Exploring the impact of HDL and LMNA gene expression on immunotherapy outcomes in NSCLC: a comprehensive analysis using clinical & gene data.

Objectives: Analyzing the impact of peripheral lipid levels on the efficacy of immune checkpoint inhibitor therapy in non-small cell lung cancer (NSCLC) patient populations and exploring whether it can serve as a biomarker for broadening precise selection of individuals benefiting from immunotherapy. Methods: We retrospectively collected clinical data from 201 cases of NSCLC patients receiving immune checkpoint inhibitor therapy. The clinical information included biochemical indicators like total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). We utilized machine learning algorithms and Cox proportional hazards regression models to investigate independent predictors for both short-term and long-term efficacy of immunotherapy. Additionally, we concurrently developed a survival prediction model. Analyzing the Genes of Patients with Treatment Differences to Uncover Mechanisms. Results: Correlation analysis revealed a significant positive association between HDL and ORR, DCR, and PFS. T-test results indicated that the high-HDL group exhibited higher DCR (81.97% vs. 45.57%) and ORR (61.48% vs. 16.46%). Kruskal-Wallis test showed that the high-HDL group had a longer median PFS (11 months vs. 6 months). Utilizing six machine learning algorithms, we constructed models to predict disease relief and stability. The model built using the random forest algorithm demonstrated superior performance, with AUC values of 0.858 and 0.802. Furthermore, both univariate and multivariate Cox analyses identified HDL and LDL as independent risk factors for predicting PFS. In patients with poor immunotherapy response, there is upregulation of BCL2L11, AKT1, and LMNA expression. Conclusion: HDL and LDL are independent factors influencing the survival prognosis of NSCLC patients undergoing immune checkpoint inhibitor therapy. HDL is expected to become new biomarkers for predicting the immunotherapy efficacy in patients with NSCLC. In patients with poor immunotherapy response, upregulation of the LMNA gene leads to apoptosis resistance and abnormal lipid metabolism.

A case report of a rare genetic mutation (LMNA-C.185G>C, p.Arg62Pro) associated with dilated cardiomyopathy in a Han Chinese child.

Dilated cardiomyopathy (DCM) remains an enigmatic myocardial disorder characterized either by enlargement of either the left or right ventricle or both and reduced contractility, posing a significant burden on pediatric populations as a leading cause of cardiac-related mortality and morbidity. This paper presents a compelling case of DCM in a Han Chinese child whose genomic analysis unveiled a novel LMNA-C.185G>C (p.Arg62Pro) variant. Over a meticulous 3-year clinical follow-up, spanning ten outpatient consultations and hospital admissions since the initial diagnosis, the patient exhibited a progressive emergence of various cardiac conduction anomalies closely mirroring LMNA-associated phenotypes. Delving into a comprehensive review of the patient's 14-year medical journey and familial history, antecedent signs of muscular dystrophy (MD) predated DCM onset. Familial scrutiny revealed a lineage marred by muscular atrophy, with the patient's maternal grandmother having a history of muscular dystrophy and an episode of DCM, necessitating cardiac transplantation in the patient's uncle at age 37. This scenario illuminates the intricate interplay between LMNA-associated diseases and genetic predisposition. Timely identification of etiological triggers stands paramount in DCM management. Beyond conventional genetic scrutiny, leveraging novel serum biomarkers such as anti-heart muscle antibodies (AHA) remarkably enhanced diagnostic precision. Notably, personalized therapeutic interventions comprising prednisolone regimens and intravenous immunoglobulin infusions precipitated marked amelioration in heart failure symptoms and serum biomarker profiles. It is noteworthy to identify this novel genetic locus within the Han Chinese populace, underscoring the imperative of expanding the LMNA mutation repository within this demographic cohort. Early recognition of clinical manifestations and etiological cues in pediatric DCM heralds a paradigm shift in risk prognostication and individualized therapeutic interventions, underscoring the profound significance of precision medicine in combating rare familial cardiomyopathies.

Severe familial dilated cardiomyopathy in a young adult due to a rare LMNA mutation: a case report.

