A Comprehensive Review: Pharmacogenomics and Personalized Medicine Customizing Drug Therapy Based on Individual Genetics Profiles.

Numerous factors, such as genetics, environmental factors, and illness determinants, might contribute to an unpleasant pharmaceutical response. In an effort to increase efficacy and safety, as well as to gain a better understanding of drug disposition and clinical consequences, researchers in the two quickly emerging fields of pharmacogenetics (which focuses on single genes) and pharmacogenomics (which focuses on many genes) have studied the genetic personalization of drug response. This is due to the fact that a large number of pharmacological responses seem to be genetically based, and the relationship between medication response and genotype may be important for diagnosis. We now have a better understanding of the genetic basis of individual medication responses because to research on pharmaceuticals and genes. Pharmacogenomics aims to improve patient outcomes by developing personalized medicine by using the diversity of the human genome and how it affects medication response. Translational in nature, pharmacogenomics research encompasses everything from the discovery of genotype-phenotype associations to clinical investigations that might show therapeutic relevance. Though the conversion of pharmacogenomics research findings into clinical practice has been sluggish, advances in the field offer considerable potential for future therapeutic applications in specific people.

Similar genetic profile in early and late stage urothelial tract cancer.

INTRODUCTION: Urothelial tract cancer (UTC) ranks as the tenth most prevalent cancer and holds the seventh position in terms of mortality worldwide. Despite its prevalence and mortality ranking, there are still gaps in the knowledge of the mutational landscape in patients with advanced disease who have limited therapeutic options after multiple lines of prior treatment. This study compares the genomic and transcriptomic landscape, and targeted treatment options between metastatic UTC (mUTC) patients treated with multiple lines of therapy compared to newly diagnosed, untreated Muscle Invasive Bladder Cancer (MIBC). METHODS: We compared genomic and clinical data from two cohorts: mUTC patients who received multiple lines of therapy and were referred to the Copenhagen Prospective Personalized Oncology (CoPPO) project at Rigshospitalet, University of Copenhagen. Data for MIBC UTC patients were acquired from the Cancer Genome Atlas Bladder Cancer (TCGA BLCA) cohort. Biopsies in CoPPO were performed at the time of enrollment. 523 highly important cancer-related genes (TrueSight Oncology-500 targeted sequencing panel) were used from both cohorts for comparative analysis. Analyses included RNA count data to compare predicted molecular subtypes in each cohort separately. RESULTS: Patients from the CoPPO cohort had a lower median age at first-line treatment than the TCGA BLCA cohort, with no significant gender disparity. The predominant histology was urothelial cell carcinoma in both cohorts. Genomic analysis revealed no significant difference between the top mutated genes in the two cohorts, specifically looking into DNA damage repair genes. Molecular subtyping indicated a higher frequency of neuroendocrine differentiation in the CoPPO cohort. 13% of patients in the CoPPO cohort received targeted therapy based on genomic findings, and 16% received non-targeted treatment, totaling 29% receiving CoPPO treatment (9 patients). The remaining 71% received best supportive care. Kaplan-Meier analysis showed a non-significant survival benefit for the intervention group in the CoPPO cohort. CONCLUSION: When focusing on 523 highly relevant cancer genes, the mutational profile of mUTC patients who have undergone numerous treatment lines resembles that of newly diagnosed MIBC. These alterations can be targeted, indicating the potential advantage of early genomic testing for personalized treatment within clinical trials.

Comprehensive genomic analysis of adrenocortical carcinoma reveals genetic profiles associated with patient survival.

BACKGROUND: Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient stratification. Therefore our aim was to identify clinical and genetic markers that predict outcome in patients with ACC. METHODS: Clinical and genetic data from a total of 162 patients with ACC were analyzed by combining an independent cohort consisting of tumors from Yale School of Medicine, Karolinska Institutet, and Düsseldorf University (YKD) with two public databases [The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO)]. We used a novel bioinformatical pipeline combining differential expression and messenger RNA (mRNA)- and DNA-dependent survival. Data included reanalysis of previously conducted whole-exome sequencing (WES) for the YKD cohort, WES and RNA data for the TCGA cohort, and RNA data for the GEO cohort. RESULTS: We identified 3903 significant differentially expressed genes when comparing ACC and adrenocortical adenoma, and the mRNA expression levels of 461/3903 genes significantly impacted survival. Subsequent analysis revealed 45 of these genes to be mutated in patients with significantly worse survival. The relationship was significant even after adjusting for stage and age. Protein-protein interaction showed previously unexplored interactions among many of the 45 proteins, including the cancer-related proteins DNA polymerase delta 1 (POLD1), aurora kinase A (AURKA), and kinesin family member 23 (KIF23). Furthermore 14 of the proteins had significant interactions with TP53 which is the most frequently mutated gene in the germline of patients with ACC. CONCLUSIONS: Using a multiparameter approach, we identified 45 genes that significantly influenced survival. Notably, many of these genes have protein interactions not previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.

