Associations between static and dynamic changes of platelet counts and in-hospital mortality in critical patients with acute heart failure.

To investigate the predictive value of baseline platelet count and its short-term dynamic changes in the prognosis of patients with acute heart failure (AHF) in the intensive care unit. Patients diagnosed with AHF in the medical information mart for intensive care III and their clinical data were retrospectively filtered. Patients were divided into survivor and non-survivor groups based on their prognosis during hospitalization, and differences in baseline data between groups were compared. Logistic regression models and restricted cubic spline (RCS) plots were performed to evaluate the relationship between baseline platelet counts and in-hospital mortality. Changes and trends in platelet counts were compared between the survivor and non-survivor groups after adjusting for confounders with the generalized additive mixing model (GAMM). A total of 2930 critical patients with acute heart failure were included, of which 2720 were survivors and 210 were non-survivors. Multiple logistic regression models revealed that baseline platelet count was an independent factor in hospital mortality (OR 0.997, 95% CI 0.994-0.999, P-value = 0.018). The RCS plot demonstrated a U-shaped dose-response relationship between baseline platelet count and in-hospital mortality. GAMM analysis suggested that the platelet counts decreased and then increased in the survivor group and gradually decreased in the non-survivor group, with a gradual increase of difference between two groups. After adjusting for confounders, the mean daily increase was -6.014 (95% CI -7.076-4.953, P-value < 0.001). Baseline platelet demonstrated a U-shaped dose-response relationship with adverse outcomes in critical patients with AHF. Early elevation of platelet was correlated with higher in-hospital mortality, indicating that tracking early changes in platelet might help determine the short-term prognosis of critical patients with AHF.

Spliceosome component PHD finger 5A is essential for early B lymphopoiesis.

The spliceosome, a multi-megadalton ribonucleoprotein complex, is essential for pre-mRNA splicing in the nucleus and ensuring genomic stability. Its precise and dynamic assembly is pivotal for its function. Spliceosome malfunctions can lead to developmental abnormalities and potentially contribute to tumorigenesis. The specific role of the spliceosome in B cell development is poorly understood. Here, we reveal that the spliceosomal U2 snRNP component PHD finger protein 5A (Phf5a) is vital for early B cell development. Loss of Phf5a results in pronounced defects in B cell development, causing an arrest at the transition from pre-pro-B to early pro-B cell stage in the bone marrow of mutant mice. Phf5a-deficient B cells exhibit impaired immunoglobulin heavy (IgH) chain expression due to defective V-to-DJ gene rearrangement. Mechanistically, our findings suggest that Phf5a facilitates IgH gene rearrangement by regulating the activity of recombination-activating gene endonuclease and influencing chromatin interactions at the Igh locus.

Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

The association of female reproductive factors with risk of metabolic syndrome in women from NHANES 1999-2018.

BACKGROUND: Female reproductive factors such as age at first birth (AFB), age at last birth (ALB), number of pregnancies and live births play an essential role in women's health. However, few epidemiological studies have evaluated the association between female reproductive factors and metabolic syndrome (MetS). We therefore conducted a cross-sectional study to investigate the association between MetS risk and female reproductive factors. METHODS: We investigated the relationship between AFB, ALB, number of pregnancies and live births and the incidence of MetS using publicly available data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Weighted multivariable logistic regression analysis, restricted cubic spline (RCS) model, and subgroup analysis were used to evaluate the association between AFB and ALB and the risk of MetS in women. In addition, the relationship between the number of pregnancies, live births and MetS risk was also explored. RESULTS: A total of 15,404 women were included in the study, and 5,983 (38.8%) had MetS. RCS models showed an N-shaped relationship between AFB and MetS risk, whereas ALB, number of pregnancies, and live births were linearly associated with MetS. Weighted multivariable logistic regression analysis showed that the number of live births was associated with MetS risk, with ORs of 1.18 (95% CI: 1.04, 1.35) for women with ≥ 5 deliveries compared to women with ≤ 2 births. CONCLUSIONS: AFB was associated with the risk of MetS in an N-shaped curve in women. In addition, women with high live births have a higher incidence of MetS.

Development of the thermophilic fungus Myceliophthora thermophila into glucoamylase hyperproduction system via the metabolic engineering using improved AsCas12a variants.

