Mutations In Gene Research Articles

Co-existent MDS and lymphoma in a young pregnant woman: A case report and literature review

Myelodysplastic neoplasms (MDS) represent a diverse group of clonal myeloid disorders marked by ineffective hematopoiesis, leading to cytopenias and dysplastic hematopoietic cells. Rarely, MDS may coexist with Non-Hodgkin Lymphoma (NHL), often emerging as a secondary complication post-lymphoma treatment. However, concurrent diagnosis of MDS and lymphoma prior to any chemotherapy or radiotherapy exposure is uncommon. This article discusses a rare case of co-existent MDS and T-cell lymphoma in a young pregnant woman, along with a literature review. Clinical findings, laboratory results, and bone marrow aspiration indicated the presence of both MDS and NHL, with subsequent lymph node biopsy confirming T-cell lymphoma. Literature reveals multiple hypotheses for the coexistence of MDS and lymphomas, including common pathogenic pathways, overlapping genetic mutations, or shared immunological abnormalities. Mutations like TP53, ASXL1, DNMT3A, and RUNX1 are frequently implicated in both MDS and lymphoma and suggest a potential common origin for these diseases. Prognosis remains poor for patients with concurrent MDS and NHL due to limited therapeutic options. Treatment is complex and must consider patient age, comorbidities, and MDS and lymphoma subtypes. Advances in genetic analysis provide insights into the shared etiology of these diseases, potentially aiding in future therapeutic approaches. This case underscores the clinical and therapeutic challenges presented by concurrent MDS and lymphoma and highlights the need for specific management strategies.

Analysis of a family with hypouricemia due to type Ⅰ xanthinuria

This article reports a patient presenting with"extremely low uric acid levels in blood and urine"clinically along with reviewing relevant literature to consider a diagnosis of xanthinuria. Peripheral blood samples of the patient and her family were further collected for xanthine dehydrogenase(XDH) gene sequencing, showing that the patient had compound heterozygous mutations in exon 19:c.1995_2006del12(p.His666_Gly669del) and exon 10:c.871G>T(p.Glu291*), however no mutations were found in the gene encoding MOCOS on chromosome 18, confirming the diagnosis of hereditary xanthinuria type Ⅰ.The patient's father, son and daughter carried heterozygous mutations in exon 19:c.1995_2006del12(p.His666_Gly669del), and the mother carried heterozygous mutations in exon 10:c.871G>T(p.Glu291*).Mutations in the XDH gene cause a lack of xanthine oxidoreductase function, which hinders the production of uric acid, leading to very low or undetectable levels in blood and urine. Patients present clinically with hematuria, renal colic, urolithiasis, and even acute renal failure. Through the diagnosis and treatment of this patient and literature review, the article aims to deepen the understanding of purine metabolism and uric acid production process, and improve the clinicians' diagnosis and treatment ability of hypouricemia.

Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in Colombia

Autosomal recessive conditions are often associated with homozygous mutations showing common ancestral origins and are frequently linked to consanguinity. However, an increasing number of compound heterozygotes are found in diverse, admixed populations. Oculocutaneous albinism (OCA) is a recessive condition caused mainly by mutations in the TYR and OCA2 genes involved in skin pigmentation. We previously screened the TYR and OCA2 genes in Colombian OCA families, identifying both known and novel mutations. Affected family members were found to be either homozygous or compound heterozygous for these gene mutations. Compound heterozygosity, where two different recessive alleles inherited from each parent lead to the expression of an autosomal recessive trait, poses a challenge in genetic diagnosis. Estimating the ancestry of these disease-associated variants, in conjunction with understanding the colonization history of admixed populations, can enhance the precision of association mapping in genetic studies. The aim of this study was to determine the ancestral origins of TYR and OCA2 mutations for OCA patients from two populations located in the Andes region of Colombia–Altiplano Cundiboyacense and Marinilla-Santuario. Comparison of OCA patients, and their unaffected relatives, with global reference populations showed a pattern of European and Native American admixture, with little African ancestry, for these two populations. Mutation-bearing TYR and OCA2 haplotypes from Colombian OCA patients were compared against haplotypes from Spanish, Native American, and Sephardic Jewish reference populations to infer their ancestral origins. For 12 OCA1 patients from the Altiplano Cundiboyacense region, 21 out of 24 mutated TYR haplotypes show Spanish origins, two show Native American origins, and one shows a Sephardic Jewish origin. The two Native American TYR haplotypes, and the single Sephardic Jewish haplotype, are all found in compound heterozygote patients, paired with the predominant Spanish TYR haplotype G47D. OCA in these three patients is a result of genetic admixture that brought together disease-causing mutations with distinct ancestral origins. Both OCA2 patients from the Marinilla-Santuario region show homozygous OCA2 mutations with a Spanish origin. These findings underscore the complexity of the genetic architecture of Mendelian disease in admixed American populations, with both consanguinity and admixture contributing to the risk of autosomal recessive OCA in Colombia.