Genetic profiles of oligometastatic non-small-cell lung cancer and corresponding brain metastases.

OBJECTIVES: In patients with oligometastatic non-small-cell lung cancer (NSCLC), systemic therapy in combination with local ablative treatment of the primary tumour and all metastatic sites is associated with improved prognosis. For patient selection and treatment allocation, further knowledge about the molecular characteristics of the oligometastatic state is necessary. Here, we performed a genetic characterization of primary NSCLC and corresponding brain metastases (BM). METHODS: We retrospectively identified patients with oligometastatic NSCLC and synchronous (<3 months) or metachronous (>3 months) BM who underwent surgical resection of both primary tumour and BM. Mutation profiling of formalin-fixed paraffin-embedded tumour cell blocks was performed by targeted next-generation sequencing using the Oncomine Focus Assay panel. RESULTS: Sequencing was successful in 46 paired samples. An oncogenic alteration was present in 31 primary tumours (67.4%) and 40 BM (86.9%). The alteration of the primary tumours was preserved in the corresponding BM in 29 out of 31 cases (93.5%). The most prevalent oncogenic driver in both primary tumours and BM was a KRAS (Kirsten rat sarcoma viral oncogene) mutation (s = 21). In 16 patients (34.8%), the BM harboured additional oncogenic alterations. The presence of a private genetic alteration in the BM was an independent predictor of shorter overall survival. CONCLUSIONS: In oligometastatic NSCLC, BM retain the main genetic alterations of the primary tumours. Patients may profit from targeted inhibition of mutated KRAS. Additional private genetic alterations in the BM are dismal.

Genetic profile of Brazilian patients with LAMA2-related dystrophies.

LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population.

Genetic profile of RHCE, Kell, Duffy, Kidd, Diego and MNS hybrid glycophorins blood groups in ethnic northeastern Thais: Alleles, genotypes and risk of alloimmunisation.

BACKGROUND: Antibodies against blood group antigens play a key role in the pathophysiology of haemolytic transfusion reactions (HTRs) and haemolytic disease of the fetus and newborn (HDFN). This study aimed to determine the frequencies of alleles, genotypes, and risk of alloimmunisation of clinically significant blood group systems in ethnic northeastern Thais. METHODS: In total, 345 unrelated, healthy, ethnic northeastern Thais were tested using the in-house PCR-sequence specific primers (PCR-SSP) method for simultaneously genotyping of RHCE, Kell, Duffy, Kidd, Diego and MNS glycophorin hybrids and results confirmed by Sanger sequencing. RESULTS: In this cohort, the alleles RHCE*C (81.0%) and RHCE*e (84.8%) were more prevalent than RHCE*c (19.0%) and RHCE*E (15.2%). The most common predicted haplotype combinations of the RHCE alleles were C+c-E-e+(R1R1) (59.4%) followed by the C+c+E+e+ (R1R2) (20.6%) and C+c+E-e+ (R1r) (11.3%). The KEL*01 allele was not found in this study. The frequencies of FY*01 and FY*02 were 88.3% and 11.7%, respectively. The genotype FY*02/02 was found in four samples (1.2%). The frequencies of JK*01 and JK*02 were 52.5% and 47.5%, respectively. Homozygous JK*02/02 was found in 81 samples (23.5%). The frequencies of DI*01 and DI*02 were 0.6% and 99.4%, respectively. In total, 64 samples (18.6%) were found to carry the MNS glycophorin hybrids. CONCLUSIONS: Our results indicated a possible high risk of c, E, Fyb, Jka, Jkb and Mia alloimmunisation in these populations. Moreover, methods established for genotyping clinically significant blood groups in this study can now be utilised in routine clinical application.