BACKGROUND: Glucoamylase is an important enzyme for starch saccharification in the food and biofuel industries and mainly produced from mesophilic fungi such as Aspergillus and Rhizopus species. Enzymes produced from thermophilic fungi can save the fermentation energy and reduce costs as compared to the fermentation system using mesophiles. Thermophilic fungus Myceliophthora thermophila is industrially deployed fungus to produce enzymes and biobased chemicals from biomass during optimal growth at 45 °C. This study aimed to construct the M. thermophila platform for glucoamylase hyper-production by broadening genomic targeting range of the AsCas12a variants, identifying key candidate genes and strain engineering. RESULTS: In this study, to increase the genome targeting range, we upgraded the CRISPR-Cas12a-mediated technique by engineering two AsCas12a variants carrying the mutations S542R/K607R and S542R/K548V/N552R. Using the engineered AsCas12a variants, we deleted identified key factors involved in the glucoamylase expression and secretion in M. thermophila, including Mtstk-12, Mtap3m, Mtdsc-1 and Mtsah-2. Deletion of four targets led to more than 1.87- and 1.85-fold higher levels of secretion and glucoamylases activity compared to wild-type strain MtWT. Transcript level of the major amylolytic genes showed significantly increased in deletion mutants. The glucoamylase hyper-production strain MtGM12 was generated from our previously strain MtYM6 via genetically engineering these targets Mtstk-12, Mtap3m, Mtdsc-1 and Mtsah-2 and overexpressing Mtamy1 and Mtpga3. Total secreted protein and activities of amylolytic enzymes in the MtGM12 were about 35.6-fold and 51.9‒55.5-fold higher than in MtWT. Transcriptional profiling analyses revealed that the amylolytic gene expression levels were significantly up-regulated in the MtGM12 than in MtWT. More interestingly, the MtGM12 showed predominantly short and highly bulging hyphae with proliferation of rough ER and abundant mitochondria, secretion vesicles and vacuoles when culturing on starch. CONCLUSIONS: Our results showed that these AsCas12a variants worked well for gene deletions in M. thermophila. We successfully constructed the glucoamylase hyper-production strain of M. thermophila by the rational redesigning and engineering the transcriptional regulatory and secretion pathway. This targeted engineering strategy will be very helpful to improve industrial fungal strains and promote the morphology engineering for enhanced enzyme production.

Association of Serum Uric Acid Level with Risk of Abdominal Aortic Calcification: A Large Cross-Sectional Study.

Objective: The association between serum uric acid (sUA) and incident abdominal aortic calcification (AAC), and severe abdominal aortic calcification (SAAC) in the general population of the United States (US) is unclear. Therefore, this research aimed to investigate the association between sUA and the risk of AAC and SAAC. Methods: Individuals from National Health and Nutrition Examination Survey (NHANES) database were analyzed cross-sectionally between 2013 and 2014. The restricted cubic spline (RCS), multivariable logistic regression model and subgroup analysis were utilized to evaluate the correlation between sUA and incident AAC, and SAAC. In addition, generalized additive models with smooth functions were employed to survey the relationship between sUA and the degree of AAC. Results: This study included 3016 individuals from the NHANES database. According to the RCS plot, sUA levels were associated with the risk of AAC/SAAC in a U-shaped pattern in the US population. The degree of calcification decreased at first and then increased with the increase in the sUA level. Conclusion: Close monitoring and adequate control of sUA levels in the US general population may reduce the risk of AAC and SAAC.

The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation.

Naïve B cells become activated and differentiate into antibody-secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain-containing adapter protein with coiled-coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell-specific Wac knockout mice have severely compromised T cell-dependent and -independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell response in the mutant mice. We also observe a significant reduction in global ubH2B in Wac-deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac-mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process.

The effects of cardiometabolic factors on the association between serum uric acid and risk of all-cause mortality in adults with congestive heart failure.

