Variable Expression Research Articles

Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.

Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

[Clinical and genetic analysis of a patient with short stature due to variant of RPL13 gene].

To analyze the clinical phenotype and genetic characteristics of a patient with Isidor-Toutain spinal epiphyseal dysplasia (SEMD) due to variant of RPL13 gene. A pregnant woman at 18 weeks of gestation who had presented at Quzhou Maternal and Child Health Care Hospital on January 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the patient, and candidate variant was validated by Sanger sequencing and bioinformatic analysis. The woman was 37 years old with extremely short stature (135 cm) and "O" shaped legs. WES revealed that she has harbored a c.548G>C (p.Arg183Pro) missense variant of the RPL13 gene (NM_000977.4). The same variant was not found in her fetus. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). Isidor-Toutain type SEMD due to variants of the RPL13 gene may have variable expressivity and diverse clinical phenotypes. Above finding has facilitated the differential diagnosis and genetic counseling for this family.

Expression analysis and mapping of Viral—Host Protein interactions of Poxviridae suggests a lead candidate molecule targeting Mpox

BackgroundMonkeypox (Mpox) is an important human pathogen without etiological treatment. A viral-host interactome study may advance our understanding of molecular pathogenesis and lead to the discovery of suitable therapeutic targets.MethodsGEO Expression datasets characterizing mRNA profile changes in different host responses to poxviruses were analyzed for shared pathway identification, and then, the Protein–protein interaction (PPI) maps were built. The viral gene expression datasets of Monkeypox virus (MPXV) and Vaccinia virus (VACV) were used to identify the significant viral genes and further investigated for their binding to the library of targeting molecules.ResultsInfection with MPXV interferes with various cellular pathways, including interleukin and MAPK signaling. While most host differentially expressed genes (DEGs) are predominantly downregulated upon infection, marked enrichments in histone modifiers and immune-related genes were observed. PPI analysis revealed a set of novel virus-specific protein interactions for the genes in the above functional clusters. The viral DEGs exhibited variable expression patterns in three studied cell types: primary human monocytes, primary human fibroblast, and HeLa, resulting in 118 commonly deregulated proteins. Poxvirus proteins C6R derived protein K7 and K7R of MPXV and VACV were prioritized as targets for potential therapeutic interventions based on their histone-regulating and immunosuppressive properties. In the computational docking and Molecular Dynamics (MD) experiments, these proteins were shown to bind the candidate small molecule S3I-201, which was further prioritized for lead development.ResultsMPXV circumvents cellular antiviral defenses by engaging histone modification and immune evasion strategies. C6R-derived protein K7 binding candidate molecule S3I-201 is a priority promising candidate for treating Mpox.

The Role of Cilia and the Complex Genetics of Congenital Heart Disease

Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein–protein interactors. Assembly of the CHD genes into a protein–protein interaction network yielded a tight interactome that suggested this protein–protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.

Exceptional observation of congenital hyperinsulinism with variable phenotypic expression

Exceptional observation of congenital hyperinsulinism with variable phenotypic expression

Tumor-Tailored Ionizable Lipid Nanoparticles Facilitate IL-12 Circular RNA Delivery for Enhanced Lung Cancer Immunotherapy.

The advancement of message RNA (mRNA) -based immunotherapies for cancer is highly dependent on the effective delivery of RNA (Ribonucleic) payloads using ionizable lipid nanoparticles (LNPs). However, the clinical application of these therapies is hindered by variable mRNA expression among different cancer types and the risk of systemic toxicity. The transient expression profile of mRNA further complicates this issue, necessitating frequent dosing and thus increasing the potential for adverse effects. Addressing these challenges, a high-throughput combinatorial method is utilized to synthesize and screen LNPs that efficiently deliver circular RNA (circRNA) to lung tumors. The lead LNP, H1L1A1B3, demonstrates a fourfold increase in circRNA transfection efficiency in lung cancer cells over ALC-0315, the industry-standard LNPs, while providing potent immune activation. A single intratumoral injection of H1L1A1B3 LNPs, loaded with circRNA encoding interleukin-12 (IL-12), induces a robust immune response in a Lewis lung carcinoma model, leading to marked tumor regression. Immunological profiling of treated tumors reveals substantial increments in CD45+ leukocytes and enhances infiltration of CD8+ T cells, underscoring the ability of H1L1A1B3 LNPs to modulate the tumor microenvironment favorably. These results highlight the potential of tailored LNP platforms to advance RNA drug delivery for cancer therapy, broadening the prospects for RNA immunotherapeutics.

Genome-wide identification, characterization and functional prediction of the SRS gene family in sesame (Sesamum indicum L.)

