Current Research in Translational Medicine最新文献

Myelodysplastic neoplasms (MDS) are clonal hematopoietic neoplasms. Chromosomal abnormalities (CAs) are detected in 40–45% of de novo MDS and up to 80% of post-cytotoxic therapy MDS (MDS-pCT). Lately, several changes appeared in World Health Organization (WHO) classification and International Consensus Classification (ICC). The novel ‘biallelic TP53 inactivation’ (also called ‘multi-hit TP53’) MDS entity requires systematic investigation of TP53 locus (17p13.1). The ICC maintains CA allowing the diagnosis of MDS without dysplasia (del(5q), del(7q), -7 and complex karyotype). Deletion 5q is the only CA, still representing a low blast class of its own, if isolated or associated with one additional CA other than -7 or del(7q) and without multi-hit TP53. It represents one of the most frequent aberrations in adults’ MDS, with chromosome 7 aberrations, and trisomy 8. Conversely, translocations are rarer in MDS. In children, del(5q) is very rare while -7 and del(7q) are predominant. Identification of a germline predisposition is key in childhood MDS. Aberrations of chromosomes 5, 7 and 17 are the most frequent in MDS-pCT, grouped in complex karyotypes. Despite the ever-increasing importance of molecular features, cytogenetics remains a major part of diagnosis and prognosis. In 2022, a molecular international prognostic score (IPSS-M) was proposed, combining the prognostic value of mutated genes to the previous scoring parameters (IPSS-R) including cytogenetics, still essential. A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations.

Myeloproliferative neoplasms, mastocytosis, myeloid/lymphoid neoplasms with hypereosinophilia and tyrosine kinase gene fusions, and myelodysplastic/myeloproliferative neoplasms are clonal hematopoietic cancers that, with the exception of certain entities, have an indolent course.

In addition to their increasingly important role in the diagnosis of these entities, as shown by the recent classification of hematolymphoid tumors in the 5th edition of the World Health Organization and the International Consensus Classification of myeloid neoplasms and acute leukemias, identification of the profile of acquired genetic abnormalities is essential for adapting patient management and early detection of patients at high risk of progression.

Alongside molecular abnormalities, cytogenetic abnormalities play an important role in the diagnosis, prognosis and follow-up of these diseases.

Here, we review the recent literature on the impact of chromosomal abnormalities in these different entities and provide updated cytogenetic recommendations and guidelines for their management.

Purpose of the study

: The current study aimed to detect the frequency of normal and mutated APOL1 alleles in sickle cell disease (SCD) patients and test their relation with Microalbuminuria, Creatinine, Urea, Glomerular Filtration Rate (GFR), and Body Mass Index (BMI).

Patients and Methods

: The study included 156 SCD subjects. Serum Creatinine (mg/dl) and Urea (mg/dl) as well as Microalbuminuria (mg/l) level were measured by using Biosystems kit (Biosystems, Barcelona, Spain) and Mindary BA88A semi-automated biochemistry analyzer. Glomerular filtration rate and body mass index were calculated by equations. Blood DNA extraction was achieved by using the modified G-DEX™IIb Genomic DNA Extraction Kit protocol. The PCR was done for the detection of the APOL1 G2 rs60910145 alleles by using allele-specific PCR and primers.

Results

: The CC allele was more frequent in study cases (66.7%) than TT allele. The frequency of a mutated allele (CC) was insignificantly higher in males (67.8%) than in females (65.2%) and in rural (70.9%) than urban areas. It is also higher in Shankhab compared to other tribes and subjects 26-37 years compared to other, P˃0.05. Interstingly, the subjects who carry the CC allele showed a significantly higher level of Microalbuminuria, Creatinine, BMI, and Urea compared to those carry TT allele. Moreover, GFR is also higher in subjects who carry CC than TT allele but it is not significant.

Conculsion

: Altogether, the study findings highlighted the link of normal and mutated APOL1 G2 rs60910145 alleles with SCD and displayed the significant value of mutated APOL1 allele in the prediction of early nephropathy in SCD patients.

The incidence of pancreatic diseases has been continuously rising in recent years. Thus, research on pancreatic regeneration is becoming more popular. Chronic hyperglycemia is detrimental to pancreatic β-cells, leading to impairment of insulin secretion which is the main hallmark of pancreatic diseases. Obtaining plenty of functional pancreatic β-cells is the most crucial aspect when studying pancreatic biology and treating diabetes. According to the International Diabetes Federation, diabetes has become a global epidemic, with about 3 million people suffering from diabetes worldwide. Hyperglycemia can lead to many dangerous diseases, including amputation, blindness, neuropathy, stroke, and cardiovascular and kidney diseases. Insulin is widely used in the treatment of diabetes; however, innovative approaches are needed in the academic and preclinical stages. A new approach aims at synthesizing patient-specific functional pancreatic β-cells. The present article focuses on how cells from different tissues can be transformed into pancreatic β-cells.