BACKGROUND: Serum uric acid (SUA) has been shown to increase all-cause mortality from cardiovascular disease. However, limited studies have examined the mediating effect of dyslipidemia, hyperglycemia, or hypertension on the association between SUA and all-cause mortality in patients with congestive heart failure (CHF). METHODS: Participants in the present investigation were 620 US adults with CHF from the NHANES database (1999-2014). The relationship between SUA and all-cause mortality was evaluated utilizing multivariable Cox proportional hazards models. Additionally, the nonlinearity between SUA and mortality was investigated utilizing Restricted Cubic Splines (RCS) and 2-piecewise Cox proportional hazards models. Finally, the mediating role of cardiometabolic factors on the relationship between SUA and all-cause mortality was investigated utilizing the mediation analysis. RESULTS: During a mean follow-up of 7.6 years, 391 (63.1%) all-cause deaths occurred. Furthermore, we found a U-shaped association between SUA and all-cause mortality. The inflection point for the RCS curve was found at a SUA level of 363 umol/L. The hazard ratios (95% confidence intervals) for all-cause mortality were 0.998 (0.995-1.000) and 1.003 (1.002-1.005) to the left and right of the inflection point, respectively. This U-shaped association was also observed in both subgroups of sex and age. Moreover, the effect of SUA on all-cause mortality was not mediated by hypertension, hyperglycemia, or dyslipidemia (all P-values>0.05). CONCLUSION: The association between SUA level and all-cause mortality followed a U-shaped curve, and this association was not mediated by hypertension, hyperglycemia, or dyslipidemia.

The RNA-binding protein hnRNP F is required for the germinal center B cell response.

The T cell-dependent (TD) antibody response involves the generation of high affinity, immunoglobulin heavy chain class-switched antibodies that are generated through germinal center (GC) response. This process is controlled by coordinated transcriptional and post-transcriptional gene regulatory mechanisms. RNA-binding proteins (RBPs) have emerged as critical players in post-transcriptional gene regulation. Here we demonstrate that B cell-specific deletion of RBP hnRNP F leads to diminished production of class-switched antibodies with high affinities in response to a TD antigen challenge. B cells deficient in hnRNP F are characterized by defective proliferation and c-Myc upregulation upon antigenic stimulation. Mechanistically, hnRNP F directly binds to the G-tracts of Cd40 pre-mRNA to promote the inclusion of Cd40 exon 6 that encodes its transmembrane domain, thus enabling appropriate CD40 cell surface expression. Furthermore, we find that hnRNP A1 and A2B1 can bind to the same region of Cd40 pre-mRNA but suppress exon 6 inclusion, suggesting that these hnRNPs and hnRNP F might antagonize each-other's effects on Cd40 splicing. In summary, our study uncovers an important posttranscriptional mechanism regulating the GC response.

Cardiovascular disease preventive effects of aspirin combined with different statins in the United States general population.

The purpose of this study was to explore the use of aspirin in conjunction with various statins for cardiovascular disease (CVD) prevention in the general population of the United States (U.S.). A total of 3778 people from the National Health and Nutrition Examination Surveys from 2011 to 2018 were included in our analysis. After adjusting for sociodemographic and common cardiovascular risk factors, we used multivariable logistic regression analysis to determine aspirin should be combined with which type of statin for better CVD preventive effects. Subgroup analyses were carried out subsequently. In comparison to the aspirin use alone, the odds ratios with 95% confidence intervals for CVD were 0.43 (0.33, 0.57), 0.69 (0.42, 1.13), 0.44 (0.31, 0.62), 0.34 (0.23, 0.50) and 0.64 (0.49, 0.84) for the combination use of aspirin and atorvastatin, lovastatin, pravastatin, rosuvastatin as well as simvastatin, respectively, in the fully-adjusted model. Aspirin combined with rosuvastatin was more effective in the prevention of individual CVD, including congestive heart failure, coronary heart disease, angina pectoris and heart attack, than aspirin combined with other statins. In conclusion, statins combined with aspirin have a clear advantage over aspirin alone in preventing CVD. In addition, when various sex, age, and fitness levels were considered, as well as with and without diabetes mellitus, the combination usage of aspirin and rosuvastatin had the greatest CVD preventive effects than aspirin coupled with other statins.

Association between Serum 25-Hydroxyvitamin D and Abdominal Aortic Calcification: A Large Cross-Sectional Study.