Perfis clínicos e genéticos de pacientes com amiloidose transtiretina hereditária e do tipo selvagem: o registro de amiloidose cardíaca transtiretina no Estado de São Paulo, Brasil (REACT-SP) / Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the transthyretin cardiac amyloidosis registry in the State of São Paulo, Brazil (REACT-SP)

INTRODUÇÃO: A amiloidose transtiretina (ATTR) é uma doença multissistêmica causada pela deposição de proteína fibrilar em órgãos e tecidos. Os genótipos e fenótipos da ATTR são altamente heterogêneos. MÉTODOS: Apresentamos dados sobre sinais e sintomas físicos, avaliações cardíacas e neurológicas, e genética em pacientes incluídos no Registro de Amiloidose Cardíaca Transtiretina no Estado de São Paulo (REACT-SP), Brasil. RESULTADOS: Foram incluídos 644 pacientes, sendo 505 com a forma variante (ATTRv) e 139 com a forma selvagem (ATTRwt). Dezesseis mutações diferentes foram detectadas, sendo as mais comuns Val50Met (48,3%) e V142Ile (40,8%). No geral, mais da metade dos pacientes apresentou envolvimento cardíaco, e a diferença nessa proporção entre os grupos ATTRv e ATTRwt foi significativa (43,9 vs. 89,9%; p<0,001). O fenótipo neurológico também diferiu entre ATTRv e ATTRwt (56,8 vs. 31,7%; p<0,001). O fenótipo misto foi encontrado em 25,6% da população, sem diferença significativa entre as formas de amiloidose. Um grupo de pacientes permaneceu assintomático (10,4%), com uma proporção menor de pacientes assintomáticos no grupo ATTRwt. CONCLUSÕES: Este estudo detalha o espectro clínico e genético de pacientes com ATTR em São Paulo, Brasil. Esta análise preliminar destaca a considerável heterogeneidade fenotípica das manifestações neurológicas e cardíacas em pacientes com ATTR variante e ATTR do tipo selvagem.

Genetic profile of a large Spanish cohort with hypercalcemia.

Introduction: The disorders in the metabolism of calcium can present with manifestations that strongly suggest their diagnosis; however, most of the time, the symptoms with which they are expressed are nonspecific or present only as a laboratory finding, usually hypercalcemia. Because many of these disorders have a genetic etiology, in the present study, we sequenced a selection of 55 genes encoding the principal proteins involved in the regulation of calcium metabolism. Methods: A cohort of 79 patients with hypercalcemia were analyzed by next-generation sequencing. Results: The 30% of our cohort presented one pathogenic or likely pathogenic variant in genes associated with hypercalcemia. We confirmed the clinical diagnosis of 17 patients with hypocalciuric hypercalcemia (pathogenic or likely pathogenic variants in the CASR and AP2S1 genes), one patient with neonatal hyperparathyroidism (homozygous pathogenic variant in the CASR gene), and another patient with infantile hypercalcemia (two pathogenic variants in compound heterozygous state in the CYP24A1 gene). However, we also found variants in genes associated with primary hyperparathyroidism (GCM2), renal hypophosphatemia with or without rickets (SLC34A1, SLC34A3, SLC9A3R1, VDR, and CYP27B1), DiGeorge syndrome (TBX1 and NEBL), and hypophosphatasia (ALPL). Our genetic study revealed 11 novel variants. Conclusions: Our study demonstrates the importance of genetic analysis through massive sequencing to obtain a clinical diagnosis of certainty. The identification of patients with a genetic cause is important for the appropriate treatment and identification of family members at risk of the disease.

Validation of the 2022 European LeukemiaNet risk stratification for acute myeloid leukemia.

This study aimed to validate the 2022 European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia (AML). A total of 624 newly diagnosed AML patients from 1998 to 2014 were included in the analysis. Genetic profiling was conducted using targeted deep sequencing of 45 genes based on recurrent driver mutations. In total, 134 (21.5%) patients had their risk classification reassessed according to the 2022 ELN risk stratification. Among those initially classified as having a favorable risk in 2017 (n = 218), 31 and 3 patients were reclassified as having intermediate risk or adverse risk, respectively. Among the three subgroups, the 2022 ELN favorable-risk group showed significantly longer survival outcomes than the other groups. Within the 2017 ELN intermediate-risk group (n = 298), 21 and 46 patients were reclassified as having favorable risk or adverse risk, respectively, and each group showed significant stratifications in survival outcomes. Some patients initially classified as having adverse risk in 2017 were reclassified into the intermediate-risk group (33 of 108 patients), but no prognostic improvements were observed in this group. A multivariable analysis identified the 2022 ELN risk stratification, age, and receiving allogeneic hematopoietic cell transplantation as significant prognostic factors for survival. The 2022 ELN risk stratification enables more precise decisions for proceeding with allogeneic hematopoietic cell transplantation for AML patients.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

Similar imaging changes and their relations to genetic profiles in bipolar disorder across different clinical stages.

