Identification of novel variants in BRF1 gene from patient with developmental delay, hearing abnormality, and nervous system anomalies.

Cerebellofaciodental syndrome characterized with dysmorphic features, intellectual disability, and brain anomalies. Now its clinical spectrum expanded more manifestations including bilateral sensorineural hearing impairment and inner ear malformation. Here, we report a 14-month-old boy with global developmental delay and hearing disorder. Whole exome sequencing (WES) revealed the compound heterozygous variants [NM_001519.4: c.652 T > G (p.W218G); c.915 + 1G > T] in the BRF1 gene which inherited from his parents, respectively. The MRI results showed hypoplastic cerebellar vermis, enlarged cisterna magna, and prominent fourth ventricle, the rehabilitation therapy failed to improve the symptoms for our patient. Our finding expands the genetic spectrum of BRF1 variants, which indicates patients with the developmental delay caused by BRF1 variants require other treatments instead of rehabilitation.

Germline variants in acquired aplastic anemia: current knowledge and future perspectives.

Aplastic anemia (AA) is a disease characterized by hematopoiesis failure, bone marrow aplasia, and pancytopenia. It can be inherited or acquired. Although acquired AA is believed to be immune-mediated and random, new evidence suggests an underlying genetic predisposition. Besides confirmed genomic mutations that contribute to inherited AA (such as pathogenic mutations of TERT and TERC), germline variants, often in heterozygous states, also play an unignorable role in the onset and progression of acquired AA. These variants, associated with inherited bone marrow failure syndromes (IBMFS) and inborn errors of immunity (IEI), contribute to the disease possibly through mechanisms including gene homeostasis, DNA repair, and immune injury. This article explores the nuanced association between acquired AA and germline variants, detailed the clinical significance of germline variants in diagnosing and clinical management of this condition. More works are encouraged to better understand the role of immunogenic pathogenic variants and whether somatic mutation participate as secondary "hit" in the development of bone marrow failure.

Recent advances in hematopoietic cell kinase in cancer progression: Mechanisms and inhibitors.

Hematopoietic cell kinase (Hck), a non-receptor tyrosine kinase belonging to the Src kinase family, is intricately linked to the pathogenesis of numerous human diseases, with a particularly pronounced association with cancer. Hck not only directly impacts the proliferation, migration, and apoptosis of cancer cells but also interacts with JAK/STAT, MEK/ERK, PI3K/AKT, CXCL12/CXCR4, and other pathways. Hck also influences the tumor microenvironment to facilitate the onset and progression of cancer. This paper delves into the functional role and regulatory mechanisms of Hck in various solid tumors. Additionally, it explores the implications of Hck in hematological malignancies. The review culminates with a summary of the current research status of Hck inhibitors, the majority of which are in the pre-clinical phase of investigation. Notably, these inhibitors are predominantly utilized in the therapeutic management of leukemia, with their combinatorial potential indicating promising avenues for future research. In conclusion, this review underscores the significance of the mechanism of Hck in solid tumors. This insight is crucial for comprehending the current research trends regarding Hck: targeted therapy against Hck shows great promise in both diagnosis and treatment of malignant tumors. Further investigation into the role of Hck in cancer, coupled with the development of specific inhibitors, has the potential to revolutionize approaches to cancer treatment.

Assessing radiation-induced carotid artery injury using ultrasound in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Radiotherapy (RT) can damage neck vessels in patients with head and neck cancer (HNC). This study investigated the early effects of RT on carotid artery, including the internal media thickness (IMT) and carotid plaques of the common carotid artery (CCA). MATERIALS AND METHODS: This study included 69 patients with HNC who underwent RT at the First Hospital of Jilin University from March 2017 to September 2022, and 69 healthy participants as controls. Color Doppler ultrasound (CDUS) of the carotid artery was used to measure the CCA IMT and plaques. RESULTS: Left CCA IMT increased from 0.60 mm (0.60, 0.70) before RT to 0.70 mm (0.60, 1.20) after RT (P < 0.0001). Right CCA IMT changed from 0.60 mm (0.60, 0.71) before RT to 0.60 mm (0.60, 1.10) after RT (P = 0.0002). CCA IMT was 0.60 mm (0.60, 0.70) and 0.80 mm (0.60, 1.20) in the ≤40 Gy and >40 Gy groups (P = 0.0004). The CCA plaques number increased significantly after RT on both the left and right sides (Pleft < 0.0001; Pright <0.0001). The CCA plaques volume increased from 0 mm3 (0, 11.35) and 0 mm3 (0, 8.55) before RT to 8.8 mm3 (0, 21.5) and 5.8 mm3 (0, 16.1) on the left and right sides. Correlation analysis revealed a correlation between CCA IMT and age (r = 0.283, P = 0.001), smoking status (r = 0.179, P = 0.020), and radiation dose (r = 0.188, P = 0.028). CONCLUSION: RT significantly increased CCA IMT, and the growth was related to the radiation dose. The number and volume of the CCA plaques also increased after RT.

Effects of warming on rice production and metabolism process associated with greenhouse gas emissions.