In the American population, the relationship between the standardized serum 25-hydroxyvitamin D (25(OH)D) concentration and the risk of abdominal aortic calcification (AAC) is unclear. The purpose of our study was to investigate the relationship between serum 25(OH)D concentration and AAC risk. Participants from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014 were analyzed cross sectionally. An analysis of the relationship between serum 25(OH)D concentration and incident AAC and severe AAC (SAAC) was based on the restricted cubic spline (RCS) and multivariable logistic regression model. In addition, generalized additive models with smooth functions were used to evaluate the relationship between serum 25(OH)D concentration and the degree of AAC. Finally, a subgroup analysis was conducted. There were a total of 3,040 individuals in our study. The serum 25(OH)D concentration was divided into quartiles (Q1: 9.37-50.5 nmol/L; Q2: 50.6-67.2 nmol/L; Q3: 67.3-85.8 nmol/L; and Q4: 85.9-318.0 nmol/L); the lowest quartile served as the reference group (Q1). After adjusting for known confounding variables, compared with the lowest quartile (Q1) of serum 25(OH)D concentration, the odds ratios with 95% confidence intervals for AAC and SAAC across the quartiles (Q2, Q3, and Q4) were (1.042 (0.812, 1.338), 0.863 (0.668, 1.115), and 1.022 (0.787, 1.327)) and (1.48 (0.87, 2.52), 1.70 (1.01, 2.92), and 2.13 (1.19, 3.86)), respectively. As shown by the RCS plot, the serum 25(OH)D concentration was associated with the risk of AAC/SAAC in a U-shaped pattern (P for nonlinearity <0.05). In addition, the degree of AAC decreased at first and then increased as the serum 25(OH)D concentration increased. In conclusion, a U-shaped relationship existed between serum 25(OH)D concentration and the risk of AAC and SAAC. Consequently, the risk of AAC and SAAC may be mitigated with regular monitoring and vitamin D supplementation.

Critical roles of non-coding RNAs in lifecycle and biology of Marek's disease herpesvirus.

Over the past two decades, numerous non-coding RNAs (ncRNAs) have been identified in different biological systems including virology, especially in large DNA viruses such as herpesviruses. As a representative oncogenic alphaherpesvirus, Marek's disease virus (MDV) causes an important immunosuppressive and rapid-onset neoplastic disease of poultry, namely Marek's disease (MD). Vaccinations can efficiently prevent the onset of MD lymphomas and other clinical disease, often heralded as the first successful example of vaccination-based control of cancer. MDV infection is also an excellent model for research into virally-induced tumorigenesis. Recently, great progress has been made in understanding the functions of ncRNAs in MD biology. Herein, we give a review of the discovery and identification of MDV-encoded viral miRNAs, focusing on the genomics, expression profiles, and emerging critical roles of MDV-1 miRNAs as oncogenic miRNAs (oncomiRs) or tumor suppressor genes involved in the induction of MD lymphomas. We also described the involvements of host cellular miRNAs, lincRNAs, and circRNAs participating in MDV life cycle, pathogenesis, and/or tumorigenesis. The prospects, strategies, and new techniques such as the CRISPR/Cas9-based gene editing applicable for further investigation into the ncRNA-mediated regulatory mechanisms in MDV pathogenesis/oncogenesis were also discussed, together with the possibilities of future studies on antiviral therapy and the development of new efficient MD vaccines.

Correlation analysis between the static and the changed neutrophil-to-lymphocyte ratio and in-hospital mortality in critical patients with acute heart failure.

OBJECTIVE: Association between neutrophil-to-lymphocyte ratio (NLR) on admission and poor prognosis in patients with acute heart failure (AHF) has been well established. However, the relationship between dynamic changes in NLR and in-hospital mortality in AHF patients has not been studied. Our purpose was to determine if an early change in NLR within the first week after AHF patients was admitted to intensive care unit (ICU) was associated with in-hospital mortality. METHODS: Data from the medical information mart for intensive care IV (the MIMIC-IV) database was analyzed. The effect of baseline NLR on in-hospital mortality in critical patients with AHF was evaluated utilizing smooth curve fitting and multivariable logistic regression analysis. Moreover, comparison of the dynamic change in NLR among survivors and non-survivors was performed using the generalized additive mixed model (GAMM). RESULTS: There were 1169 participants who took part in the present study, 986 of whom were in-hospital survivors and 183 of whom were in-hospital non-survivors. The smooth curve fitting revealed a positive relationship between baseline NLR and in-hospital mortality, and multivariable logistic regression analysis indicated that baseline NLR was an independent risk factor for in-hospital mortality (OR 1.04, 95% CI 1.02,1.07, P-value = 0.001). After adjusting for confounders, GAMM showed that the difference in NLR between survivors and non-survivors grew gradually during the first week after ICU admission, and the difference grew by an average of 0.51 per day (ß = 0.51, 95% CI 0.45-0.56, P-value <0.001). CONCLUSIONS: Baseline NLR was associated with poor prognosis in critical patients with AHF. Early rises in NLR were linked to higher in-hospital mortality, which suggests that keeping track of how NLR early changes might help identify short-term prognosis of critical patients with AHF.