Sesame (Sesamum indicum L.) is an ancient oilseed crop of the Pedaliaceae family with high oil content and potential health benefits. SHI RELATED SEQUENCE (SRS) proteins are the transcription factors (TFs) specific to plants that contain RING-like zinc figure domain and are associated with the regulation of several physiological and biochemical processes. They also play vital roles in plant growth and development such as root formation, leaf development, floral development, hormone biosynthesis, signal transduction, and biotic and abiotic stress responses. Nevertheless, the SRS gene family was not reported in sesame. In this study, identification, molecular characterization, phylogenetic relationship, cis-acting regulatory elements, protein-protein interaction, syntenic relationship, duplication events and expression pattern of SRS genes were analyzed in S. indicum. We identified total six SiSRS genes on seven different linkage groups in the S. indicum genome by comparing the other species, including the model plant Arabidopsis thaliana. The SiSRS genes showed variation in their structure like 2-5 exons and 1-4 introns. Like other species, SiSRS proteins also contained ‘RING-like zinc figure’ and ‘LRP1’ domains. Then, the SiSRS genes were clustered into subclasses via phylogenetic analysis with proteins of S. indicum, A. thaliana, and some other plant species. The cis-acting regulatory elements analysis revealed that the promoter region of SiSRS4 (SIN_1011561) showed the highest 13 and 16 elements for light- and phytohormone-responses whereas, SiSRS1 (SIN_1015187) showed the highest 15 elements for stress-response. The ABREs, or ABA-responsive elements, were found in a maximum of 8 copies in the SiSRS3 (SIN 1009100). Moreover, the available RNA-seq based expression of SiSRS genes revealed variation in expression patterns between stress-treated and non-treated samples, especially in drought and salinity conditions in. S. indicum. Two SiSRS genes like SiSRS1 (SIN_1015187) and SiSRS5 (SIN_1021065), also exhibited variable expression patterns between control vs PEG-treated sesame root samples and three SiSRS genes, including SiSRS1 (SIN_1015187), SiSRS2 (SIN_1003328) and SiSRS5 (SIN_1021065) were responsive to salinity treatments. The present outcomes will encourage more research into the gene expression and functionality analysis of SiSRS genes in S. indicum and other related species.

Comparative characteristics of student groups with positive and negative social and psychological development dynamics in the process of studying at university

Introduction. The article examines the problem of significant differences between student groups with pronounced positive and negative dynamics of team development. Identifying these differences will lead to appropriate teaching interventions in order to prevent the disintegration of the group and developing a negative psychological atmosphere in it. The purpose of the study is to identify socio-psychological differences between student groups who have experienced a pronounced positive and negative dynamics of the team’s development during their studies at the university. Materials and Methods. The theoretical and methodological basis of the study was the parametric conception of the team. In order to achieve the objective of the study and verify the hypothesis, the authors used theoretical (analysis, comparison, generalization, systematization) and empirical (in-depth interview and retrospective self-report) methods. The total sample size of participants in the interview was 38 people, including 13 people from the group with positive dynamics of team development (group 1) and 25 people from the group with negative dynamics (group 2). The obtained data were processed using statistical methods: the multifunctional Fisher test (to identify differences in the expression of variables obtained by content analysis), the Wilcoxon T test (to assess statistically significant changes in the group participants). Results. The article presents a theoretical analysis of approaches to the problem of researching a student group as a permanent educational team. In the course of the study, the authors revealed socio- psychological differences between student groups with pronounced positive and negative dynamics of team development: the presence/absence of a positive image of the group shared by the majority as a cohesive and unified team; transforming this image into a group target; the presence/absence of a positive set of values, reflecting the ideas of collective action and individual well-being; the presence/absence of transfer of target and meaningful guidelines for joint activities from extra-curricular creative activities to the field of professional activities; the existence/absence of community-accepted norms and rules of compatibility, which are not protective, but developing; the presence/absence of a conflict atmosphere, competition and isolated microgroups, which collectively increase the group's closeness and its lower inclusion in the university environment. The authors revealed that the negative group dynamics is more clearly recognized by the respondents, the reasons for it are conflicts and the influence of informal leaders with different values and norms. The impact of the university environment is strongest in the first year and has been declining since the second term of the second year. Adult activity is not perceived by students as a factor in changes in the group. A significant discrepancy was revealed between the cyclical nature of educational activities and the changing request of a student from year 3. The most significant influence on students is exerted by the formats where students occupy the most subjective position and the most active formats of education, which are distinguished by a high degree of subjective novelty. The influence of the group on each student (both positive and negative) is perceived as very significant. The modality of assessing this influence depends on the nature of the group dynamics. Conclusions. Based on the data obtained, the authors identified significant socio-psychological differences between student groups with pronounced positive and negative dynamics of team development. Targeted teaching interventions on these significant differences will reduce the likelihood of negative socio-psychological dynamics in student groups.

