosis and remission samples using two capture-based panels.

Short Tandem Repeats (STRs) as Biomarkers for the Quantitative Follow-Up of Chimerism after Stem Cell Transplantation: Methodological Considerations and Clinical Application.

Chimerism refers to the relative proportion of donor and recipient DNA after hematopoietic stem cell transplantation (HSCT) and its quantitative follow-up is of great clinical utility in this setting. PCR of short tandem repeats (STR-PCR) constitutes the gold standard method for chimerism quantification, although more sensitive PCR techniques (such as qPCR) have recently arisen. We compared the sensitivity and the quantification capacity of both techniques in patient samples and artificial mixtures and demonstrated adequate performance of both methods, with higher sensitivity of qPCR and better quantification skills of STR-PCR.

Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms.

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels.

Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release Function (IRF) Approach.

In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world.

Leptin inhibits angiotensin II-induced intracellular calcium increase and vasoconstriction in the rat aorta.

Besides its role in body weight control leptin may also act as a vasoactive hormone. This study was designed to investigate whether leptin modifies angiotensin II (ANG II)-induced vascular responses. The expression of functional leptin receptors (OB-Rb) was detected in vascular smooth muscle cells (VSMCs) from adult Wistar rats by RT-PCR.