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Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
OBJECTIVE
To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
METHODS
Clinical characteristics of 62 patients diagnosed de novo MPN at Central Hospital Affiliated to Shandong First Medical University from September 2016 to September 2022 were retrospectively analyzed. Next-generation sequencing was used to detect 35 MPN-related genes, and the DTA mutations in MPN patients and their relationship with thromboembolic events were analyzed.
RESULTS
75.8% (47/62) of the patients presented pathogenic non-driver mutations, and the mean number of pathogenic non-driver mutations per patient was 1.08. Among them, the most frequently mutated non-driver genes were (38.7%, 24/62), (9.7%, 6/62) and (6.5%, 4/62). The presence of DTA gene mutations was 50% (31/62) in the total MPN patients, and mainly accompanied by driver mutations. The mutation rate of DTA in patients aged ≥60 years was significantly higher than that in patients <60 years old ( =0.039). The incidence of thromboembolism in patients with DTA mutation was 58.1% (18/31), which was significantly higher than that in patients without DTA mutation (19.4%, 6/31) ( =0.002). The gene mutation rate in MPN patients with thromboembolism was 66.7% (16/24), which was significantly higher than that in patients without thromboembolism (21.1%, 8/38) ( =0.00).
CONCLUSION
Patients with MPN have a higher incidence of DTA mutations, which are mainly accompanied by driver gene mutations. The incidence of thromboembolism in MPN patients with DTA mutations is higher than that in patients without DTA mutations. Especially, the elderly (≥60 years) essential thrombocythemia(ET) and polycythemia vera(PV) patients with mutation should be vigilant for thromboembolic events.
Topics: Humans; Mutation; Dioxygenases; Middle Aged; Myeloproliferative Disorders; Thromboembolism; Retrospective Studies; Proto-Oncogene Proteins; DNA-Binding Proteins; Repressor Proteins; DNA Methyltransferase 3A; DNA (Cytosine-5-)-Methyltransferases; Male; Female; High-Throughput Nucleotide Sequencing
PubMed: 38926973
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.025 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the clinical significance of allelic state in patients with myelodysplastic syndromes (MDS).
OBJECTIVE
To investigate the clinical significance of allelic state in patients with myelodysplastic syndromes (MDS).
METHODS
The clinical data of 858 MDS patients who underwent second-generation sequencing (NGS) testing in the First Affiliated Hospital of Soochow University from January 2019 to December 2021 were retrospectively analyzed.
RESULTS
The median age of the patients was 52 years old, and median follow-up time was 23.8 (0.4-109.6) months. Four hundred and one patients (46.7%) had at least one chromosomal abnormality, including 106 complex karyotypes and 78 monosomal karyotypes. A total of 103 cases of mutations were identified, with a mutation rate of 12%. Compared with wild-type, various types of chromosomal abnormalities were significantly more common in patients with mutations (all < 0.001). Patients with mutations had lower hemoglobin levels, lower platelet counts and higher percentage of bone marrow primitive cell compared with wild type (all < 0.05), and significantly shorter overall survival (OS). Among 97 evaluable patients, 33 cases (34%) were mono-allelic mutation, while 64 cases were bi-allelic mutation. Patients in bi-allelic mutation subgroup had a higher proportion of chromosomal abnormalities and a lower number of co-mutations compared with mono-allelic mutation. The median OS was 33.6 months in patients with mono-allelic state and only 11.4 months in patients with bi-allelic state (=2.138, 95% : 1.053-4.343, >0.05). Median OS was not reached in wild-type patients, and there was a significant difference in OS among wild-type, mono-allelic and bi-allelic mutation patients ( < 0.001). Multivariable Cox regression analysis showed that bi-allelic was an independent predictor of poor outcomes (=2.808, 95% : 1.487-5.003, =0.001), while mono-allelic mutation and wild-type were not.
CONCLUSION
Patients with mutations have a poor prognosis, and bi-allelic mutations have a worse prognosis compared with mono-allelic mutations and independently affect the prognosis of MDS patients.
Topics: Humans; Myelodysplastic Syndromes; Middle Aged; Prognosis; Retrospective Studies; Tumor Suppressor Protein p53; Mutation; Alleles; Chromosome Aberrations; Male; Female
PubMed: 38926972
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.024 -
Hamostaseologie Jun 2024Atypical sites for thrombosis include deep vein thrombosis (DVT) of the upper extremity (UE-DVT), splanchnic vein thrombosis (SVT), and cerebral venous sinus...