T-Large Granular Lymphocytic Leukemia with Hepatosplenic T-Cell Lymphoma? A Rare Case of Simultaneous Neoplastic T-Cell Clones Highlighted by Flow Cytometry and Review of Literature

Lymphoproliferative diseases are a heterogeneous set of malignant clonal proliferations of lymphocytes. Despite well-established diagnostic criteria, the diagnosis remains difficult due to their variety in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are less common than B-cell entities, and the lack of a clear immunophenotypic characteristic makes their identification hard. Flow cytometry turned out to be a useful tool in diagnosing T-cell disorders and to resolve complicated cases, especially if the number of analyzable neoplastic cells is small. We present a case of a 55-year-old man with simultaneous lymphoproliferative neoplastic T-cell clones, one αβ and the other γδ, identified and characterized by flow cytometry (FC), exploiting the variable expression intensity of specific markers. However, the patient’s rapid decline made it impossible to define a differential diagnosis in order to confirm the identity of the γδ clone, which remains uncertain. This case is added to the few other cases already documented in the literature, characterized by the co-existence of T-large granular lymphocytic leukemia (T-LGLL)-αβ and T-LGLL-γδ/Hepatosplenic T-cell lymphoma (HSTCL). Our case underlines the key role of sensitive diagnostic tools in the assessment of potential relationship between the diagnosis, prognosis, and treatment in the two pathologies.

A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability.

Pettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss-of-function alleles. The severity of ID in Pettigrew syndrome is mostly severe-to-profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder.

Unraveling the molecular dynamics of Pseudomonas aeruginosa biofilms at the air-liquid interface.

Aim: The aim of this study was to probe the dynamics of Pseudomonas aeruginosa PA14 air-liquid interface (ALI) biofilms over time through global proteomic analysis. Materials & methods: P. aeruginosa PA14 ALI biofilm samples, collected over 48-144h, underwent differential expression analysis to identify varying proteins at each time point. Results: A consistent set of 778 proteins was identified, with variable expression over time. Upregulated proteins were mainly linked to 'amino acid transport and metabolism'. Biofilm-related pathways, including cAMP/Vfr and QS, underwent significant changes. Flagella were more influential than pili, especially in early biofilm development. Proteins associated with virulence, transporters and iron showed differential expression throughout. Conclusion: The findings enhance our understanding of ALI biofilm development.

Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.

The expression and role of the Lem-D proteins Ankle2, Emerin, Lemd2, and TMPO in triple-negative breast cancer cell growth.

Triple-negative breast cancer (TNBC) is a sub-classification of breast carcinomas, which leads to poor survival outcomes for patients. TNBCs do not possess the hormone receptors that are frequently targeted as a therapeutic in other cancer subtypes and, therefore, chemotherapy remains the standard treatment for TNBC. Nuclear envelope proteins are frequently dysregulated in cancer cells, supporting their potential as novel cancer therapy targets. The Lem-domain (Lem-D) (LAP2, Emerin, MAN1 domain, and Lem-D) proteins are a family of inner nuclear membrane proteins, which share a ~45-residue Lem-D. The Lem-D proteins, including Ankle2, Lemd2, TMPO, and Emerin, have been shown to be associated with many of the hallmarks of cancer. This study aimed to define the association between the Lem-D proteins and TNBC and determine whether these proteins could be promising therapeutic targets. GENT2, TCGA, and KM plotter were utilized to investigate the expression and prognostic implications of several Lem-D proteins: Ankle2, TMPO, Emerin, and Lemd2 in publicly available breast cancer patient data. Immunoblotting and immunofluorescent analysis of immortalized non-cancerous breast cells and a panel of TNBC cells were utilized to establish whether protein expression of the Lem-D proteins was significantly altered in TNBC. SiRNA was used to decrease individual Lem-D protein expression, and functional assays, including proliferation assays and apoptosis assays, were conducted. The Lem-D proteins were generally overexpressed in TNBC patient samples at the mRNA level and showed variable expression at the protein level in TNBC cell lysates. Similarly, protein levels were generally negatively correlated with patient survival outcomes. siRNA-mediated depletion of the individual Lem-D proteins in TNBC cells induced aberrant nuclear morphology, decreased proliferation, and induced cell death. However, minimal effects on nuclear morphology or cell viability were observed following Lem-D depletion in non-cancerous MCF10A cells. There is evidence to suggest that Ankle2, TMPO, Emerin, and Lemd2 expressions are correlated with breast cancer patient outcomes, but larger patient sample numbers are required to confirm this. siRNA-mediated depletion of these proteins was shown to specifically impair TNBC cell growth, suggesting that the Lem-D proteins may be a specific anti-cancer target.

