Mutations In Gene Research Articles

STAR gene mutation in a patient with congenital lipoid adrenal hyperplasia.

Not required for Clinical Vignette.

COL4A1 gene mutations and perinatal intracranial hemorrhage in neonates: case reports and literature review.

Intracranial hemorrhage may represent a complication of the perinatal period that affects neonatal morbidity and mortality. Very poor data exist about a possible association between mutations of the type IV collagen a1 chain (COL4A1) gene and the development of intracranial hemorrhage, and only sporadic reports focus on intracerebral bleedings already developing in utero or in the neonatal period in infants with such a mutation. This study presents a case series of term neonates affected by intracranial hemorrhage, with no apparent risk factors for the development of this condition, who were carriers of COL4A1 gene variants. This study also provides a review of the most recent scientific literature on this topic, specifically focusing on the available scientific data dealing with the perinatal period.

Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

MDB-54. GENOMIC VARIANCE OF MATCHED PRIMARY AND RECURRENT HUMAN MEDULLOBLASTOMA

Abstract BACKGROUND To investigate the difference between matched primary and recurrent human medulloblastoma across four molecular subgroups and to further expand the existing mutational spectrum in the recurrence or dissemination lesions. METHODS We analyzed the whole-exome sequencing (WES) data of 56 matched samples from 28 pairs with primary and recurrent/disseminated medulloblastoma. WES was performed using the Illumina HiSeq 2500 system, and the sequencing data were then subjected to variant detection, genome annotation, GO functional enrichment analysis, and GWAS. RESULTS All tumor samples were classified as four subgroups, including 4 cases of WNT-MB, 8 cases of SHH-MB, 20 cases of G3-MB and 24 cases of G4-MB. Conical and non-conical chromosomal variations were observed in each subgroup. Recurrent G3-MB cohort exhibited the loss of chr1p and chr22q and gain of the chr16p. The gain of chr2p, 2q, and 9p, as well as the loss of chr9q were found in the recurrent lesions of G4-MB. Recurrence of SHH-MB exhibited the loss of chr19q and chr4p, and loss of chr5p was found in the WNT-MB recurrences. CTNNB1, IDH1, and ARID1A were only observed in recurrent tumors of G3-MB; MYC was only observed in the recurrent tumors of G4-MB; IDH1 and TERT were only observed in recurrent tumors of the SHH-MB. Compared to primary medulloblastoma, recurrent tumor samples obtained a higher level of tumor mutation burden. The mutant gene profiles were mainly enriched in cell adhesion function. CONCLUSIONS When relapsing, medulloblastoma subgroup generally remains consistent, but exhibits the specific CNV, SNV and mutated gene profiles.

MITOCHONDRIAL DYSFUNCTION IN THE PATHOMORPHOGENESIS OF HYPERTROPHIC CARDIOMYOPATHY

The pathomorphogenesis of hypertrophic cardiomyopathy is a disruption of the arrangement of bundles of muscle cells in the myocardium and is associated with mutations in genes encoding the synthesis of myocardial contractile proteins. Metabolic changes in this pathology are caused by hypertrophy of the interventricular septum due to disruption of the myocardial contractile apparatus associated with these mutations, as well as mitochondrial dysfunction. Mutations in myofiber proteins can negatively affect mitochondria through increased oxidative stress due to increased ATP demand. Mitochondria are complex organelles with their own circular DNA, as well as the presence of enzyme complexes involved in redox reactions, which causes frequent damage to mitochondrial protein structures and membranes by reactive oxygen species. In this regard, mitochondrial dysfunction can also be caused by mutations in genes encoding mitochondrial proteins, which leads to disruption of mitophagy and mitochondrial dynamics. The functioning of defective mitochondria is associated with insufficient ATP synthesis and ineffective muscle contraction, which leads to the same consequences at the tissue level as mutations in contractile protein genes. In this review, we tried to summarize the role of mitochondrial dysfunction in the pathomorphogenesis of hypertrophic cardiomyopathy.

SLC40A1-related hemochromatosis associated with a p.Y333H mutation in mainland China: a pedigree report and literature review

BackgroundHaemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete.Case presentationWe report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin.ConclusionsThis study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.

EGFR and K-Ras Gene Mutations in the Diagnosis of Non-Small Cell Lung Cancer and their Pathological Correlation

EGFR and K-Ras Gene Mutations in the Diagnosis of Non-Small Cell Lung Cancer and their Pathological Correlation

Low phospholipid-associated cholelithiasis syndrome (LPAC), a not uncommon cause of biliary problems and hospital admissions.