Background: Familial dilated cardiomyopathy prognosis and disease progression vary greatly depending upon the type of genetic mutation. Family history and genetic testing are paramount in developing the best treatment plan for a patient. However, with rare or novel mutations, the significance may be unknown. Regarding this, the following case report highlights the importance of vigilance and suspicion when treating a patient with a variant of unknown significance. Additionally, it shows the importance of thoroughly investigating the family history of cardiovascular disease. Case summary: A 25-year-old Caucasian male was found to have a right bundle branch block and dilated cardiomyopathy upon presentation to the emergency department. Later testing showed that the dilated cardiomyopathy was due to an incredibly rare lamin A/C (LMNA) gene mutation, R349L. Despite treatment with a maximum-tolerable medication regimen and an automatic implantable cardioverter-defibrillator, the patient continued to decline and required a heart transplant. Discussion: This case provides more information on the severity of this specific LMNA mutation that has only been documented once before. Of note, the time from the initial emergency department visit to the heart transplant was approximately 2 years. Given the patient's young age and rapid disease progression, in addition to a strong family history of sudden cardiac death, the significance of this mutation should not be understated. The additional knowledge gained from this case report can be used to aid in timely interventions and prognosis evaluation.

Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids.

The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The "nodal" cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with in vivo-like gene expression and electrophysiological profiles. We created the so-called "assembloids" composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the "fast-slow-fast" activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.

A cohort analysis of familial partial lipodystrophy from two Mediterranean countries.

AIM: To assess the disease burden of familial partial lipodystrophy (FPLD) caused by LMNA (FPLD2) and PPARG (FPLD3) variants to augment the knowledge of these rare disorders characterized by selective fat loss and metabolic complications. MATERIALS AND METHODS: An observational longitudinal study, including 157 patients (FPLD2: 139 patients, mean age 46 ± 17 years, 70% women; FPLD3: 18 patients, mean age: 44 ± 17 years, 78% women) from 66 independent families in two countries (83 from Turkey and 74 from Spain), was conducted. RESULTS: Patients were diagnosed at a mean age of 39 ± 19 years, 20 ± 16 years after the first clinical signs appeared. Men reported symptoms later than women. Symptom onset was earlier in FPLD2. Fat loss was less prominent in FPLD3. In total, 92 subjects (59%) had diabetes (age at diagnosis: 34 ± 1 years). Retinopathy was more commonly detected in FPLD3 (P < .05). Severe hypertriglyceridaemia was more frequent among patients with FPLD3 (44% vs. 17%, P = .01). Hepatic steatosis was detected in 100 subjects (66%) (age at diagnosis: 36 ± 2 years). Coronary artery disease developed in 26 patients (17%) and 17 (11%) suffered from a myocardial infarction. Turkish patients had a lower body mass index, a higher prevalence of hepatic steatosis, greater triglyceride levels and a tendency towards a higher prevalence of coronary artery disease. A total of 17 patients died, with a mean time to death of 75 ± 3 years, which was shorter in the Turkish cohort (68 ± 2 vs. 83 ± 4 years, P = .01). Cardiovascular events were a major cause of death. CONCLUSIONS: Our analysis highlights severe organ complications in patients with FPLD, showing differences between genotypes and Mediterranean countries. FPLD3 presents a milder phenotype than FPLD2, but with comparable or even greater severity of metabolic disturbances.

Nuclear envelope lamin-related dilated cardiomyopathy: a case series including histopathology.

Background: Lamin A/C gene (LMNA) mutations cause myocardial fibrosis manifesting as arrhythmogenic, non-compaction, or dilated cardiomyopathies. Fibro-fatty replacement largely involves the conduction system and conduction disease commonly occurs prior to contractile dysfunction. Case summary: Two young, unrelated Caucasian males, aged 34 and 25, were referred to our centre for treatment of advanced heart failure. Both patients had a family history of heart failure and sudden cardiac death among their first-degree relatives and were diagnosed with Lamin A/C mutations, but they had not been screened prior to disease onset. Although the initial phenotypes were dilated cardiomyopathy and left ventricular non-compaction cardiomyopathy, both patients' disease progressed rapidly to include ventricular arrhythmias, severe global left ventricular hypokinesis, and dependence on outpatient milrinone to complete activities of daily living. Both patients received heart transplantation within 2 years of initial disease onset. The surgical pathology of the explanted hearts revealed characteristic findings of fibro-fatty degeneration of the conduction system, and using light microscopy, they were found to have nuclear membrane thinning, bubbling, and convolution throughout all areas sampled. Discussion: Lamin A/C-related cardiomyopathy is associated with sudden cardiac death early in the disease course, warranting early consideration of implantable cardioverter defibrillator implantation, and rapid progression to end-stage cardiomyopathy refractory to standard medical therapies, necessitating early referral to an advanced heart failure centre. We report a newly observed and recorded finding of morphologic nuclear alterations in late-stage disease using high-power light microscopy. These alterations underscore the pathophysiology of Lamin A/C-related cardiomyopathy and provide a basis for future research into disease-specific therapies.