Imaging findings of children with PTEN-related hamartoma tumor syndrome: a 20-year multicentric pediatric cohort.

PTEN-related hamartoma tumor syndrome results from a mutation in the PTEN gene located at 10q23.31. This syndrome represents a spectrum of different phenotypes of variable expressions, now recognized as part of the same condition. Patients with this mutation have an increased risk of developing a wide range of findings, including malignancies. Although widely described in adults, there are no large series describing the imaging findings in patients before adulthood. Knowledge of the findings seen in children and adolescents with PTEN-related hamartoma tumor syndrome can help guide further management and improve surveillance recommendations. To describe the spectrum of imaging abnormalities in pediatric patients with PTEN-related hamartoma tumor syndrome. We performed a retrospective, cross-sectional, multicenter study conducted between January 2000 and October 2021 in three tertiary pediatric institutions evaluating the imaging findings in children and adolescents (≤ 18 years) with confirmed diagnoses of a PTEN mutation. For each patient, the imaging findings, histopathology reports, and at least a 2-year follow-up of clinical outcomes for non-operative cases were documented. The cohort included 78 children (37 girls), with a mean age at diagnosis of 7.5 years (range 0 days to 18 years). Benign brain findings included enlarged Virchow-Robin perivascular spaces, white matter changes, developmental venous anomalies, and cerebellar hamartomas. Benign thyroid findings were common, but 5/45 (11.1%) with thyroid abnormalities had a malignant nodule. Soft tissue adipocytic tumors, GI/GU polyps, other soft tissue abnormalities, along with vascular anomalies in various anatomic locations were common. Brain abnormalities, benign non-vascular soft tissue abnormalities, and vascular anomalies are commonly seen in children and adolescents with PTEN-related hamartoma tumor syndrome. However, malignancies involving the thyroid gland are not uncommon. Familiarity with the phenotype of PTEN-related hamartoma tumor syndrome in the pediatric population can improve diagnosis and prompt appropriate clinical surveillance of abnormal findings that warrant further management.

SLC35A2 expression is associated with HER2 expression in breast cancer

The role of SLC35A2 in breast cancer remains poorly understood, with limited available information on its significance. This study aimed to investigate the expression of SLC35A2 and clinicopathological variables in breast cancer patients. Immunohistochemical analysis of SLC35A2 protein was conductedon 40 adjacent non-neoplastic tissues and 320 breast cancer tissues. The study also assesed the association between SLC35A2 expression and breast cancer clinicopathological features of breast cancer, as well as its impact on overall survival. In comparison to adjacent non-neoplastic tissues, a significantly higher expression of SLC35A2 was observed in breast cancer tissues (P = 0.020), and this expression was found to be independently correlated with HER2 positivity (P = 0.001). Survival analysis indicated that patients with low SLC35A2 expression had a more favorable prognosis in HER2-positive subtype breast cancer (P = 0.017). These results suggest that SLC35A2 is overexpressed in breast cancer tissues compared to adjacent non-neoplastic tissues and may serve as a potential prognostic marker for HER2-positive subtype breast cancer. Furthermore, breast cancer patients with the HER2 positive subtype who exhibited decreased levels of SLC35A2 expression demonstrated improved long-term prognostic outcomes.

Novel findings in a Swedish primary familial brain calcification cohort

IntroductionBrain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. MethodsLongitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, were performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. ResultsAmong the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. ConclusionsThis report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered.

Assessment of Levels of Occupational Stress among the Intensive Care Workers in a Selected Hospital in Lagos State

Background: Working in an Intensive Care Unit (ICU) comes with a great deal of physical, emotional, and psychological strain that can get worse with time if not properly managed. Numerous factors contribute to the extreme levels of stress experienced by healthcare professionals, such as long and demanding work hours, the burden of paperwork and legal matters, the disruption of work-life balance, the complexity of shared decision-making, and the high expectations placed ICU workers by on both patients and carers.  Some outcomes of occupational stress among intensive care workers include bad safety culture, poor standard of care for patients and depression. Research Objective: The Purpose of the study was to ascertain the levels of occupational stress among the intensive care workers of a hospital. Methodology: The research was a cross-sectional descriptive study conducted in Lagos State University Teaching Hospital (LASUTH). An aggregate of 108 intensive care workers were sampled for the study. A pre-tested, semi-structured self-administered questionnaire was used to gather the data, and the statistical package for social sciences, SPSS version, was used for analysis. The means and standard deviations, or the median and interquartile range, were used to express continuous variables. The expressions for categorical variables were frequencies accompanied by percentages. The study employed chi square statistics to evaluate the correlation between categorical variables. Results: There is an average prevalence of stress among intensive care workers of LASUTH. Recommendation: Staff sshould undergo training on stress handling, in order to be able to manage their individual stressors and reduce the overall stress.