High level non-carbapenemase carbapenem resistance by overlaying mutations of mexR , oprD, and ftsI in Pseudomonas aeruginosa

ABSTRACT Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the mechanism of non-carbapenemase carbapenem resistance is still unclear. In the current study, we investigated the contributions of point mutations in mexR , oprD , and ftsI to carbapenem resistance in P. aeruginosa during in vivo evolution studies with consecutive clinical isolates. Real-time qPCR and Electrophoretic Mobility Shift Assay demonstrated that MexR (Gln55Pro) mutation increased MexAB efflux pump genes expression by altering MexR’s binding capacity, leading to a four- to eight-fold increase in meropenem MIC in the Pae d1 Green ∆ mexR and PAO1∆ mexR mutants. The OprD (Trp415*) truncation affected porin structure, and the constructed mutant Pae d1 Green oprD Trp415* increased meropenem MIC by 16-fold (from 0.25 to 4 µg/mL). The contribution of ftsI mutation to meropenem resistance was confirmed by clinical linkage analysis and was estimated to cause a two-fold increase in meropenem MIC by comparing the resistant clinical isolate with the Pae d1 Green oprD Trp415*∆ mexR double mutant. The study found that the oprD Trp415* allele alone accounts for the imipenem MIC in clinical isolates, while the ∆ mexR and ftsI Arg504Cys alleles do not contribute to imipenem resistance. In conclusion, we identified and explored the contributions of mexR , oprD, and ftsI mutations to high level non-carbapenemase carbapenem resistance in P. aeruginosa . These findings highlight the interplay of different mutations in causing non-carbapenemase carbapenem-resistance in P. aeruginosa . IMPORTANCE The emergence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant global health threat, complicating treatment options for infections caused by this pathogen. Understanding the mechanisms behind non-carbapenemase carbapenem resistance is critical for developing effective therapeutic strategies. This study provides crucial insights into how specific point mutations in key genes- mexR , oprD , and ftsI -contribute to carbapenem resistance, particularly the MexR (Gln55Pro) mutation’s effect on efflux pump expression and the OprD (Trp415*) truncation’s impact on porin structure. The findings elucidate the complex interplay of these mutations, highlighting their roles in conferring high-level resistance, and underscore the imperative for continued research to inform therapeutic strategies against CRPA infections.

Plumage polymorphism in the black sparrowhawk (Accipiter melanoleucus) is strongly associated with expression level of agouti signalling protein

Abstract Melanin-based plumage polymorphisms in birds are often associated with mutations in the melanogenesis genes, notably the melanocortin-1 receptor (MC1R), but may also arise through changes in the expression of these genes. Here we investigate the molecular basis of plumage polymorphism in both adult and juvenile black sparrowhawks (Accipiter melanoleucus), an African raptor that occurs in two adult colour morphs, light and dark, and also exhibits variation in juvenile plumage colouration. Our results confirmed that plumage differences in adult morphs were a result of differential deposition of eumelanin in their ventral contour feathers. No polymorphisms in the coding regions of the MC1R or the agouti signalling protein (ASIP) genes associated with adult colour morph were identified. However, lack of pigmentation in the developing breast feathers of light morph birds was strongly associated with elevated ASIP expression, and concomitant down-regulation of the downstream melanogenesis genes microphthalmia-associated transcription factor (MITF), tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Variation in the rufous coloured plumage of juveniles was found to be due to covariation in eumelanin and pheomelanin levels in dorsal and ventral contour feathers. As in adult birds, an inverse relationship between melanin pigmentation and ASIP expression was observed. This covariation between eumelanin and pheomelanin levels is not consistent with the pigment type-switching model of melanogenesis, where increased ASIP expression results in a switch from eumelanin to pheomelanin production. This highlights the need for caution when extrapolating results from model systems to other animals and the value of conducting research in wild species.