Bipolar disorder (BD) across different clinical stages may present shared and distinct changes in brain activity. We aimed to reveal the neuroimaging homogeneity and heterogeneity of BD and its relationship with clinical variables and genetic variations. In present study, we conducted fractional amplitude of low-frequency fluctuations (fALFF), functional connectivity (FC) and genetic neuroimaging association analyses with 32 depressed, 26 manic, 35 euthymic BD patients and 87 healthy controls (HCs). Significant differences were found in the bilateral pre/subgenual anterior cingulate cortex (ACC) across the four groups, and all bipolar patients exhibited decreased fALFF values in the ACC when compared to HCs. Furthermore, positive associations were significantly observed between fALFF values in the pre/subgenual ACC and participants' cognitive functioning. No significant changes were found in ACC-based FC. We identified fALFF-alteration-related genes in BD, with enrichment in biological progress including synaptic and ion transmission. Taken together, abnormal activity in ACC is a characteristic change associated with BD, regardless of specific mood stages, serving as a potential neuroimaging feature in BD patients. Our genetic neuroimaging association analysis highlights possible heterogeneity in biological processes that could be responsible for different clinical stages in BD.

Predicting drug activity against cancer through genomic profiles and SMILES.

Due to the constant increase in cancer rates, the disease has become a leading cause of death worldwide, enhancing the need for its detection and treatment. In the era of personalized medicine, the main goal is to incorporate individual variability in order to choose more precisely which therapy and prevention strategies suit each person. However, predicting the sensitivity of tumors to anticancer treatments remains a challenge. In this work, we propose two deep neural network models to predict the impact of anticancer drugs in tumors through the half-maximal inhibitory concentration (IC50). These models join biological and chemical data to apprehend relevant features of the genetic profile and the drug compounds, respectively. In order to predict the drug response in cancer cell lines, this study employed different DL methods, resorting to Recurrent Neural Networks (RNNs) and Convolutional Neural Networks (CNNs). In the first stage, two autoencoders were pre-trained with high-dimensional gene expression and mutation data of tumors. Afterward, this genetic background is transferred to the prediction models that return the IC50 value that portrays the potency of a substance in inhibiting a cancer cell line. When comparing RSEM Expected counts and TPM as methods for displaying gene expression data, RSEM has been shown to perform better in deep models and CNNs model can obtain better insight in these types of data. Moreover, the obtained results reflect the effectiveness of the extracted deep representations in the prediction of the IC50 value that portrays the potency of a substance in inhibiting a tumor, achieving a performance of a mean squared error of 1.06 and surpassing previous state-of-the-art models.

Genetic Profile of Rotavirus Type A in Children under 5 Years Old in Africa: A Systematic Review of Prevalence.

Human type A rotavirus (RV-A) is world-recognized as the major pathogen causing viral gastroenteritis in children under 5 years of age. The literature indicates a substantial increase in the diversity of rotavirus strains across continents, especially in Africa, which can pose significant challenges including an increase of disease burden and a reduction of vaccines' effectiveness. However, few studies have mapped the variety of circulating virus strains in different regions, which may hamper decisions on epidemiological surveillance and preventive public health measures. Thus, our aim was to compile the most updated available evidence on the genetic profile of RV-A among children in Africa and determine the prevalence of different genotypes according to the geographical regions by means of a broad systematic review. Systematic searches were performed in PubMed, Scopus, Web of Science, and Scielo without language, time limits, or geographical restrictions within the African continent. We selected full-text peer-reviewed articles assessing the genetic profile (i.e., genotyping) of RV-A in children up to 5 years old in Africa. Overall, 682 records were retrieved, resulting in 75 studies included for evidence synthesis. These studies were published between 1999 and 2022, were conducted in 28 countries from the five African regions, and 48% of the studies were carried out for 24 months or more. Most studies (n = 55; 73.3%) evaluated RV-A cases before the introduction of the vaccines, while around 20% of studies (n = 13) presented data after the vaccine approval in each country. Only seven (9.3%) studies compared evidence from both periods (pre- and post-vaccine introduction). Genotyping methods to assess RV-A varied between RT-PCR, nested or multiplex RT-PCR, testing only the most common P and G-types. We observed G1 and P[8] to be the most prevalent strains in Africa, with values around 31% and 43%, respectively. Yet if all the genotypes with the following highest prevalence were added ((G1 + G2, G3, G9) and (P[8] + P[6], P[4])), these figures would represent 80% and 99% of the total prevalence. The combination G1P[8] was the most reported in the studies (around 22%). This review study demonstrated an increased strain diversity in the past two decades, which could represent a challenge to the efficacy of the current vaccine.