A case of restrictive dermopathy in a Hutterite newborn: Diagnosis and creative skin-directed management.

Restrictive dermopathy is a lethal autosomal recessive disease characterized by tightly adherent skin, distinctive facial dysmorphisms, arthrogryposis, and pulmonary hypoplasia. While clinical findings are unique, histopathology and genetic analysis are critical for early diagnostic confirmation and to initiate appropriate management for this lethal disease. We report on a preterm Hutterite male neonate with biallelic ZMPSTE24 mutations to highlight the clinical and histopathological features of restrictive dermopathy and share our skin-directed management strategies.

DNA methylation of the Lamin A/C gene is associated with congenital heart disease.

BACKGROUND: Prior studies report associations of maternal serum Lamin A, encoded by the LMNA gene, with fetal congenital heart disease (CHD). It is unknown whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites in LMNA impacts the CHD susceptibility. METHODS: We investigated the associations of LMNA DNAm with CHD using publicly available data of CHD cases (n = 197) and controls (n = 134) from the Gene Expression Omnibus repository. Peripheral blood DNAm was measured using Illumina 850 K BeadChip for cases and 450 K BeadChip for controls. We tested 31 LMNA CpGs to identify differences in DNAm between cases and controls using linear regression correcting for multiple testing with false discovery rate (FDR). In a case-only analysis, we tested the variations in LMNA DNAm between CHD subtypes. To identify the consistency of DNAm across tissue types we compared peripheral blood (n = 197) and heart tissue DNAm (n = 20) in CHD cases. RESULTS: After adjusting for age, sex, and cell types there were significant differences in 17 of the 31 LMNA CpGs between CHD cases and controls (FDR p ≤ .05). We identified lower DNAm of cg09820673 at 3' UTR for hypoplastic left heart syndrome compared to other CHD subtypes. Three CpGs exhibited uniform DNAm in blood and heart tissues in cases. Eleven CpGs showed changes in the same direction in blood and heart tissues in cases compared to controls. CONCLUSION: We identify statistically significant differences in LMNA DNAm between CHD cases and controls. Future studies should investigate the role of maternal LMNA DNAm in CHD development.

Lipomatoses.

Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.

The Expression of a Subset of Aging and Antiaging Markers Following the Chondrogenic and Osteogenic Differentiation of Mesenchymal Stem Cells of Placental Origin.

Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However, their utility has been limited by their tendency to undergo premature senescence and phenotypic drift into adipocytes. This study aimed to explore the potential involvement of a specific subset of aging and antiaging genes by measuring their expression prior to and following in vitro-induced differentiation of placental MSCs into chondrocytes and osteoblasts as opposed to adipocytes. The targeted genes of interest included the various LMNA/C transcript variants (lamin A, lamin C, and lamin A∆10), sirtuin 7 (SIRT7), and SM22α, along with the classic aging markers plasminogen activator inhibitor 1 (PAI-1), p53, and p16INK4a. MSCs were isolated from the decidua basalis of human term placentas, expanded, and then analyzed for phenotypic properties by flow cytometry and evaluated for colony-forming efficiency. The cells were then induced to differentiate in vitro into chondrocytes, osteocytes, and adipocytes following established protocols. The mRNA expression of the targeted genes was measured by RT-qPCR in the undifferentiated cells and those fully differentiated into the three cellular lineages. Compared to undifferentiated cells, the differentiated chondrocytes demonstrated decreased expression of SIRT7, along with decreased PAI-1, lamin A, and SM22α expression, but the expression of p16INK4a and p53 increased, suggesting their tendency to undergo premature senescence. Interestingly, the cells maintained the expression of lamin C, which indicates that it is the primary lamin variant influencing the mechanoelastic properties of the differentiated cells. Notably, the expression of all targeted genes did not differ from the undifferentiated cells following osteogenic differentiation. On the other hand, the differentiation of the cells into adipocytes was associated with decreased expression of lamin A and PAI-1. The distinct patterns of expression of aging and antiaging genes following in vitro-induced differentiation of MSCs into chondrocytes, osteocytes, and adipocytes potentially reflect specific roles for these genes during and following differentiation in the fully functional cells. Understanding these roles and the network of signaling molecules involved can open opportunities to improve the handling and utility of MSCs as cellular precursors for the treatment of cartilage and bone diseases.