Proposing the concept of a brain-gut-skin axis has led some researchers to recognize the relationship among brain activity, gut microbiota, and the skin. Hair follicles are skin accessory organs, a previously unnoticed target tissue for classical neurohormones, neurotrophins, and neuropeptides. Some studies have shown a relationship between the central nervous system and hair follicles that an imbalance in the gut bacteria can affect hair follicle density. This review summarizes existing evidence from literature and explores clues supporting a connection linking the brain, gut microbiota, and hair follicles. It amalgamates previously proposed partial concepts into a new, unified concept—the “brain-gut microbiota-hair follicle” axis, —which suggests that modulation of the microbiome via probiotics can have positive effects on hair follicles. This review also explores how preclinical research on hair follicles can propel novel and clinically untapped applications.

Advanced systemic mastocytosis (AdvSM) is a rare, life-limiting mast cell (MC) neoplasm, with approximately 70% patients having an associated haematological neoplasm (AHN). Avapritinib, a selective tyrosine kinase inhibitor targeting KIT D816V, has shown potent activity translating clinically into durable responses in the phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies.

We report three patients with AdvSM-AHN on avapritinib who achieved complete remission (CR) of SM and were successfully bridged to allogeneic haematopoietic cell transplant (allo-HCT). Two cases additionally highlight the risk of clonal evolution within the AHN component and requirement for close monitoring while on targeted therapy.

Coexisting malignancies is not only an uncommon event but, it can also represent a medical challenge. Its complexity relies on the difficulty of management and the need for personalized and prioritized therapeutic approaches, on the one hand, and in the potential misdiagnosis of recurrence or even a de novo disease, on the other.

Here, we present a case of a 69-year-old patient, who was initially diagnosed with a chronic myelomonocytic leukemia (CMML), followed by monoclonal gammopathy of uncertain significance (MGUS). Few years later, the patient developed Hodgkin's lymphoma (HL), and a new mutation, previously undocumented in the medical literature, was also detected.

As a conclusion, we can say that the decision must be taken with caution and must be based on two major factors: 1- The rapid evolution of malignancies: give priority to treating the most rapid/life-threatening disease. 2- Prioritize the treatment of symptomatic disease and/or that which may most improve patients’ quality of life.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T-cell lymphoma type with distinct clinical, molecular and genetic features. Establishment of BIA-ALCL cell lines and patient-derived xenograft (PDX) models are essential experimental tools to investigate the molecular pathogenesis of the disease. We characterized a novel BIA-ALCL cell line and PDX model, named BIA-XR1, derived from a patient with textured breast implant who developed lymphoma. Next-generation sequencing revealed a STAT3 mutation, commonly detected in BIA-ALCL, and a unique KRAS mutation reported for the first time in this lymphoma type. Both JAK/STAT3 and RAS/MEK/ERK oncogenic pathways were activated in BIA-XR1, which are targetable with clinically available agents.

Introduction

In the era of JAK inhibitors, allogeneic stem cell transplantation (HSCT) remains the only curative treatment for patients with Myelofibrosis (MF). Splenic irradiation (SI) may be used to reduce spleen size and related symptoms.

Methods

We conducted a retrospective analysis on 14 patients with MF who underwent HSCT with SI from any donor source at our center between June 2016 and March 2021. All patients received a conditioning backbone based on treosulfan and fludarabine, with post-transplant cyclophosphamide (PTCy) and sirolimus as graft-versus-host disease (GvHD) prophylaxis. Patients received SI with 10 Gy involved-field radiotherapy in five 2-Gy fractions over the course of a week prior to the beginning of conditioning.

Results

At transplant all patients were transfusion-dependent and had splenomegaly (median bipolar diameter by ultrasound: 20.75 cm). Overall, 12 patients had received ruxolitinib prior to transplant. Re-evaluation of spleen dimensions was available for 13 patients: median splenic bipolar diameter after at least 3 months from transplant decreased by a median of 25%. With a median post-transplant follow-up of 25 months, 6 patients remain in CR with full-donor chimerism, 3 patients died due to NRM. Overall, 4 patients relapsed. At last follow-up, nine patients are currently alive and achieved transfusion-independence.

Conclusions

In a small cohort of mostly ruxolitinib pre-treated patients, SI and treosulfan-based conditioning appeared a safe and effective tool to reduce spleen dimensions and ameliorate symptoms. Future prospective studies with adequate sample size are warranted to further investigate the usefulness and safety of this approach in MF.