CCN2/CTGF expression does not correlate with fibrosis in myeloproliferative neoplasms, consistent with noncanonical TGF-β signaling driving myelofibrosis.

The classical BCR::ABL1-negative myeloproliferative neoplasms (MPN) form a group of bone marrow (BM) diseases with the potential to progress to acute myeloid leukemia or develop marrow fibrosis and subsequent BM failure. The mechanism by which BM fibrosis develops and the factors that drive stromal activation and fibrosis are not well understood. Cellular Communication Network 2 (CCN2), also known as CTGF (Connective Tissue Growth Factor), is a profibrotic matricellular protein functioning as an important driver and biomarker of fibrosis in a wide range of diseases outside the marrow. CCN2 can promote fibrosis directly or by acting as a factor downstream of TGF-β, the latter already known to contribute to myelofibrosis in MPN.To study the possible involvement of CCN2 in BM fibrosis in MPN, we assessed CCN2 protein expression by immunohistochemistry in 75 BM biopsies (55 × MPN and 20 × normal controls). We found variable expression of CCN2 in megakaryocytes with significant overexpression in a subgroup of 7 (13%) MPN cases; 4 of them (3 × essential thrombocytemia and 1 × prefibrotic primary myelofibrosis) showed no fibrosis (MF-0), 2 (1 × post-polycythemic myelofibrosis and 1 × primary myelofibrosis) showed moderate fibrosis (MF-2), and 1 (primary myelofibrosis) severe fibrosis (MF-3). Remarkably, CCN2 expression did not correlate with fibrosis or other disease parameters such as platelet count or thrombovascular events, neither in this subgroup nor in the whole study group. This suggests that in BM of MPN patients other, CCN2-independent pathways (such as noncanonical TGF-β signaling) may be more important for the development of fibrosis.

Abstract CT155: Trial in progress: A phase Ia/Ib, an open-label, multicenter study of ZL-1310 to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer

Abstract Background: ZL-1310, a novel antibody-drug conjugate (ADC) targeting delta-like protein 3 (DLL3) with a camptothecin derivative as its payload via a protease-cleavable linker, employs TMALIN® (Tumor Microenvironment Activable LINker-payload) ADC technology platform. DLL3, an inhibitory Notch pathway ligand and a validated target for directed therapy, is highly expressed in more than 80% of patients with small cell lung cancer (SCLC) and also has variable expression in other neuroendocrine (NE) tumors. There remains an unmet medical need for 2nd-line SCLC, as the standard of care chemotherapy has a modest response rate of ~25%. ZL-1310 is designed to minimize payload toxicity and improve anti-tumor effectiveness. Methods: This is an open-label, multiple-dose, phase 1 study of ZL-1310 administered to subjects with relapsed/refractory (r/r) metastatic SCLC who have progressed after at least one platinum-based chemotherapy regimen. The study consists of two parts: Part 1 (dose escalation) and Part 2 (dose expansion). In Part 1, the Bayesian optimal interval (BOIN) design is employed for dose escalation, while in Part 2, patients will be randomized into two cohorts with different doses of ZL-1310 to further define safety and preliminary antitumor activity. The major inclusion criteria are as follows: (1) Subjects must have histologically or cytologically confirmed metastatic or extensive-stage SCLC with no more than 3 prior regimens in the r/r setting. (2) Subjects must have at least one measurable target lesion as defined by RECIST v1.1. (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The major exclusion criteria include: (1) Prior exposure to DLL3-targeted therapy. (2) Subjects with symptomatic or uncontrolled brain metastasis requiring concurrent treatment, impaired major organ functions, active autoimmune disease, or active infections.Part 1 Dose Escalation is recruiting subjects in the US and China. Citation Format: Afshin Dowlati, Alexander Spira, Xiaodong Shen, Yinjia Fu, Yiyuan Pan, Linda Liu, Renke Zhou, Yi-Long Wu. Trial in progress: A phase Ia/Ib, an open-label, multicenter study of ZL-1310 to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT155.