Genetic profiling of azoospermic men to identify the etiology and predict reproductive potential.

PURPOSE: To identify germline mutations related to azoospermia etiology and reproductive potential of surgically retrieved spermatozoa, and to investigate the feasibility of predicting seminiferous tubule function of nonobstructive azoospermic men by transcriptomic profiling of ejaculates. MATERIALS AND METHODS: Sperm specimens were obtained from 30 men (38.4 ± 6 years) undergoing epididymal sperm aspiration for obstructive azoospermia (OA, n = 19) acquired by vasectomy, or testicular biopsy for nonobstructive azoospermia (NOA, n = 11). To evaluate for a correlation with azoospermia etiology, DNAseq was performed on surgically retrieved spermatozoa, and cell-free RNAseq on seminal fluid (n = 23) was performed to predict spermatogenesis in the seminiferous tubule. RESULTS: Overall, surgically retrieved sperm aneuploidy rates were 1.7% and 1.8% among OA and NOA cohorts, respectively. OA men carried housekeeping-related gene mutations, while NOA men displayed mutations on genes involved in crucial spermiogenic functions (AP1S2, AP1G2, APOE). We categorized couples within each cohort according to ICSI clinical outcomes to investigate genetic causes that may affect reproductive potential. All OA-fertile men (n = 9) carried mutations in ZNF749 (sperm production), whereas OA-infertile men (n = 10) harbored mutations in PRB1, which is essential for DNA replication. NOA-fertile men (n = 8) carried mutations in MPIG6B (stem cell lineage differentiation), whereas NOA-infertile individuals (n = 3) harbored mutations in genes involved in spermato/spermio-genesis (ADAM29, SPATA31E1, MAK, POLG, IFT43, ATG9B) and early embryonic development (MBD5, CCAR1, PMEPA1, POLK, REC8, REPIN1, MAPRE3, ARL4C). Transcriptomic assessment of cell-free RNAs in seminal fluid from NOA men allowed the prediction of residual spermatogenic foci. CONCLUSIONS: Sperm genome profiling provides invaluable information on azoospermia etiology and identifies gene-related mechanistic links to reproductive performance. Moreover, RNAseq assessment of seminal fluid from NOA men can help predict sperm retrieval during testicular biopsies.

SARS-CoV-2 receptor a distinct genetic profile specific to the Iraqi Kurdish population.

SARS-CoV-2, the virus responsible for COVID-19, enters host cells by binding its spike protein's receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 (ACE2) receptor's peptidase domain (PD). This interaction plays a crucial role in the virus's ability to invade host cells and establish infection. Numerous studies have identified specific residues crucial for their binding interaction. Our objective was to determine whether natural variations in the ACE2 receptor could impact its affinity for the S-protein RBD. To explore this, we focused on investigating the effects of natural variations in the ACE2 PD residues on its binding affinity to the S-protein RBD interface of SARS-CoV-2. We conducted a genotyping study in the Iraqi Kurdish population and identified significant genetic variations in key binding residues of the ACE2 PD residues, including N330K, K353R, R357Q, P389H, and R393H. These variations suggest a distinct genetic profile specific to the Kurdish population regarding their interaction with the SARS-CoV-2 virus. Understanding the implications of these variations is essential for comprehending the mechanisms of viral infection, developing targeted therapeutics, and refining treatment strategies and vaccine design. Additionally, studying these variations can provide insights into population-specific vulnerabilities, help monitor viral evolution and transmission, and guide the development of effective interventions.

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome.

BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. METHODS: Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. RESULTS: Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. CONCLUSIONS: Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Exploring Immune-Related Gene Profiling and Infiltration of Immune Cells in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma.