The endocytosis of foot-and mouth disease virus requires clathrin and caveolin and is dependent on the existence of Rab5 and Rab7 in CHO-677 cells.

Foot-and-mouth disease virus (FMDV) is a highly contagious virus that causes severe vesicular disease of cloven-hoofed animals. Various endocytosis mechanisms are involved in the entry of FMDV after binding to the integrin and heparan sulfate (HS) receptors. However, the mechanism of FMDV using other unknown receptors to enter the cells remains unclear. Here, we reported that the endocytosis and endosomal pathways are employed by FMDV to invade the Chinese hamster ovary cell line (CHO-677) without the integrin and HS receptors. We demonstrated that the internalization of FMDV into CHO-677 cells was abrogated by chlorpromazine, an inhibitor of clathrin-mediated endocytosis. Knockdown of the clathrin heavy chain decreased the viral protein abundance. Incubation of the CHO-677 cells with the inhibitors of caveolae-mediated endocytosis or transfection by caveolin-1 siRNA also limited FMDV replication. In addition, we determined that the acidic environment and the existence of dynamin were essential for FMDV infection in CHO-677 cells. The endosomal proteins Rab5 (early endosome) and Rab7 (late endosome), but not Rab11 (recycling endosome), were utilized by FMDV during infection. These data provide a new entry model of FMDV by unknown receptors which will help to better understand the pathogenesis mediated by FMDV.

MtTRC-1, a Novel Transcription Factor, Regulates Cellulase Production via Directly Modulating the Genes Expression of the Mthac-1 and Mtcbh-1 in Myceliophthora thermophila.

The thermophilic fungus Myceliophthora thermophila has been used to produce industrial enzymes and biobased chemicals. In saprotrophic fungi, the mechanisms regulating cellulase production have been studied, which revealed the involvement of multiple transcription factors. However, in M. thermophila, the transcription factors influencing cellulase gene expression and secretion remain largely unknown. In this study, we identified and characterized a novel cellulase regulator (MtTRC-1) in M. thermophila through a combination of functional genomics and genetic analyses. Deletion of Mttrc-1 resulted in significantly decreased cellulase production and activities. Transcriptome analysis revealed downregulation of not only the encoding genes of main cellulases but also the transcriptional regulator MtHAC-1 of UPR pathway after disruption of MtTRC-1 under cellulolytic induction conditions. Herein, we also characterized the ortholog of the yeast HAC1p in M. thermophila. We show that Mthac-1 mRNA undergoes an endoplasmic reticulum (ER) stress-induced splicing by removing a 23-nucleotide (nt) intron. Notably, the protein secretion on cellulose was dramatically impaired by the deletion of MtHAC-1. Moreover, the colonial growth on various carbon sources was defective in the absence of MtHAC-1. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays verified MtTRC-1 regulates the transcription of Mthac-1 and the major cellulase gene Mtcbh-1 by binding directly to the promoters in vitro and in vivo. Furthermore, DNase I footprinting assays identified the putative consensus binding site (5'-GNG/C-3'). These results revealed the importance of MtTRC-1 for positively regulating cellulase production. This finding has clarified the complex regulatory pathways involved in cellulolytic enzyme production. IMPORTANCE In the present study, we characterized a novel regulator MtTRC-1 in M. thermophila, which regulated cellulase production through direct transcriptional regulation of the Mthac-1 and Mtcbh-1 genes. Our data demonstrated that MtHAC-1 is a key factor for the cellulase secretion capacity of M. thermophila. Our data indicate that this thermophilic fungus regulates cellulase production through a multilevels network, in which the protein secretory pathway is modulated by MtHAC-1-dependent UPR pathway and the cellulase gene expression is directly regulated in parallel by transcription factors. The conservation of Mttrc1 in filamentous fungi suggests this mechanism may be exploited to engineer filamentous fungal cell factories capable of producing proteins on an industrial scale.