Utilizing Upadacitinib for the Management of Hailey-Hailey Disease

Hailey-Hailey Disease (HHD) is a rare disease associated with mutation of the ATP2C1 gene characterized by skin blistering and erosion. Here, we report a case of a patient with HHD who significantly improved after treatment with upadacitinib. A 55-year-old male with biopsy-confirmed Hailey-Hailey disease presented with a 20-year history of ill-defined, brightly erythematous, painful patches initially on the neck and subsequently involving the penile shaft. Following treatment with 30mg of upadacitinib, the patients neck ulcers gradually re-epithelized. This case adds to the growing body of literature supporting the use of Janus kinase inhibitors as a therapeutic modality for this condition.

Jordans’ anomaly in Chanarin-Dorfman syndrome

Abstract Objectives Chanarin-Dorfman syndrome is a rare disease inherited in an autosomal recessive pattern whose prevalence does not exceed 130 cases worldwide. Case presentation A 4-year-old patient with generalized erythematous-desquamative ichthyosiform syndrome since birth. The main laboratory finding was persistent hypertransaminasemia. Supplementary studies included peripheral blood smear (PBS), which revealed the presence of multiple cytoplasmatic vacuoles in polymorphonuclear leukocytes (PMN) and platelets. Ichthyosiform lesions concomitant to the presence of lipid vacuoles in peripheral blood PMNs are signs of Chanarin-Dorfman syndrome. Diagnostic suspicion was confirmed by genetic sequencing. Conclusions Chanarin-Dorfman syndrome is characterized by a mutation in the CGI-58 gene. This gene is involved in the catabolism of long-chain triglycerides stored in cytoplasmic lipid droplets. Jordans’ anomaly is a congenital alteration characterized by the presence of multiple vacuoles in the granulocytic series due to defective lipid metabolism. In this syndrome, long-chain triglycerides build up in tissues, thereby causing dermatological manifestations that are controllable through diet.

Exploring the Molecular Interaction Between NR2E3 and NR1D1 in Retinitis Pigmentosa: A Docking and Molecular Dynamics Study

ABSTRACTBackground and AimsRetinitis pigmentosa (RP) is a hereditary retinal disorder that gradually leads to vision loss due to photoreceptor cell degeneration. This study aims to investigate the clinical features and genetic underpinnings of RP within a large Iranian family. Our focus centered on mutations in the NR2E3 gene, which plays a critical role in the development and maintenance of the retina.MethodsTwenty‐five family members showed symptoms of RP, and fourteen of them underwent clinical examinations conducted by geneticists and ophthalmologists. The DNA samples of five individuals diagnosed with RP from the family were subjected to whole‐exome sequencing (WES) as part of the study. The candidate variant identified through WES was subsequently confirmed using bidirectional sequencing in additional family members. Additionally, in silico analysis, including molecular modeling, protein–protein docking, and molecular dynamics simulation (MD), was employed to assess potential pathogenic effects associated with the candidate variants.ResultsOphthalmic examination revealed night blindness, which is a common symptom among affected individuals. Genetic analysis identified a homozygous missense variant (c.934G>A/p.R311Q) in NR2E3 exon 6, which co‐segregates with other affected family members. Furthermore, molecular docking analysis indicated potential disruption in the binding affinity between NR2E3 and NR1D1 proteins. In‐depth, molecular dynamics analysis, considering parameters such as RMSD, RMSF, and hydrogen bonding, revealed notable differences between normal and mutant protein complexes.ConclusionExploring the molecular interaction between NR2E3 and NR1D1 provides new insights into the pathogenic mechanism of the p.R311Q mutation in RP.