Biliary diseases are a major source of morbidity and mortality for patients and a burden for the healthcare system. The genetic syndrome LPAC (low phospholipid-associated cholelithiasis) is a little known and rare entity whose treatment with bile salts avoids symptoms, admissions and the need for surgery. Our aim is to determine its incidence and characteristics in our center. Prospective study between February 2021 and September 2022. LPAC was diagnosed if (at least two): onset of biliary problems <40 years of age, recurrence of symptoms after cholecystectomy, ultrasound image of hepatolithiasis (multiple echoic foci, comet-tail images, hepatolithiasis with acoustic shadow). Demographic, clinical, genetic (analysis of MDR3 gene mutations) and ultrasound characteristics were analyzed, as well as their incidence in hospital admissions for biliary causes. 36 patients with LPAC were identified. Of these, 6 were among 237 admissions for biliary causes in the previous 9 months, with an incidence of 2.5% (95%CI 1.17-5.41). By age subgroup, the incidence was 16.7% in those admitted <40 years and 9.1% in those <50 years. Considering women only, the incidence was 21% in those admitted <40 years and 15.8% in those <50 years. All patients remained asymptomatic after treatment with ursodeoxycholic acid and there were no new admissions. LPAC syndrome is not as uncommon as it may appear, especially in women <50 years of age admitted with biliary problems. Its correct diagnosis based on simple criteria would avoid a significant number of hospital admissions and unnecessary cholecystectomies.

АТИПИЧНЫЙ ГЕМОЛИТИКО-УРЕМИЧЕСКИЙ СИНДРОМ У ДЕТЕЙ В РЕСПУБЛИКЕ БЕЛАРУСЬ: ПЕРВЫЙ ОПЫТ КОМПЛЕМЕНТБЛОКИРУЮЩЕЙ ТЕРАПИИ

Atypical hemolytic uremic syndrome (aHUS) is one of the most complex and severe forms of thrombotic microangiopathy with an unfavorable outcome in its natural course. The purpose of this research was to study the epidemiology, demographics, course and outcomes of aHUS in comparison with patients with typical hemolytic uremic syndrome (tHUS) as well as to conduct a personal analysis of all cases of aHUS and evaluate the response to therapy, including comple-ment-blocking with Eculizumab. Materials and methods used: the study was longitudinal, obser-vational and included all 349 cases of HUS in children in Belarus in 2015-2023. A comparative analysis of demographic and clinical data, laboratory results and outcomes was performed in pa-tients with HUS hospitalized at the Center for Pediatric Nephrology and Renal Replacement Therapy of the Republic of Belarus (Minsk, Belarus). Results: of 349 HUS cases, the proportion of aHUS was 3,7% (13). Children with aHUS were older (4,6 (1,6; 6,7) v. 2,7 (1,7; 4,8) y/o with tHUS) due to the portion of patients older than 5 y/o (46%). In aHUS, severe central nervous system disorders were more often observed (62% v. 14%, p=0,002), the development of critical conditions requiring transfer to mechanical ventilation (39% v. 9%, p=0,006), prolonged anuria with the need for dialysis therapy in 100% of cases and severe adverse outcomes (death or end-stage renal disease) during natural course (66,0% v. 2,7%, p&lt;0,001). The most common trigger for aHUS was acute intestinal infections in 54% of cases. A genetic study was performed in 9 (69%) children with aHUS and in 8 (89%) of them the CFHR3/CFHR1 deletions were detected: in 4 cases (3 hetero- and a single homozygous) and heterozygous pathogenic and probably patho-genic gene mutations, CFHR5 in 2 cases, CFH in a single case and combined CD46 and CFI in a single case as well. Antibodies to complement factor H were detected in 5 patients, 3 of which had a CFHR3/CFHR1 deletion. Therapy with a biosimilar of the original Eculizumab showed its effectiveness in aHUS: in 3 (100%) children it was possible to prevent the return of the disease in the kidney graft, in single patient who did not receive prophylaxis it was able to block the recur-rence of aHUS in the transplanted kidney while preserving its function, in 3 (100%) patients with late administration of treatment the urine output was restored after prolonged anuria (24, 33 and 59 days); in a single child with the antibody variant of aHUS, with early administration of the drug, renal function was preserved. No complications of complement blocking therapy were not-ed. Conclusions: the introduction into clinical practice of a biosimilar of the original Eculizumab in children in Belarus has significantly improved the outcomes and prognosis of the disease.

Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors.

