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Background The World Health Organization recommends the provision of intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) at 4-week intervals from gestational week 13 to delivery in areas of moderate to high malaria transmission intensity. However, the effect of IPTp-SP has been compromised in some areas due to parasite resistance, raising the importance of parasitological and chemoprophylactic surveillance, and monitoring SP-resistance markers in the Plasmodium falciparum population. Methods Between November 2013 and April 2014 in Nchelenge, Zambia, 1086 pregnant women received IPTp-SP at antenatal-care bookings. Blood samples were collected on day 0, and on day 28 post-treatment to test for malaria parasites and to estimate SP parasitological efficacy in the treatment and prevention of parasitaemia. A random sample of 96, day 0 malaria-positive samples were analysed to estimate the prevalence of SP-resistance markers in the P. falciparum population. Results The overall parasitological and prophylactic failure among women who had paired day 0 and day 28 blood slides was 18.6% (95% CI 15.5, 21.8; 109 of 590). Among pregnant women who had asymptomatic parasitaemia on day 0, the day 28 PCR-uncorrected parasitological failure was 30.0% (95% CI 23.7, 36.2; 62 of 207) and the day 28 PCR-corrected parasitological failure was 15.6% (95% CI: 10.6, 20.6; 32 of 205). Among women who tested negative at day 0, 12.3% (95% CI: 9.0, 15.6; 47 of 383) developed parasitaemia at day 28. Among the 96 malaria-positive samples assayed from day 0, 70.8% (95% CI: 60.8, 79.2) contained the DHPS double (Gly-437 + Glu-540) mutation and 92.7% (95% CI: 85.3, 96.5) had the DHFR triple (Asn-108 + Ile-51 + Arg-59) mutation. The quintuple mutation (DHFR triple + DHPS double) and the sextuple mutant (DHFR triple + DHPS double + Arg-581) were found among 68.8% (95% CI: 58.6, 77.3) and 9.4% (95% CI: 4.2, 16.0) of samples, respectively. Conclusion The parasitological and chemoprophylactic failure of SP, and the prevalence of resistance markers in Nchelenge is alarmingly high. Alternative therapies are urgently needed to safeguard pregnant women against malarial infection.

Jinzao Chen, Department of Cardiology, The First Hospital of Putian City, No. 449, Nanmen West Road, Chengxiang District, Putian, Fujian, 351100, People’s Republic of China, Tel +86-13950793989, Fax +86-0594-2330980, Email chen5858@sina.comPurpose: To explore clinical manifestations and treatment strategies in a patient with dual GLA and MYH7 mutations causing Fabry disease (FD) and hypertrophic cardiomyopathy (HCM), emphasizing the value of comprehensive genetic testing in complex cardiomyopathies.Patients and Methods: We studied a 40-year-old Han Chinese woman with FD and familial HCM due to GLA and MYH7 mutations. Diagnosis involved echocardiography, electrocardiography, cardiac MRI, genetic sequencing, and α-galactosidase A activity assays. Treatment included pharmacotherapy (rivaroxaban, sacubitril/valsartan, bisoprolol, spironolactone, torasemide), agalsidase α enzyme replacement, and surgery for left ventricular outflow tract obstruction.Results: The patient had severe left ventricular hypertrophy (interventricular septum 35 mm) and significant obstruction (LVOTG 121 mmHg). After 3 months, the 6-minute walk test distance increased from 132 to 369 meters, NT-proBNP levels dropped from 2164 to 1911 pg/mL, and the KCCQ score rose from 30.9 to 85.5, indicating improved quality of life.Conclusion: Comprehensive genetic testing is crucial for diagnosing complex cardiomyopathies. A multidisciplinary approach effectively improves symptoms and quality of life in patients with dual genetic mutations.

The human immunodeficiency virus type-1 Reverse Transcriptase (HIV-1 RT) plays a pivotal role in essential viral replication and is the main target for antiviral therapy. The anti-HIV-1 RT drugs address resistance-associated mutations. This research focused on isolating the potential specific DNA aptamers against K103N/Y181C double mutant HIV-1 RT. Five DNA aptamers showed low IC50 values against both the KY-mutant HIV-1 RT and wildtype (WT) HIV-1 RT. The kinetic binding affinity forms surface plasmon resonance of both KY-mutant and WT HIV-1 RTs in the range of 0.06–2 μM and 0.15–2 μM, respectively. Among these aptamers, the KY44 aptamer was chosen to study the interaction of HIV-1 RTs-DNA aptamer complex by NMR experiments. The NMR results indicate that the aptamer could interact with both WT and KY-mutant HIV-1 RT at the NNRTI drug binding pocket by inducing a chemical shift at methionine residues. Furthermore, KY44 could inhibit pseudo-HIV particle infection in HEK293 cells with nearly 80% inhibition and showed low cytotoxicity on HEK293 cells. These together indicated that the KY44 aptamer could be a potential inhibitor of both WT and KY-mutant HIV-RT.