Abstract A042: Desmosome mutations in the microenvironment regulate melanoma proliferation

Abstract Desmosomes are transmembrane protein complexes critical for cell-cell adhesion in epithelial tissues and other cell types. In skin cancers like melanoma, epithelial cells called keratinocytes are the predominant cells in the primary melanoma microenvironment, yet it remains largely unknown whether this cell type is subject to genetic alterations during melanoma development and its role in early melanoma progression. In this study, using an integrative analysis of tumor mutations and protein biophysical interactions, we identify a high frequency of genetic alterations in desmosome-related genes in human cancers, with the highest occurrences in cutaneous melanoma. Notably, over 70% of cutaneous melanoma cases exhibit mutations in desmosome genes and desmosome gene mutations are associated with lowered expression of the desmosome complex in melanoma. Using spatial transcriptomics and immunohistochemistry analyses, we find that the decrease in desmosome gene expression predominantly occurs in keratinocytes within the tumor microenvironment rather than in the melanoma cells themselves. To study the functional significance of this alteration in melanoma development, we used a human melanoma/keratinocyte co-culture system using primary melanoma cell lines. Our studies show that knockdown of desmosome genes in keratinocytes markedly increased proliferation of adjacent melanoma cells in melanoma/keratinocyte co-cultures. Additionally, melanoma cell proliferation is enhanced when exposed to media preconditioned by desmosome-deficient keratinocytes. These observations suggest that the gradual accumulation of mutations in desmosome genes within neighboring keratinocytes may create a conducive environment that primes melanoma cells for neoplastic transformation. This study underscores the critical role of genetic alterations in the tumor microenvironment in melanoma progression and highlights the potential for targeting desmosome-related pathways in therapeutic strategies against melanoma. Citation Format: Mohita Tagore. Desmosome mutations in the microenvironment regulate melanoma proliferation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A042.

Abstract C046: PARP inhibitors as immune modulators in metastatic ovarian cancer treatment

Abstract Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes. Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C046.

Cohesin rad21 mutation dysregulates erythropoiesis and granulopoiesis output within the whole kidney marrow of adult zebrafish.

Cohesin complex is essential for cell division and for regulating cell type-specific gene expression programs. Mutations in genes encoding the cohesin subunits are associated with hematological malignancies, pre-leukemia and clonal hematopoiesis of indeterminate potential. In this study, we examined how cohesin mutation impacts hematopoiesis using adult zebrafish that carry heterozygous germline nonsense mutation in the cohesin subunit, rad21 (rad21+/-) that is orthologous to human RAD21. Single cell RNA sequencing analyses showed that adult zebrafish harboring rad21+/- mutation exhibit significant transcriptional dysregulation within the whole kidney marrow and have altered erythroid and granulocyte output. Erythroid progenitors were expanded in rad21+/- and erythroid differentiation was altered. The expression profile of several erythroid genes, including gata1a, was dysregulated in rad21+/- erythroid cells. Mature granulocyte population declined in rad21+/-, and the transcriptional program of granulocytes was impaired but granulocytic maturation was maintained. Granulocytes from rad21+/- showed upregulation of stress hematopoiesis factor, cebpb. These findings show that normal rad21 is required to maintain steady erythropoiesis and granulopoiesis in the adult zebrafish marrow.

High-grade B-cell lymphoma not otherwise specified, with diffuse large B-cell lymphoma gene expression signatures: Genomic analysis and potential therapeutics.

High-grade B-cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (n = 55) in adults (n = 45) and in children (n = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with de novo DLBCL (n = 85) and BL (n = 52). This subgroup, representing ~60% of HGBCL, NOS, lack gene-expression signature of BL and double hit/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB- or ABC-like mRNA signatures and exhibit higher genomic complexity, similar to de novo DLBCL, and show alteration in genes regulating B-cell activation (CD79B, MYD88, PRDM1, TBLIXR1, CARD11), epigenome (KMT2D, TET2) and cell cycle transition (TP53, ASPM). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL-NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B-cell activation (del-PRDM1, gain-BCL6, -REL, -STAT3) and cell cycle regulators (del-TP53, del-CDKN2A, del-RB1, gain-CCND3) were observed. Pediatric cases showed GCB-DLBCL-like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic PIM1 mutations were present in adult HGBCL, NOS. In vitro analyses with pharmacologic or genetic inhibition of PIM1 expression triggered B-cell activation and NF-κB-induced apoptosis, suggesting that PIM1 is a rational therapeutic target.