High Prevalence of F2 20210G > A in Splanchnic Vein Thrombosis and Cerebral Venous Sinus Thrombosis: A Retrospective Cohort Study of Patients with Thrombosis in Atypical Sites.
INTRODUCTION
Atypical sites for thrombosis include deep vein thrombosis (DVT) of the upper extremity (UE-DVT), splanchnic vein thrombosis (SVT), and cerebral venous sinus thrombosis (CVST). In addition to specific pathogenic factors, their underlying mechanisms share similarities with typical venous thromboembolism (VTE), namely, DVT of the lower extremity and/or pulmonary embolism, but are less understood.
METHODS
Records of unselected patients with a history of typical VTE ( = 2,011), UE-DVT ( = 117), SVT ( = 83), and CVST ( = 82), who were referred to the Institute in Bonn for ambulatory thrombophilia testing, were retrospectively analyzed. Acquired and hereditary thrombosis risk factors were comparatively assessed.
RESULTS
UE-DVT was characterized by a high rate (50.4%) of site-specific acquired risk factors. Compared with typical VTE, SVT was more frequently associated with systemic inflammation, infection, or malignancy (2.2 vs. 12.0%, = 3·10) and the V617F mutation was present in 16.9%. In CVST compared with typical VTE, demographics and higher rates of oral contraception (43.2 vs. 57.6%, = 0.011) and pregnancy (4.2 vs. 10.9%, = 0.012) suggest a significant hormonal influence on etiology. While the prevalence of inhibitor deficiencies and factor V Leiden mutation did not differ between cohorts, the prevalence of 20210G > A was higher in SVT (15.7%, = 0.003) and CVST (15.9%, = 0.003) than in typical VTE (7.0%).
CONCLUSION
The cohorts with thrombosis in atypical sites showed distinctive patterns of acquired risk factors. Further studies are warranted to provide additional mechanistic insight into the role of hormonal influence in CVST and the contribution of 20210G > A to the development of SVT and CVST.
PubMed: 38925156
DOI: 10.1055/a-2329-1798 -
Protein Science : a Publication of the... Jul 2024Variation in mutation rates at sites in proteins can largely be understood by the constraint that proteins must fold into stable structures. Models that calculate...
Variation in mutation rates at sites in proteins can largely be understood by the constraint that proteins must fold into stable structures. Models that calculate site-specific rates based on protein structure and a thermodynamic stability model have shown a significant but modest ability to predict empirical site-specific rates calculated from sequence. Models that use detailed atomistic models of protein energetics do not outperform simpler approaches using packing density. We demonstrate that a fundamental reason for this is that empirical site-specific rates are the result of the average effect of many different microenvironments in a phylogeny. By analyzing the results of evolutionary dynamics simulations, we show how averaging site-specific rates across many extant protein structures can lead to correct recovery of site-rate prediction. This result is also demonstrated in natural protein sequences and experimental structures. Using predicted structures, we demonstrate that atomistic models can improve upon contact density metrics in predicting site-specific rates from a structure. The results give fundamental insights into the factors governing the distribution of site-specific rates in protein families.
Topics: Proteins; Protein Conformation; Thermodynamics; Evolution, Molecular; Mutation; Models, Molecular; Molecular Dynamics Simulation
PubMed: 38923241
DOI: 10.1002/pro.5086 -
Animal Genetics Aug 2024We recently discovered that the Manech Tête Rousse (MTR) deficient homozygous haplotype 2 (MTRDHH2) probably carries a recessive lethal mutation in sheep. In this...