Acute myeloid leukemias are a group of hematological malignancies characterized by a poor prognosis for survival. The discovery of oncogenic mutations in the FLT3 gene has led to the development of tyrosine kinase inhibitors such as Quizartinib. However, achieving complete remission in patients remains challenging because these new TKIs are unable to completely eradicate all leukemic cells. Residual leukemic cells persist during Quizartinib treatment, leading to the rapid emergence of drug-resistant leukemia. Given that mitochondrial oxidative metabolism promotes the survival of leukemic cells after exposure to multiple anticancer drugs, we characterized the metabolism of leukemic cells that persisted during Quizartinib treatment and developed metabolic strategies to eradicate them. In our study, employing biochemical and metabolomics approaches, we confirmed that the survival of leukemic cells treated with FLT3 inhibitors critically depends on maintaining mitochondrial metabolism, specifically through glutamine oxidation. We uncovered a synergistic interaction between the FLT3 inhibitor Quizartinib and L-Asparaginase, operating through anti-metabolic mechanisms. Utilizing various models of persistent leukemia, we demonstrated that leukemic cells resistant to Quizartinib are susceptible to L-Asparaginase. This combined therapeutic strategy shows promise in reducing the development of resistance to FLT3 inhibitors, offering a potential strategy to enhance treatment outcomes.

Ataxia Telangiectasia patient-derived neuronal and brain organoid models reveal mitochondrial dysfunction and oxidative stress

Ataxia Telangiectasia (AT) is a rare disorder caused by mutations in the ATM gene and results in progressive neurodegeneration for reasons that remain poorly understood. In addition to its central role in nuclear DNA repair, ATM operates outside the nucleus to regulate metabolism, redox homeostasis and mitochondrial function. However, a systematic investigation into how and when loss of ATM affects these parameters in relevant human neuronal models of AT was lacking. We therefore used cortical neurons and brain organoids from AT-patient iPSC and gene corrected isogenic controls to reveal levels of mitochondrial dysfunction, oxidative stress, and senescence that vary with developmental maturity. Transcriptome analyses identified disruptions in regulatory networks related to mitochondrial function and maintenance, including alterations in the PARP/SIRT signalling axis and dysregulation of key mitophagy and mitochondrial fission-fusion processes. We further show that antioxidants reduce ROS and restore neurite branching in AT neuronal cultures, and ameliorate impaired neuronal activity in AT brain organoids. We conclude that progressive mitochondrial dysfunction and aberrant ROS production are important contributors to neurodegeneration in AT and are strongly linked to ATM's role in mitochondrial homeostasis regulation.

Assessment of Early Glaucomatous Optic Neuropathy in the Dog by Spectral Domain Optical Coherence Tomography (SD-OCT).

Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the ADAMTS10 gene. Using this model, the study describes early clinical disease markers for canine glaucoma. Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, ADAMTS10-mutant (median age 45.6 months, range 28.8-52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/- SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/- SEM 0.53 mmHg). Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/- SEM 38.4 μm to 9.3 +/- SEM 22.1 μm; p < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: -0.78; p < 0.003). There were no significant differences in the thickness of any retinal layers evaluated. SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin.

Assessment of genome mutation analysis for tumor-informed detection of circulating tumor DNA in patients with breast cancer

IntroductionBreast cancer, one of the most aggressive types of cancer, poses significant challenges for diagnosis and treatment. Emerging as a promising biomarker, circulating tumor DNA (ctDNA) can be used to identify and monitor disease risk. This study sought to examine the impact of mutations in various genes on the progression of breast cancer. Genetic variants associated with breast cancer have been examined in individuals diagnosed with the disease worldwide. MethodsFifty female participants underwent breast cancer testing. Sanger sequencing was used to analyze peripheral blood DNA from these individuals to detect disease-causing mutations in the BRCA1, BRCA2, PTEN, TP53, and ATM genes. Genetic alterations linked to breast cancer were screened and the findings were compared with those of tumor genes. ResultsThe development of hereditary/early onset breast cancer in this study was significantly associated with mutations in ATM, PTEN, TP53, and BRCA1/BRCA2, according to the analysis of sequencing data. ConclusionThis study demonstrates the feasibility of analyzing ctDNA in patients with breast cancer (BC) undergoing palliative treatment using an SS-based technique.