Metamaterial-based Artificial magnetic conductor for efficient breast cancer diagnosis using a low-cost antenna array.

Breast cancer is the most common malignancy in women globally, stemming from gene mutations that prompt irregular cellular growth and subsequent tumor development. Early-stage detection of cancer cells results in a remarkable 99% survival rate. This research presents a microwave imaging technique for the non-invasive identification of tumors in the initial stages within the women's breast. A low-cost antenna array with an Artificial Magnetic Conductor (AMC) is proposed, featuring a compact structure size of 37.2 37.2 mm . The AMC, a metamaterial, acts as a reflective surface to enhance frequency selectivity, specifically at 8.48 GHz. The maximum gains reached 9.35 dBi in simulated results and 10.51 dBi in measured results. The fabricated antenna validates the simulated findings, and its operational efficiency has undergone experimental validation. Moreover, fidelity factors in face-to-face (FtF) and side-by-side (SbS) scenarios are delineated. The antenna, operating as a transceiver, is applied to a modeled breast phantom across five distinct cases for numerical simulations pertaining to cancer cell detection applications. The outcomes of this research bear considerable implications for advancing early-stage breast cancer detection methodologies.

Single-center experience of four cases with iron-refractory iron deficiency anemia (IRIDA)

Background. Iron refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive type of anemia characterized by unresponsiveness to oral iron therapy and partial response to parenteral iron therapy. In this article, we report the clinical presentation of four patients with IRIDA admitted to our clinic, including their laboratory values at admission and after oral and parenteral iron treatment, and the analysis of their mutation(s) in TMPRSS6 gene. Case. Four patients from different families, aged between 3 and 14 years, two girls and two boys, two of whom were from consanguineous marriages, who were diagnosed with iron deficiency anemia in primary health care institutions and referred to our clinic because of inadequate response to oral iron treatment were included. Patients were evaluated for the differential diagnosis of microcytic, hypochromic anemia and investigated for the etiology of IDA. Homozygous or compound heterozygous mutations causing defective matriptase-2 protein expression were detected in the TMPRSS6 gene; these mutations included four frameshift mutations-two of which were the same in two cases and causing premature terminal stop codons-and a nonsense mutation, all of which were previously demonstrated in the literature. The response to parental iron therapy ranged from complete non-response to mild to good response in hemoglobin levels, but none of the patients showed improvement in iron parameters. Conclusions. Increased awareness of IRIDA and keeping it in mind in the differential diagnosis in the presence of hypochromic microcytic anemia that does not respond to iron treatment will be crucial in improving the diagnosis and treatment of the disease and ultimately enhancing the quality of care for affected individuals.

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress.

Most autoinflammatory diseases are caused by mutations in innate immunity genes. Previously, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive. Here, we show that the recurrent p.R186C CDC42 variant, which is trapped in the Golgi apparatus, elicits a block in both anterograde and retrograde transports. Consequently, it favours STING accumulation in the Golgi in a COPI-dependent manner. This is also observed for the other Golgi-trapped p.*192 C*24 CDC42 variant, but not for the p.Y64C and p.C188Y variants that do not accumulate in the Golgi. We demonstrate that the two Golgi-trapped CDC42 variants are the only ones that exhibit overactivation of the STING pathway and the type I interferon response, and elicit endoplasmic reticulum stress. Consistent with these results, patients carrying Golgi-trapped CDC42 mutants present very high levels of circulating IFNα at the onset of their disease. In conclusion, we report further mechanistic insights on the impact of the Golgi-trapped CDC42 variants. This increase in STING activation provides a rationale for combination treatments for these severe cases.