Missense and Non-Missense Lamin A/C Gene Mutations Are Similarly Associated with Major Arrhythmic Cardiac Events: A 20-Year Single-Centre Experience.

Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups (p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.

Creatine and L-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish.

Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this study, we delve into the investigations of five distinct LMNA mutations, including three novel variants and two pathogenic variants identified in patients with muscular laminopathy. Our approach employs zebrafish models to comprehensively study these variants. Transgenic zebrafish expressing wild-type LMNA and each mutation undergo extensive morphological profiling, swimming behavior assessments, muscle endurance evaluations, heartbeat measurement, and histopathological analysis of skeletal muscles. Additionally, these models serve as platform for focused drug screening. We explore the transcriptomic landscape through qPCR and RNAseq to unveil altered gene expression profiles in muscle tissues. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish exhibit reduced swim speed compared to LMNA(WT) measured by DanioVision. All LMNA transgenic adult fish exhibit reduced swim speed compared to LMNA(WT) in T-maze. Moreover, all LMNA transgenic adult fish, except LMNA(E358K), display weaker muscle endurance than LMNA(WT) measured by swimming tunnel. Histochemical staining reveals decreased fiber size in all LMNA mutations transgenic fish, excluding LMNA(WT) fish. Interestingly, LMNA(A539V) and LMNA(E358K) exhibited elevated heartbeats. We recognize potential limitations with transgene overexpression and conducted association calculations to explore its effects on zebrafish phenotypes. Our results suggest lamin A/C overexpression may not directly impact mutant phenotypes, such as impaired swim speed, increased heart rates, or decreased muscle fiber diameter. Utilizing LMNA zebrafish models for drug screening, we identify L-carnitine treatment rescuing muscle endurance in LMNA(L35P) and creatine treatment reversing muscle endurance in LMNA(R453W) zebrafish models. Creatine activates AMPK and mTOR pathways, improving muscle endurance and swim speed in LMNA(R453W) fish. Transcriptomic profiling reveals upstream regulators and affected genes contributing to motor dysfunction, cardiac anomalies, and ion flux dysregulation in LMNA mutant transgenic fish. These findings faithfully mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Furthermore, our drug screening results suggest L-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models. Our study offers valuable insights into the future development of potential treatments for LMNA-related muscular laminopathy.

Troponin T Assessment Allows for Identification of Mutation Carriers among Young Relatives of Patients with LMNA-Related Dilated Cardiomyopathy.

Background:LMNA-related dilated cardiomyopathy (LMNA-DCM) caused by mutations in the lamin A/C gene (LMNA) is one of the most common forms of hereditary DCM. Due to the high risk of mutation transmission to offspring and the high incidence of ventricular arrhythmia and sudden death even before the onset of heart failure symptoms, it is very important to identify LMNA-mutation carriers. However, many relatives of LMNA-DCM patients do not report to specialized centers for clinical or genetic screening. Therefore, an easily available tool to identify at-risk subjects is needed. Methods: We compared two cohorts of young, asymptomatic relatives of DCM patients who reported for screening: 29 LMNA mutation carriers and 43 individuals from the control group. Receiver operating characteristic (ROC) curves for potential indicators of mutation carriership status were analyzed. Results: PR interval, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hscTnT) serum levels were higher in the LMNA mutation carrier cohort. Neither group differed significantly with regard to creatinine concentration or left ventricular ejection fraction. The best mutation carriership discriminator was hscTnT level with an optimal cut-off value at 5.5 ng/L, for which sensitivity and specificity were 86% and 93%, respectively. The median hscTnT level was 11.0 ng/L in LMNA mutation carriers vs. <3.0 ng/L in the control group, p < 0.001. Conclusions: Wherever access to genetic testing is limited, LMNA mutation carriership status can be assessed reliably using the hscTnT assay. Among young symptomless relatives of LMNA-DCM patients, a hscTnT level >5.5 ng/L strongly suggests mutation carriers.

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice.

Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardio-myocyte of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy in the mouse model. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.

Rescue retrograde coronary venous ethanol ablation of ventricular tachycardia storm in a patient with Lamin A/C cardiomyopathy: a case report.