SS-31 treatment ameliorates cardiac mitochondrial morphology and defective mitophagy in a murine model of Barth syndrome

Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations in the TAFAZZIN gene, which is responsible for the remodeling of the phospholipid cardiolipin (CL), lead to abnormalities in mitochondrial membrane, including alteration of mature CL acyl composition and the presence of monolysocardiolipin (MLCL). The dramatic increase in the MLCL/CL ratio is the hallmark of patients with BTHS, which is associated with mitochondrial bioenergetics dysfunction and altered membrane ultrastructure. There are currently no specific therapies for BTHS. Here, we showed that cardiac mitochondria isolated from TAFAZZIN knockdown (TazKD) mice presented abnormal ultrastructural membrane morphology, accumulation of vacuoles, pro-fission conditions and defective mitophagy. Interestingly, we found that in vivo treatment of TazKD mice with a CL-targeted small peptide (named SS-31) was able to restore mitochondrial morphology in tafazzin-deficient heart by affecting specific proteins involved in dynamic process and mitophagy. This agrees with our previous data showing an improvement in mitochondrial respiratory efficiency associated with increased supercomplex organization in TazKD mice under the same pharmacological treatment. Taken together our findings confirm the beneficial effect of SS-31 in the amelioration of tafazzin-deficient dysfunctional mitochondria in a BTHS animal model.

Identification and properties of TRPV4 mutant channels present in polycystic kidney disease patients.

Polycystic kidney disease (PKD), a disease characterized by enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. TRPV4, a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations.

Revolutionary multi-omics analysis revealing prognostic signature of thyroid cancer and subsequent in vitro validation of SNAI1 in mediating thyroid cancer progression through EMT

Thyroid carcinoma (TC), the most commonly diagnosed malignancy of the endocrine system, has witnessed a significant rise in incidence over the past few decades. The integration of scRNA-seq with other sequencing approaches offers researchers a distinct perspective to explore mechanisms underlying TC progression. Therefore, it is crucial to develop a prognostic model for TC patients by utilizing a multi-omics approach. We acquired and processed transcriptomic data from the TCGA-THCA dataset, including mRNA expression profiles, lncRNA expression profiles, miRNA expression profiles, methylation chip data, gene mutation data, and clinical data. We constructed a tumor-related risk model using machine learning methods and developed a consensus machine learning-driven signature (CMLS) for accurate and stable prediction of TC patient outcomes. 2 strains of undifferentiated TC cell lines and 1 strain of PTC cell line were utilized for in vitro validation. mRNA, protein levels of hub genes, epithelial-mesenchymal transition (EMT)-associated phenotypes were detected by a series of in vitro experiments. We identified 3 molecular subtypes of TC based on integrated multi-omics clustering algorithms, which were associated with overall survival and displayed distinct molecular features. We developed a CMLS based on 28 hub genes to predict patient outcomes, and demonstrated that CMLS outperformed other prognostic models. TC patients of relatively lower CMLS score had significantly higher levels of T cells, B cells, and macrophages, indicating an immune-activated state. Fibroblasts were predominantly enriched in the high CMLS group, along with markers associated with immune suppression and evasion. We identified several drugs that could be suitable for patients with high CMLS, including Staurosporine_1034, Rapamycin_1084, gemcitabine, and topotecan. SNAI1 was elevated in both undifferentiated TC cell lines, comparing to PTC cells. Knockdown of SNAI1 reduced the cell proliferation and EMT phenotypes of undifferentiated TC cells. Our findings highlight the importance of multi-omics analysis in understanding the molecular subtypes and immune characteristics of TC, and provide a novel prognostic model and potential therapeutic targets for this disease. Moreover, we identified SNAI1 in mediating TC progression through EMT in vitro.

Biomarkers in breast cancer 2024: an updated consensus statement by the Spanish Society of Medical Oncology and the Spanish Society of Pathology.

This revised consensus statement of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathological Anatomy (SEAP) updates the recommendations for biomarkers use in the diagnosis and treatment of breast cancer that we first published in 2018. The expert group recommends determining in early breast cancer the estrogen receptor (ER), progesterone receptor (PR), Ki-67, and Human Epidermal growth factor Receptor 2 (HER2), as well as BReast CAncer (BRCA) genes in high-risk HER2-negative breast cancer, to assist prognosis and help in indicating the therapeutic options, including hormone therapy, chemotherapy, anti-HER2 therapy, and other targeted therapies. One of the four available genetic prognostic platforms (Oncotype DX®, MammaPrint®, Prosigna®, or EndoPredict®) may be used in ER-positive patients with early breast cancer to establish a prognostic category and help decide with the patient whether adjuvant treatment may be limited to hormonal therapy. In second-line advanced breast cancer, in addition, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and estrogen receptor 1 (ESR1) should be tested in hormone-sensitive cases, BRCA gene mutations in HER2-negative cancers, and in triple-negative breast cancer (TNBC), programmed cell death-1 ligand (PD-L1). Newer biomarkers and technologies, including tumor-infiltrating lymphocytes (TILs), homologous recombination deficiency (HRD) testing, serine/threonine kinase (AKT) pathway activation, and next-generation sequencing (NGS), are at this point investigational.