Serous Tubal Intraepithelial Carcinoma (STIC): A Review of the Literature on the Incidence at the Time of Prophylactic Surgery

Background: Serous tubal intraepithelial carcinoma (STIC) is an early-stage cancerous lesion found in the fallopian tubes, often at the fimbrial end. It is strongly associated with high-grade serous carcinoma (HGSC), a highly aggressive type of ovarian cancer. STIC is considered a precursor to many HGSC cases, originating in the fallopian tubes. Its development is frequently linked to mutations in the TP53 gene, leading to the formation of a p53 signature, an early abnormality that may progress to HGSC. This signature is more common in BRCA mutation carriers, explaining the higher incidence of STIC in this group. The aim of this review is to evaluate the literature on the incidence of serous tubal intraepithelial carcinoma in patients (both BRCA-positive and BRCA-negative) undergoing preventive salpingo-oophorectomy, analysing the available data and identifying associations between specific characteristics and the onset of STIC. Methods: A comprehensive review of the literature from 2016 to 2023 was conducted using PubMed, focusing on studies analysing the incidence of STIC in BRCA-positive patients undergoing preventive salpingo-oophorectomy. Data on patient characteristics, interventions, outcomes, and incidence of STIC were extracted and analysed. Results: Nine international studies were included in the review, reporting varying incidences of STIC among patients undergoing salpingo-oophorectomy. The overall incidence of STIC in all the women included in the studies was 7.31%, while that in the BRCA-mutated women was approximately 6.08%. Notably, the presence of the TP53 signature was significantly associated with the occurrence of STIC. Conclusions: The etiopathogenesis of STIC involves complex interactions between genetic, environmental, and molecular factors. Further research is needed to fully understand its mechanisms and identify additional risk factors beyond BRCA mutations. Establishing a national database of STIC cases could facilitate future research and improve patient outcomes.

Detection and functional validation of point mutations in acetylcholinesterase-1 associated with organophosphate resistance in field populations of Helicoverpa armigera.

Point mutations in the acetylcholinesterase-1 gene (ace-1) have been associated with resistance to OPs in many insects. However, the presence and function of ace-1 mutations associated with OP resistance in Helicoverpa armigera (Lepidoptera: Noctuidae), a significant lepidopteran pest damaging a wide range of crops, remain largely unexplored. This study investigated resistance to the OP insecticide phoxim in 12 field populations of H. armigera from northern China in 2022, revealing low levels of resistance (2.5- to 6.7-fold). Using an amplicon sequencing approach, we screened for ace-1 mutations in 13,874 moths collected from 114 populations collected between 2006 and 2022. We found 3 amino acid substitutions (A201S, G227E, and F290V) potentially related to OP resistance. The mean frequencies of A201S, G227E, and F290V mutations were 0.0032, 0.0001, and 0.0001, respectively. To assess these mutations' role in OP resistance, we expressed wild-type and mutant AChE1 proteins in Sf9 cells. Biochemical characterization revealed a 3.1-fold and 3.3-fold increase in the I50 of chlorpyrifos-oxon for A201S and F290V mutants compared to the wild-type enzyme, correlating with a 2.9-fold and 2.7-fold decrease in the Ki value. No enzyme activity was observed in the G227E mutant, indicating that only A201S and F290V confer insensitivity to chlorpyrifos-oxon. Our study demonstrates that amplicon sequencing is an effective method for large-scale screening of resistance-associated point mutations in field populations of H. armigera and potentially other insect pests. It also identifies A201S and F290V in AChE1 as potential point mutations conferring OP resistance in field populations of H. armigera.

Update and narrative review of avian influenza (H5N1) infection in adult patients.

The avian influenza is a serious infection caused by influenza virus that is native to birds. Avian influenza remains a global challenge due to high transmission and mortality rates. The highly pathogenic strain of H5N1 resulted in significant outbreaks and deaths globally since the late 1800s. The most recent outbreaks in wild birds, domestic birds, and cows with some genetic variations and mutations among H5N1 strains has raised major concerns about potential transmission and public health risks. Symptoms range from asymptomatic to mild flu-like illness to severe illness that requires hospitalization. There are multiple vaccines in development for humans to protect against avian influenza, specifically the H5N1 virus. This includes a cell-based vaccine approved by the FDA for people aged 6 months and older who are at higher risk of exposure to the H5N1 virus called Audenz. Chemoprophylaxis against avian influenza following a suspected exposure should be started as soon as possible or no later than 48 h, and it is recommended to be continued for 7 days. The majority of avian influenza viruses are susceptible to neuraminidase inhibitors and cap-dependent endonuclease inhibitor. Neuraminidase inhibitors are the mainstay of the avian influenza treatment and includes oseltamivir, peramivir, and zanamivir. Baloxavir marboxil is a cap-dependent endonuclease inhibitor. This clinical review aims to highlight the background, epidemiology, clinical presentation, complications and current treatment and prevention strategies for avian influenza H5N1.