The aim of this study was to explore the clinical features and prognostic significance of CSF3R mutations in AML patients with CEBPA double mutations (CEBPAdm). One hundred one AML patients with CEBPAdm were retrospectively analyzed in this study. Mutation status of CSF3R gene, clinical features, and long-term outcomes were analyzed. The frequency of CSF3R mutations in patients with CEBPAdm was 19.80% (20/101). Patients with CSF3R mutations were associated with a lower platelet (u = 2.728, P = 0.006) and higher leukocytes (u = 3.178, P = 0.001) compared with those with wide-type CSF3R gene. The 5-year relapse-free survival (RFS) was 18.7% in patients with CSF3R mutations, which was significantly lower than those with wide-type CSF3R (31.8%) (P = 0.015). The 5-year overall survival (OS) was also significantly different between patients with and without CSF3R mutations (17.5% versus 57.4%, P = 0.019). The prevalence of CSF3R mutations was high in AML patients with CEBPAdm, which indicated a poor prognosis, and CSF3R mutations may be a new potential candidate for prognostically re-stratifying AML patients with CEBPAdm.

Human leukemia cell lines play a crucial role in leukemia research, particularly in understanding the pathogenesis of acute leukemia and developing novel therapeutic strategies. We here describe the generation of a novel monocytic cell line SDEY-AML1, harboring alterations in KMT2A::MLLT3, IKZF1::EVX1, ETV6, and TP53 double mutations, and its biological characteristics. We established a cell line, SDEY-AML1, from the mononuclear cells isolated from the bone marrow of a patient with acute myeloid leukemia (AML-M5). Comprehensive morphological and cytogenetic characterization of SDEY-AML1 cells was performed using cytochemical staining, flow cytometry, and karyotype analysis. The molecular features of the cell line were identified by transcriptomic analysis and reverse transcription-polymerase chain reaction (PT-PCR). The proliferative capacity of the SDEY-AML1 cells was assessed using a clonogenic assay. And we conducted drug sensitivity experiments on SDEY-AML1 to tested its sensitivity to commonly used chemotherapy drugs and targeted drugs. Additionally, we created an in vivo tumor model of SDEY-AML1 cells by injecting 1×10 7 cells subcutaneously in NSG mice via the tail vein. The SDEY-AML1 cells were maintained in continuous culture for one year without the addition of exogenous cytokines. Cytochemical assays revealed that the cells were positive for α-naphthyl acetate esterase reactivity that was partially inhibited by sodium fluoride but negative for peroxidase and periodic acid-Schiff staining. Flow cytometry showed the expression of myeloid markers in SDEY-AML1 cells. Karyotypic analysis revealed a t(9;11) (p22;q23) translocation in SDEY-AML1 cells, mirroring the chromosomal aberrations identified in the primary leukemia cells of the patient. Genetic profiling confirmed the presence of alterations in KMT2A::MLLT3, IKZF1::EVX1, ETV6, and TP53 genes. SDEY-AML1 cultures were negative for EBV and mycoplasma. NSG mice showed tumor infiltration within 40-50 days of tail vein injection of SDEY-AML1 cells. The new AML cell line, SDEY-AML1, harbored KMT2A::MLLT3, IKZF1::EVX1, ETV6 gene alterations, and TP53 double mutations. These cells were highly tumorigenic in NSG mice. This cell line has applications in the research and development of new agents targeting KMT2A::MLLT3, IKZF1::EVX1-associated leukemia, making it a valuable tool in the study of leukemogenesis.

ABSTRACT Background: The genetic profiling of non-small cell lung cancer (NSCLC) has contributed to the discovery of actionable targetable mutations, which have significantly improved outcomes in disease with poor prognosis. Molecular epidemiological data of driver mutations in Indian populations have not been extensively elaborated compared to western and eastern Asian NSCLC populations. This study assessed the prevalence and clinical outcomes of EGFR (epidermal growth factor receptor) mutations among the Indian NSCLC cohort in South India. Patients and Methods: Retrospective analysis of 2,003 NSCLC patients who had undergone EGFR mutational analysis from 2013 to 2020 was performed. Clinical analysis was performed for 141 patients from 2013 to 2017 using Kaplan-Meier and Chi-square methods. Descriptive and survival statistics were performed using IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Results: EGFR-sensitizing mutations were detected in 41.6% (834/2003) in the study cohort with compound mutations detected in 7.55% (63/834) of EGFR-positive cases. A significant relationship with regard to female gender and EGFR mutation status (P <.001) was observed. Exon 18 G719X (8.7%) mutations and exon 20 T790M point mutation (3.1%) were the most frequently isolated uncommon EGFR mutations. In the clinical cohort, EGFR mutations were detected at a significantly higher prevalence in females (P =0.002) and never-smokers (P < 0.001). EGFR mutation demonstrated a significant relationship with regard to brain metastasis (P = 0.011). EGFR mutated individuals had significantly longer median overall survival compared to EGFR wild type (26 months vs. 12 months, P = 0.044). Conclusion: We reports the highest number of EGFR mutation analysis performed from India and mutational analysis indicated a loco-regional variation in India with regard to EGFR mutation frequency and its subtypes.