We recently discovered that the Manech Tête Rousse (MTR) deficient homozygous haplotype 2 (MTRDHH2) probably carries a recessive lethal mutation in sheep. In this study, we fine-mapped this region through whole-genome sequencing of five MTRDHH2 heterozygous carriers and 95 non-carriers from various ovine breeds. We identified a single base pair duplication within the SLC33A1 gene, leading to a frameshift mutation and a premature stop codon (p.Arg246Alafs*3). SLC33A1 encodes a transmembrane transporter of acetyl-coenzyme A that is crucial for cellular metabolism. To investigate the lethality of this mutation in homozygous MTR sheep, we performed at-risk matings using artificial insemination (AI) between heterozygous SLC33A1 variant carriers (SLC33A1_dupG). Pregnancy was confirmed 15 days post-AI using a blood test measuring interferon Tau-stimulated MX1 gene expression. Ultrasonography between 45 and 60 days post-AI revealed a 12% reduction in AI success compared with safe matings, indicating embryonic/fetal loss. This was supported by the MX1 differential expression test suggesting fetal losses between 15 and 60 days of gestation. We also observed a 34.7% pre-weaning mortality rate in 49 lambs born from at-risk matings. Homozygous SLC33A1_dupG lambs accounted for 47% of this mortality, with deaths occurring mostly within the first 5 days without visible clinical signs. Therefore, appropriate management of SLC33A1_dupG with an allele frequency of 0.04 in the MTR selection scheme would help increase overall fertility and lamb survival.
Topics: Animals; Female; Sheep, Domestic; Pregnancy; Gene Duplication; Insemination, Artificial; Homozygote; Frameshift Mutation; Abortion, Veterinary; Haplotypes; Sheep
PubMed: 38922751
DOI: 10.1111/age.13459 -
Cancer Research Communications Jun 2024Evaluate the efficacy of WEE1 inhibitor adavosertib in patients (pts) with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B).
PURPOSE
Evaluate the efficacy of WEE1 inhibitor adavosertib in patients (pts) with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B).
PATIENTS AND METHODS
NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in pts with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was objective response rate (ORR). Correlative assays evaluated loss of H3K36me3 by immunohistochemistry (IHC), a downstream consequence of SETD2 loss, in archival tumor tissue.
RESULTS
Eighteen pts were enrolled (9/cohort). Median age was 60 years (range 45 - 74). The median duration of treatment was 1.28 months (range 0 - 24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable pts. Stable disease (SD) was the best overall response in 10/18 (56%) pts, including three pts with SD >4 months. One pt with ccRCC remains on treatment for >24 months. The most common adverse events (AE) of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine pts (50%) experienced a Grade ≥ 3 AE. Of 8 evaluable archival tissue samples, 6 (75%) had loss of H3K36me3 by IHC.
CONCLUSIONS
Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies though prolonged stable disease was observed in a subset of pts. Combination approaches may yield greater depth of tumor response.
PubMed: 38920407
DOI: 10.1158/2767-9764.CRC-24-0213 -
Scientific Reports Jun 2024Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR... (Comparative Study)
Comparative Study
Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR T790M-positive non-small-cell lung cancer. We evaluated the effectiveness of lazertinib compared with osimertinib using an external control. We obtained individual patient data for the lazertinib arm from the LASER201 trial and the osimertinib arm from registry data at the Samsung Medical Center. In total, 75 and 110 patients were included in the lazertinib and osimertinib groups, respectively. After propensity score matching, each group had 60 patients and all baseline characteristics were balanced. The median follow-up duration was 22.0 and 29.6 months in the lazertinib and osimertinib group, respectively. The objective response rate (ORR) were 76.7% and 86.7% for lazertinib and osimertinib, respectively (p = 0.08). The median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI] 9.5-19.1) and 14.4 months (95% CI 11.8-18.1) for the lazertinib and osimertinib group, respectively (hazard ratio [HR] 0.97; 95% CI 0.64-1.45, p = 0.86). The median overall survival with lazertinib was not reached and that with osimertinib was 29.8 months (HR 0.44; 95% CI 0.25-0.77, p = 0.005). Our study suggests that lazertinib has an ORR and PFS comparable to those of osimertinib and has the potential for superior survival benefits.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Male; Female; Lung Neoplasms; Aged; Middle Aged; Acrylamides; Aniline Compounds; Protein Kinase Inhibitors; Aged, 80 and over; Treatment Outcome; Progression-Free Survival; Mutation; Adult; Pyrimidines; Indoles; Morpholines; Pyrazoles
PubMed: 38918528
DOI: 10.1038/s41598-024-65220-z -
Pediatrics and Neonatology Jun 2024Chronic granulomatous disease (CGD), one of the phagocytic cell defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex in...
BACKGROUND
Chronic granulomatous disease (CGD), one of the phagocytic cell defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex in neutrophils.
METHODS
The clinical, demographic and laboratory findings of 17 CGD patients who were followed-up between 2002 and 2021 were obtained retrospectively from the records of the patients.