SLITRK2 as a prognostic and immunological biomarker in gastric cancer.

SLIT and NTRK-like protein 2 (SLITRK2) encodes a transmembrane protein that regulates neurite outgrowth. Some studies have demonstrated that SLITRK2 overexpressed in glioma. But the expression pattern, prognostic value and immunologic function of SLITRK2 in tumors remains unknown. The expression pattern of SLITRK2 among pan-cancers was examined through the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). We analyzed the association between SLITRK2 expression level and tumor stage among pan-cancers. Kaplan-Meier survival analysis was utilized to investigate the prognostic relevance of SLITRK2 across 33 different types of cancers. Moreover, the correlations among SLITRK2 expression, immune cell infiltration, immunomodulatory related genes, tumor mutation burden (TMB), microsatellite instability (MSI) were evaluated. The relationship between SLITRK2 expression and crucial genes mutations was also illustrated. By using tissue microarray (TMA), the expression of SLITRK2 in 89 paired gastric cancer (GC) tissues was investigated. Our study indicated that SLITRK2 expression varied across cancers. Elevated SLITRK2 expression was positively related to advanced tumor stage, poor overall survival (OS) and reduced disease-free survival (DFS). Bioinformatic analyses underscore SLITRK2's role in immune response, with its expression significantly tied to immune cell infiltration and marker expression. Based on TMA data, SLITRK2 expression level was positively associated with differentiation, lymph node metastasis, AJCC stage, TNM stage, and poor survival outcome in GC patients. Our findings provided that SLITRK2 may function as a biomarker by regulating immune cell infiltration. In addition, we verified that high SLITRK2 expression was correlated with poor prognosis in GC.

Detection of BRCA-1 gene mutations in epithelial ovarian tumors at tertiary care hospital Karachi

ABSTRACT Background: Ovarian cancer is the most common and lethal gynecological malignancy. Ovarian malignancy is the 3rd most common cancer in Pakistan. More than 90% ovarian cancers are of epithelial cell origin, about 24-40% such cancers have hereditary or sporadic mutation in the BRCA-1 or BRCA-2 genes. The present study was designed to detect BRCA-1 gene mutations in different histological sub-types of epithelial origin of benign, borderline and malignant ovarian tumors. Methods: This cross-sectional study was based on the analysis of BRCA-1 gene mutations in the epithelial origin of benign, borderline and malignant ovarian tumors received at the department of Pathology, Basic Medical Sciences Institute, Jinnah Post graduate Medical Centre, from 01-01-2011 to 31-12-2015. A total of 80 diagnosed cases were selected and analyzed for PCR. Results: BRCA-1 gene mutations were detected in 22 (27.5%) cases out of the 80 randomly selected epithelial ovarian tumors. Serous cyst adenocarcinoma was the commonest including 63% cases. BRCA-1 gene mutations were also positive in other epithelial ovarian tumors, including Mucinous cyst adenocarcinoma (13.6%), Endometroid adenocarcinoma and Mixed Mullerian tumor (4.5% each). In addition mutations were also detected in borderline tumors including Mucinous borderline tumor (9.09%) and Seromucinous borderline tumors (4.5%).The observations and results of the study were elaborated with the assistance of tables, figures and photomicrographs. Conclusion: BRCA-1 gene mutations manifestations were identified in a large number of serous malignant ovarian tumor cases. Small percentages of borderline and malignant mucinous tumors, endometroid adenocarcinoma and mixed mullerian tumor were also positive for BRCA-1 gene mutations.