PfHDAC1 is an essential regulator of P. falciparum asexual proliferation and host cell invasion genes with a dynamic genomic occupancy responsive to artemisinin stress.

Malaria is a major public health problem, with the parasite Plasmodium falciparum causing most of the malaria-associated mortality. It is spread by the bite of infected mosquitoes and results in symptoms such as cyclic fever, chills, and headache. However, if left untreated, it can quickly progress to a more severe and life-threatening form. The World Health Organization currently recommends the use of artemisinin combination therapy, and it has worked as a gold standard for many years. Unfortunately, certain countries in southeast Asia and Africa, burdened with a high prevalence of malaria, have reported cases of drug-resistant infections. One of the major problems in controlling malaria is the emergence of artemisinin resistance. Population genomic studies have identified mutations in the Kelch13 gene as a molecular marker for artemisinin resistance. However, several reports thereafter indicated that Kelch13 is not the main mediator but rather hinted at transcriptional deregulation as a major determinant of drug resistance. Earlier, we identified PfGCN5 as a global regulator of stress-responsive genes, which are known to play a central role in artemisinin resistance generation. In this study, we have identified PfHDAC1, a histone deacetylase as a cell cycle regulator, playing an important role in artemisinin resistance generation. Taken together, our study identified key transcriptional regulators that play an important role in artemisinin resistance generation.

Systematic analysis of IGF2BP family members in non-small-cell lung cancer

BackgroundThe insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, and IGF2BP3) are known to be involved in tumorigenesis, metastasis, prognosis, and cancer immunity in various human cancers, including non-small cell lung cancer (NSCLC). However, the literature on NSCLC largely omits the specific context of lung squamous cell carcinoma (LUSC), an oversight we aim to address.MethodsOur study evaluated the differential expression of IGF2BP family members in tumors and normal tissues. Meta-analyses were conducted to assess the prognostic value of IGF2BPs in lung adenocarcinoma (LUAD) and LUSC. Additionally, correlations between IGF2BPs and tumor immune cell infiltration, mutation characteristics, chemotherapy sensitivity, and tumor mutation burden (TMB) were investigated. GSEA was utilized to delineate biological processes and pathways associated with IGF2BPs.ResultsIGF2BP2 and IGF2BP3 expression were found to be upregulated in LUSC patients. IGF2BP2 mRNA levels were correlated with cancer immunity in both LUSC and LUAD patients. A higher frequency of gene mutations was observed in different IGF2BP1/2/3 expression groups in LUAD compared to LUSC. Meta-analyses revealed a significant negative correlation between overall survival (OS) and IGF2BP2/3 expression in LUAD patients but not in LUSC patients. GSEA indicated a positive association between VEGF and IGF2BP family genes in LUAD, while matrix metallopeptidase activity was inversely correlated with IGF2BP family genes in LUSC. Several chemotherapy drugs showed significantly lower IC50 values in high IGF2BP expression groups in both LUAD and LUSC.ConclusionOur findings indicated that IGF2BPs play different roles in LUAD and LUSC. This divergence highlights the need for tailored therapeutic strategies and prognostic tools, cognizant of the unique molecular profiles of LUAD and LUSC.

Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells

Sickle cell disease is a devastating blood disorder that originates from a single point mutation in the HBB gene coding for hemoglobin. Here, we develop a GMP-compatible TALEN-mediated gene editing process enabling efficient HBB correction via a DNA repair template while minimizing risks associated with HBB inactivation. Comparing viral versus non-viral DNA repair template delivery in hematopoietic stem and progenitor cells in vitro, both strategies achieve comparable HBB correction and result in over 50% expression of normal adult hemoglobin in red blood cells without inducing β-thalassemic phenotype. In an immunodeficient female mouse model, transplanted cells edited with the non-viral strategy exhibit higher engraftment and gene correction levels compared to those edited with the viral strategy. Transcriptomic analysis reveals that non-viral DNA repair template delivery mitigates P53-mediated toxicity and preserves high levels of long-term hematopoietic stem cells. This work paves the way for TALEN-based autologous gene therapy for sickle cell disease.