RESULTS
The number of male and female patients was 10/7. The median age at diagnosis was 5.3 months (range 4-120) for 3 patients with X-CGD, and 42.4 months (range 8-350) for 14 patients with AR-CGD. We have investigated rare CYBA exon 3-6 deletion in 7 patients and hotspot mutation with delGT at the beginning of exon 2 of NCF1 in 5 patients. The most common clinical findings were pneumonia and lymphadenitis with recurrent fever, respectively (41.2%, 35.3%). A total of 154 microbial infections requiring hospital admission (27 in 3 XL and 127 in 14 AR patients) were detected in the follow-up of the patients and median infection number for a patient was 9 in both groups. Eight of 17 patients had stem cell transplantation and the survival rate was 87.5%.
CONCLUSIONS
X-CGD patients are more rapidly recognized by family history and severe infections than those with AR-CGD and early prophylaxis may decrease infectious episodes. We have investigated the large deletion suggesting a possible founder effect for CYBA exon 3-6 deletion in Central Anatolia. Additionally, HSCT transplantation leads to a high survival rate for the patients with CGD.
PubMed: 38918167
DOI: 10.1016/j.pedneo.2024.02.008 -
PloS One 2024This paper studied an integrated process planning and scheduling problem from a machining workshop for large-size valves in a valve manufacturing plant. Large-size...
This paper studied an integrated process planning and scheduling problem from a machining workshop for large-size valves in a valve manufacturing plant. Large-size valves usually contain several key parts and are generally produced in small-series production. Almost all the parts need to be manufactured in the same workshop at the same time in the plant. Facilities have to handle various items in one order, including different models, sizes, and types. It is a classical NP-hard problem on a large scale. An improved NSGA-II algorithm is suggested to obtain satisfactory solutions for makespan and manufacturing costs, which involve large optimization parameters and interactions. A two-section encoding method and an inserting greedy decoding method are chosen to enable the algorithm. The dynamic population update strategy based on dynamic population update and the adaptive mutation technique depending on the population entropy changing rate are selected for enhancing both the solution quality and population diversity. The methodology was successfully implemented in a real-life case at a major valve machining workshop operated by Yuanda Valve Company in China. By taking into account realistic factors and restrictions that have been identified from a real-world manufacturing setting, this technique aids in bridging the knowledge gap between present IPPS research and practical valve production implementations.
Topics: Algorithms; Humans; China; Manufacturing Industry
PubMed: 38917183
DOI: 10.1371/journal.pone.0306024 -
Rice (New York, N.Y.) Jun 2024Great yield-enhancing prospects of autotetraploid rice was restricted by various polyploidy-induced reproductive dysfunction. To surmount these challenges, our group has...
Great yield-enhancing prospects of autotetraploid rice was restricted by various polyploidy-induced reproductive dysfunction. To surmount these challenges, our group has generated a series of valuable fertile tetraploid lines (denoted as neo-tetraploid rice) through 20-year efforts. With this context, a G-type lectin receptor-like kinase, OsNRFG6, was identified as a pivotal factor associated with reproductive regulation in neo-tetraploid rice. Nevertheless, it is still elusive about a comprehensive understanding of its precise functional roles and underlying molecular mechanisms during reproduction of neo-tetraploid rice. Here, we demonstrated that OsNRFG6 executed a constitutive expression pattern and encoded proteins localizing in perinucleus and endoplasmic reticulum. Subsequently, four independent mutant lines of OsNRFG6 within neo-tetraploid rice background were further identified, all displaying low seed-setting rate due to abortive embryo sacs and defective double fertilization. RNA-seq and RT-qPCR revealed a significant down-regulation of OsNRFG6 and female reproductive genes such as OsMEL1 and LOG in ovaries prior to and post-fertilization, attributing this effect to OsNRFG6 mutation. Furthermore, through yeast-two hybrids, bimolecular fluorescence complementation assays, and luciferase complementation imaging assays, it was determined that OsNRFG6 could interact with itself and two female reproductive proteins (LOG and OsDES1) to form protein complexes. These results elucidate the reproductive functions and molecular pathway governed by OsNRFG6 in regulating fertility of neo-tetraploid rice, offering insights into molecular understanding of fertility improvement in polyploid rice.
PubMed: 38916708
DOI: 10.1186/s12284-024-00720-0