Cryptotanshinone alleviates myocardial ischemia and reperfusion injury in rats to mitigate ER stress-dependent apoptosis by modulating the JAK1/STAT3 axis.

OBJECTIVE: Myocardial ischemia is the stoppage or insufficiency of blood flow to the myocardium, depriving cells of oxygen supply which leads to their apoptosis or death. Currently, the management of patients has improved, making it possible to reduce myocardial infarction injury with new strategies of reperfusion and pharmacologic treatment. METHODS: A rat model of myocardial ischemia and reperfusion injury (MIRI) was created and subjected to cryptotanshinone (CRY) with or without JAK1 inhibitor filgotinib (FILGO) treatment. H&E staining was used for histopathologic evaluation of heart injury, and TTC staining was employed for evaluation of the infarct size. Western blotting and immunofluorescence were used to measure the protein expression and qRT-PCR for determining mRNA expression. RESULTS: CRY significantly reduced the area of the infarct, the number of apoptotic cells, and the concentrations of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) induced by ischemia/reperfusion (I/R). Subsequent analysis showed that CRY repressed the expression of caspase-12, CHOP, and GRP78, but enhanced the phosphorylation of JAK and STAT3. However, FILGO treatment markedly abolished the beneficial effect of CRY pretreatment on cardiomyocyte damage, apoptosis, cardiac function, and inhibition of endoplasmic reticulum stress (ERS)-dependent apoptosis marker proteins. CONCLUSION: CRY may alleviate MIRI by inhibiting ERS-dependent apoptosis by activating the JAK1/STAT3 signaling pathway.

Pathogenicity and Pathotype Analysis of Henan Isolates of Marek's Disease Virus Reveal Long-Term Circulation of Highly Virulent MDV Variant in China.

In recent years, outbreaks of Marek's disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek's disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the HN302 strain induced 100% MD incidence, 54.84% mortality, and 87.10% tumor incidence, together with extensive atrophy of immune organs. Pathotyping of HN302 was performed in comparison to a standard very virulent (vv) MDV strain Md5. We found that both CVI988 and HVT vaccines significantly reduced morbidity and mortality induced by HN302 or Md5 strains, but the protection indices (PIs) provided by these two vaccines against HN302 were significantly lower (27.03%) or lower (33.33%) than that against Md5, which showed PIs of 59.89% and 54.29%, respectively. These data suggested that HN302 possesses a significant higher virulence than Md5 and at least could be designated as a vvMDV strain. Together with our previous phylogenetic analysis on MDV-1 meq genes, we have presently suggested HN302 to be a typical highly virulent MDV variant belonging to an independent Chinese branch. To our knowledge, this is the first report to provide convincible evidence to identify a pathogenic MDV variant strain with a higher virulence than Md5 in China, which may have emerged and circulating in poultry farms in China for a long time and involved in the recent MD outbreaks.

Evaluating the influence of 6MV and 10MV photon beams on cervical cancer volumetric-modulated arc therapy plans.

BACKGROUND: Cervical cancer is a common gynecological cancer among women worldwide. OBJECTIVE: To determine the effects of 6 MV and 10 MV volumetric-modulated arc therapy (VMAT) photon beams on the target volume (TV) planning and critical organs in cases of cervical cancer. METHODS: Fifty patients with carcinoma of the cervix who underwent radiotherapy were selected. The transverse diameter (T) of the cross section of the upper edge of the sacroiliac joint on computerized tomography (CT) images of the patients was measured, and the mean value was calculated as 34 cm. All patients were divided into two groups: Group A (T < 34 cm) and Group B (T > 34 cm). The VMAT plans were generated using 6 MV and 10 MV plans separately. The prescription dose was 47.5 Gy, and the daily dose was 1.9 Gy. RESULTS: In Group A, the planning target volume (PTV) dose assessment parameters of 6 MV and 10 MV plans and their homogeneity and conformity indices were not statistically significantly different. A significant difference was observed between the 6 MV and 10 MV plans for the PTV dose assessment parameters and the homogeneity index of the plans for Group B. The monitor units (MUs) of the 10 MV plans were lower than in the 6 MV plans in both Groups A and B, and the difference was statistically significant. The assessment parameter V40 Gy of both the rectum and bladder in the 6 MV plans was smaller than the corresponding parameter in the 10 MV plans in Group A; in Group B, the assessment parameter V50 Gy of the rectum in the 10 MV plans was smaller than in the 6 MV plans. CONCLUSION: When T < 34 cm, 6 MV energy is more suitable for the external irradiation of cervical cancer. When T > 34 cm, 10 MV energy is more suitable for cervical cancer radiotherapy. Therefore, 10 MV should be considered for patients with a large abdominal size.