Background: Left ventricular (LV) summit arrhythmias account for up to 14% of LV arrhythmias. The ablation of LV summit arrhythmias is challenging, as testified by the fact that radiofrequency (RF) catheter ablation failure is frequent. Retrograde coronary venous ethanol infusion has been proposed as an alternative approach for the ablation of LV summit arrhythmias. Case summary: A 47-year-old man with Lamin A/C cardiomyopathy was referred for the ablation of a pleiomorphic ventricular tachycardia (VT) storm, with dominant morphology compatible with LV summit origin. He first received a combined endo- and epicardial RF ablation with the elimination of three clinically relevant VTs. However, the dominant VT could not be ablated due to the proximity of the coronary vasculature and phrenic nerve and remained inducible. Accordingly, an urgent rescue redo procedure consisting of retrograde coronary venous ethanol ablation was performed. Based on the best pace-match and precocity, the first septal, retro-pulmonary branch and the first diagonal branch were infused with ethanol with immediate cessation of the tachycardia and non-inducibility. Anti-arrhythmic drugs were withdrawn, while guideline-directed medical therapy for heart failure was continued. No complications occurred. After 3 months, the patient remained free from any arrythmias. Discussion: Ablation of LV summit arrythmias is challenging, especially in the context of an electrical storm or in patients with structural heart disease. In such a situation, rescue ablation with retrograde coronary venous ethanol infusion represents an attractive alternative ablation modality.

Gene expression of iron transporters, markers of vascularization and structural integrity in placenta of mothers with and without anemia.

OBJECTIVE: To compare the mRNA expression of placental iron transporters (TfR-1 and FPN), markers of placental vascularization (VEGF and sFLT1) and marker of structural integrity (LMN-A) in term women with and without iron deficiency anemia. MATERIALS AND METHODS: A total of 30 pregnant women were enrolled; 15 cases of iron deficiency anemia (Hb 7-10.9 gm/dL) and 15 gestational age matched healthy controls (Hb ≥ 11 gm/dL). Peripheral venous blood was collected for assessment of hemoglobin levels and serum iron profile. Placental tissue was used for assessing the mRNA expression of TfR-1, FPN, VEGF, sFLT-1 and LMN-A via real time PCR. RESULTS: Placental expression of TfR-1, VEGF and LMN-A was increased in pregnant women with anemia compared to healthy pregnant controls. Placental expression of sFLT-1 was decreased in pregnant women with anemia compared to healthy pregnant controls. There was no change in the placental expression of FPN. CONCLUSION: The increased expression of TfR-1, VEGF and LMN-A in cases of iron deficiency anemia are most likely to be compensatory in nature to help maintain adequate fetal iron delivery. WHAT DOES THIS STUDY ADDS TO THE CLINICAL WORK: Compensatory changes in the placenta aimed at buffering transport of iron to the fetus are seen in pregnant women with anemia compared to healthy pregnant controls.

Differential Expression of LMNA/C and Insulin Receptor Transcript Variants in Peripheral Blood Mononuclear Cells of Leukemia Patients.

Background: Recent research has identified alternative transcript variants of LMNA/C (LMNA, LMNC, LMNAΔ10, and LMNAΔ50) and insulin receptors (INSRs) as potential biomarkers for various types of cancer. The objective of this study was to assess the expression of LMNA/C and INSR transcript variants in peripheral blood mononuclear cells (PBMCs) of leukemia patients to investigate their potential as diagnostic biomarkers. Methods: Quantitative TaqMan reverse transcriptase polymerase chain reaction (RT-qPCR) was utilized to quantify the mRNA levels of LMNA/C (LMNA, LMNC, LMNAΔ10, and LMNAΔ50) as well as INSR (IR-A and IR-B) variants in PBMCs obtained from healthy individuals (n = 32) and patients diagnosed with primary leukemias (acute myeloid leukemia (AML): n = 17; acute lymphoblastic leukemia (ALL): n = 8; chronic myeloid leukemia (CML): n = 5; and chronic lymphocytic leukemia (CLL): n = 15). Results: Only LMNA and LMNC transcripts were notably present in PBMCs. Both exhibited significantly decreased expression levels in leukemia patients compared to the healthy control group. Particularly, the LMNC:LMNA ratio was notably higher in AML patients. Interestingly, IR-B expression was not detectable in any of the PBMC samples, precluding the calculation of the IR-A:IR-B ratio as a diagnostic marker. Despite reduced expression across all types of leukemia, IR-A levels remained detectable, indicating its potential involvement in disease progression. Conclusions: This study highlights the distinct expression patterns of LMNA/C and INSR transcript variants in PBMCs of leukemia patients. The LMNC:LMNA ratio shows promise as a potential diagnostic indicator for AML, while further research is necessary to understand the role of IR-A in leukemia pathogenesis and its potential as a therapeutic target.