While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described.BACKGROUNDWhile previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described.We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection.CASE SERIESWe present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection.The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected.CONCLUSIONThe present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected.

The etiology of early-onset Alzheimer’s disease (EOAD) is associated with alterations in the production of amyloid beta (Aβ) species caused by mutations in the APP, PSEN1, and PSEN2 genes. Mutations affect intra- or inter-molecular interactions and processes between the γ-secretase complex and amyloid precursor protein (APP), leading to the aberrant sequential cleavage of Aβ species. A 64-year-old woman presented with progressive memory decline, mild right hippocampal atrophy, and a family history of Alzheimer’s dementia (AD). Whole exome sequencing was performed to evaluate AD-related gene mutations, which were verified by Sanger sequencing. A mutation-caused structural alteration of APP was predicted using in silico prediction programs. Two AD-related mutations, in APP (rs761339914; c.G1651A; p.V551M) and PSEN2 (rs533813519; c.C505A; p.H169N), were identified. The APP Val551Met mutation in the E2 domain may influence APP homodimerization through changes in intramolecular interactions between adjacent amino acids, altering Aβ production. The second mutation was PSEN2 His169Asn mutation, which was previously reported in five EOAD patients from Korea and China, with a relatively high frequency in the East Asian population. According to a previous report, the presenilin 2 protein was predicted to result in a major helical torsion by PSEN2 His169Asn mutation. Notably, the co-existence of APP Val551Met and PSEN2 His169Asn may induce a synergistic effect by both mutations. Future functional studies are needed to clarify the pathological effects of these double mutations.

Background Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. Methods The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant ( TscD +/− ) mice. Results TscD +/− mice exhibited impairments in social behaviors, and the severity of impairments was similar to Tsc2 +/− mice rather than Tsc1 +/− mice. Impairments in social behaviors were rescued by rapamycin treatment in all mutant mice. Gene expression profiles in the brain were greatly altered in TscD +/− mice more than in Tsc1 +/− and Tsc2 +/− mice. The gene expression changes compared with wild type (WT) mice were similar between TscD +/− and Tsc2 +/− mice, and the overlapping genes whose expression was altered in mutant mice compared with WT mice were enriched in the neoplasm- and inflammation-related canonical pathways. The “signal transducer and activator of transcription 3, interferon regulatory factor 1, interferon regulatory factor 4, interleukin-2R α chain, and interferon-γ” signaling pathway, which is initiated from signal transducer and activator of transcription 4 and PDZ and LIM domain protein 2, was associated with impairments in social behaviors in all mutant mice. Limitations It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. Conclusions These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype–phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.

Flixweed [Descurainia sophia (L.) Webb ex Prantl] is a notorious broadleaf weed that is widely distributed in winter wheat–growing areas of China and has evolved resistance to tribenuron-methyl mainly due to target-site resistance (TSR) mutations in acetolactate synthase (ALS). In the current research, two ALS genes were identified in tribenuron-methyl–susceptible (TS) or tribenuron-methyl–resistant (TR) D. sophia. Resistance mutations of Asp-376-Glu and Pro-197-Ala were identified on ALS1 and ALS2 isozymes in TR D. sophia, respectively. The TR D. sophia evolved 10,836.3-fold resistance to tribenuron-methyl and displayed cross-resistance to multiple ALS-inhibiting herbicides with different chemical structures. Dose response experiments and ALS activity assay indicated that two mutated ALS isozymes contributed differentially in resistance to tribenuron-methyl, flucetosulfuron, and pyribenzoxim. In addition, the relative expression level of the ALS1 gene was 2.2- and 1.6-fold higher than ALS2 genes in TR D. sophia at 1 and 7 d after tribenuron-methyl treatment, respectively. In contrast, the relative expression level of ALS1 and ALS2 in TS D. sophia is similar. This is the first research that explored different roles of ALS isozymes in resistance to ALS-inhibiting herbicides, which might provide a new perspective for the weed resistance management.