Cervical cancer is a widespread malignancy among women, leading to a substantial global health impact. Despite extensive research, our understanding of the basic molecules and pathogenic processes of cervical squamous cell carcinoma is still insufficient. This investigation aims to uncover immune-related genes linked to CESC and delineate their functions. Leveraging data from the GEO and ImmPort databases, a total of 22 immune-related genes were identified. Multiple tools, including DAVID, the human protein atlas, STRING, GeneMANIA, and TCGA, were employed to delve into the expression and roles of these immune genes in CESC, alongside their connections to the disease's pathological features. Through RT-PCR, the study confirmed notable disparities in CXCL8 and CXCL10 mRNA expression between CESC and normal cervical tissue. The TCGA dataset's immune-related information reinforced the association of CXCL8 and CXCL10 with immune infiltration in CESC. This research sheds light on the potential of CXCL8 and CXCL10 as promising therapeutic targets and essential prognostic factors for individuals diagnosed with CESC.

Genetic assessment of captive breeding program of Indian Pangolin: implications for conservation and management.

BACKGROUND: Captive breeding programs play a vital role in conservation of threatened species, necessitating an understanding of genetic diversity among captive individuals to ensure long-term genetic viability, appropriate mate selection, and successful reintroduction to native habitats. METHODS AND RESULTS: We did not observe any recent genetic bottleneck, and population showed moderate genetic diversity. The estimated effective population size, representing individuals capable of contributing genetically to future generations, was estimated as 18.6 individuals (11.4-35.1 at 95% CI). Based on the genetic make-up and allelic diversity, we found seventeen pangolins (11 females and 6 males) were genetically unrelated and relatively more potent than others. CONCLUSION: In this study, we evaluated the captive breeding program of the Indian pangolin population at the Pangolin Conservation Breeding Centre in Nandankanan Zoological Park, Bhubaneswar, Odisha. We highlight the significance of genetic monitoring within the captive population of Indian pangolin for preserving genetic diversity and ensuring the long-term survival of the species. We established the genetic profiles of all 29 pangolins and identified 17 pangolins to be prioritized for enhanced breeding and future zoo exchange programs. We appreciate the zoo authorities for promoting genetic assessment of pangolin for better and more effective monitoring of the captive breeding of the endangered Indian pangolin.

Clinical and genetic profile of patients with dystonia: An experience from a tertiary neurology center from India.

BACKGROUND: The genetics of dystonia have varied across different ethnicities worldwide. Its significance has become more apparent with the advent of deep brain stimulation. OBJECTIVE: To study the clinico-genetic profile of patients with probable genetic dystonia using whole exome sequencing (WES). METHODS: A prospective, cross-sectional study was conducted from May 2021 to September 2022, enrolling patients with dystonia of presumed genetic etiology for WES. The study compared genetically-determined cases harboring pathogenic/likely-pathogenic variants (P/LP subgroup) with the presumed idiopathic or unsolved cases. RESULTS: We recruited 65 patients (males, 69.2%) whose mean age of onset (AAO) and assessment were 25.0 ± 16.6 and 31.7 ± 15.2 years, respectively. Fifteen had pathogenic/likely-pathogenic variants (yield = 23.1%), 16 (24.6%) had variants of uncertain significance (VUS), 2 were heterozygous carriers while the remaining 32 cases tested negative (presumed idiopathic group). The P/LP subgroup had a significantly younger AAO (16.8 ± 12.3 vs 31.3 ± 17.0 years, p = 0.009), longer duration of illness (10.9 ± 10.3 vs 4.8 ± 4.3 years, p = 0.006), higher prevalence of generalized dystonia (n = 12, 80.0% vs n = 10, 31.3%, p = 0.004), lower-limb onset (n = 5, 33.3% vs n = 1, 3.1%, p = 0.009), higher motor (p = 0.035) and disability scores (p = 0.042). The classical DYT genes with pathogenic/likely pathogenic variants included 3 cases each of TOR1A, and KMT2B, and single cases each of SGCE, EIF2AK2, and VPS16. Non-DYT pathogenic/likely-pathogenic cases included PINK1, PANK2, CTSF, POLG, MICU1, and TSPOAP1. CONCLUSIONS: The yield of WES was 23.1% among cases of probable genetic dystonia. Pathogenic or likely pathogenic variants in TOR1A, KMT2B, and SGCE genes were commoner. The absence of family history emphasizes the importance of accurate assessment of clinical predictors before genetic testing.