Dosimetric analysis of postoperative radiotherapy for thymoma.

PURPOSE: To compare the dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) in the treatment of male and female thymoma. MATERIAL AND METHODS: This single-institutional analysis included 20 patients with thymoma treated with RT between January 2017 and December 2020. Twenty patients were retrospectively planned for IMRT (IMRT1 with an average field angle of 216°, 288°, 0°, 72°,and 144°; IMRT2 with fan-shaped field angles of 280°, 320°, 0°, 40°, and 80°) and VMAT (VMAT1 with two arcs ranging form 280° to 80°,clockwise and then counterclockwise; VMAT2 with two 360° arcs). The plans for all investigated RT modalities were optimized for a prescriptional dose of 50Gy and fractional dose of 2.0Gy. Planning target volume (PTV) and organs-at-risk (OARs: heart, breasts, lungs, spinal cord, and esophagus) dosimetric parameters were compared. RESULTS: All plans met the preparation aims for all the included metrics. There was little difference in the median values of PTV parameters (D2%, D98%, Dmean, homogeneity index[HI], and conformity index [CI]). The CI of the VMAT2 plan was the closest to 1 in both therapy groups. The monitor unit (MU) of IMRT2 and the estimated total delivery time of VMAT1 were the lowest in both therapy groups and were statistically significant. In the male group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) for VMAT1 were the lowest and showed statistical significance. In the female group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) and bilateral breast parameters (Dmean, V5Gy, V10Gy, and V20Gy) of IMRT2 were the lowest and showed statistical significance. CONCLUSIONS: In male thymoma patients undergoing postoperative RT (PORT) treatment, the choice of fan-shaped VMAT may be a better option for protecting the lungs. For female thymoma patients receiving PORT, fan-shaped IMRT can better protect the lungs and breasts. The fan-shaped field performed better than the average and the full arc fields in PORT for thymoma.

Development and validation of ferroptosis-related lncRNAs signature for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) with high heterogeneity is one of the most frequent malignant tumors throughout the world. However, there is no research to establish a ferroptosis-related lncRNAs (FRlncRNAs) signature for the patients with HCC. Therefore, this study was designed to establish a novel FRlncRNAs signature to predict the survival of patients with HCC. METHOD: The expression profiles of lncRNAs were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. FRlncRNAs co-expressed with ferroptosis-related genes were utilized to establish a signature. Cox regression was used to construct a novel three FRlncRNAs signature in the TCGA cohort, which was verified in the GEO validation cohort. RESULTS: Three differently expressed FRlncRNAs significantly associated with prognosis of HCC were identified, which composed a novel FRlncRNAs signature. According to the FRlncRNAs signature, the patients with HCC could be divided into low- and high-risk groups. Patients with HCC in the high-risk group displayed shorter overall survival (OS) contrasted with those in the low-risk group (P < 0.001 in TCGA cohort and P = 0.045 in GEO cohort). This signature could serve as a significantly independent predictor in Cox regression (multivariate HR > 1, P < 0.001), which was verified to a certain extent in the GEO cohort (univariate HR > 1, P < 0.05). Meanwhile, it was also a useful tool in predicting survival among each stratum of gender, age, grade, stage, and etiology,etc. This signature was connected with immune cell infiltration (i.e., Macrophage, Myeloid dendritic cell, and Neutrophil cell, etc.) and immune checkpoint blockade targets (PD-1, CTLA-4, and TIM-3). CONCLUSION: The three FRlncRNAs might be potential therapeutic targets for patients, and their signature could be utilized for prognostic prediction in HCC.