Evaluating the impact of global warming on rice production and greenhouse gas (GHG) emissions is critical for ensuring food security and mitigating the consequences of climate change. Nonetheless, the impacts of warming on crop production, GHG emissions, and microbial mechanisms in the single-cropping rice systems remain unclear. Here, a two-year field experiment was conducted to explore the effects of warming (increased by 2.7-3.0 °C on average) in the rice growing season on crop production and functional microorganisms associated with GHG emissions. Results showed that warming resulted in significant reduction (p < 0.01) in the aboveground biomass and grain yield as well as in grain weight, the number of spikelets per panicle, and the seed-setting rate. However, it caused a significant increase (p < 0.01) in the number of panicles by 15.6 % and 34.9 %, respectively. Furthermore, warming significantly increased (p < 0.01) seasonal methane (CH4) emissions but reduced nitrous oxide (N2O) emissions, particularly in 2022.The relative abundance of genes associated with CH4 metabolism and nitrogen metabolism was increased by 40.7 % and 32.7 %, respectively, in response to warming. Moreover, warming had a positive impact on the abundance of genes related to CH4 production and oxidation processes but did not affect the denitrification processes associated with N2O production. These results showed that warming decreased rice yield and biomass in the single cropping rice system but increased CH4 emissions and global warming potential. Taken together, to address the increasing food demand of a growing population and mitigate the impacts of global warming, it is imperative to duce GHG emissions and enhance crop yields.

Successful Treatment of an AML Patient Infected with Hypervirulent ST463 Pseudomonas Aeruginosa Harboring Rare Carbapenem-Resistant Genes blaAFM-1 and blaKPC-2 Following Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Carbapenem-resistant P. aeruginosa (CRPA) is a common hospital-acquired bacterium. It exhibits high resistance to many antibiotics, including ceftazidime/avibactam and cefteolozane/tazobactam. The presence of carbapenem-resistant genes and co-existence Klebsiella pneumoniae carbapenemase (KPC) and metallo-ß-lactamases (MBLs) further inactivated all ß-lactams. Understanding the resistance genes of CRPA can help in uncovering the resistance mechanism and guiding anti-infective treatment. Herein, we reported a case of perianal infection with hypervirulent ST463 Pseudomonas aeruginosa. Case Presentation: The case is a 32-year-old acute myeloid leukemia (AML) patient with fever and septic shock during hematopoietic stem cell transplantation (HSCT), and the pathogen was finally identified as a highly virulent sequence type 463 (ST463) P. aeruginosa harboring carbapenem-resistant genes blaAFM-1 and blaKPC-2, which was detected in the bloodstream and originated from a perianal infection. The strain was resistant to ceftazidime/avibactam but successfully treated with polymyxin B, surgical debridement, and granulocyte engraftment after HSCT. The AML was cured during the 19-month follow-up. Conclusion: This case emphasizes the importance of metagenomic next-generation sequencing (mNGS) and whole-genome sequencing (WGS) in identifying microbes with rare resistant genes, and managing CRPA, especially in immunocompromised patients. Polymyxin B may be the least resistant option.

Rabeprazole mitigates obesity-induced chronic inflammation and insulin resistance associated with increased M2-type macrophage polarization.

Macrophage polarization is closely associated with obesity-induced chronic inflammation and insulin resistance. Proton pump inhibitor Rabeprazole has long been used to treat gastritis and gastric ulcers. However, whether Rabeprazole plays a role in macrophage polarization during obesity is unknown. Here, we show that Rabeprazole suppresses M1-type macrophage-mediated inflammation, leads to increased M2-type macrophages and alters the polarization status from M1 to M2 in vitro. Mechanistically, Rabe-regulated macrophage polarization is associated with inhibition of NF-κB and activation of STAT6 signaling pathways. Furthermore, Rabeprazole induces M2-type adipose tissue macrophages and alleviates chronic inflammation, improving glucose tolerance and insulin sensitivity in high-fat diet-fed mice. In addition, Rabeprazole increases CD206+ M2-type liver macrophages and relieves liver inflammation, alleviating liver injury and lipid accumulation. Thus, our findings show that Rabeprazole effectively regulates macrophage polarization and controls obesity-associated chronic inflammation and insulin resistance, thus providing a potential therapeutic strategy against obesity-associated metabolic diseases.

Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Metabolism of asparagine in the physiological state and cancer.

Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses.

Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered. Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53fl/flLSL-KrasG12D, Ccr7-/-, Cd93-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed. Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93. Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.

Hemoglobin levels and clinical outcomes after extracorporeal circulation auxiliary to open heart surgery: a retrospective cohort study.

BACKGROUND: Extracorporeal circulation auxiliary to open heart surgery is a common procedure used to treat heart diseases. However, the optimal transfusion strategy for patients undergoing this surgery remains a subject of debate. This study aims to investigate the association between hemoglobin levels and clinical outcomes in patients undergoing extracorporeal circulation auxiliary to open heart surgery, with the ultimate goal of improving surgical success rates and enhancing patients' quality of life. METHODS: A retrospective analysis was conducted on data from the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database, including 4144 patients. The patients were categorized into five groups based on their minimum hemoglobin levels during hospitalization. Baseline characteristics, clinical scores, laboratory results, and clinical outcome data were collected. Statistical analyses utilized descriptive statistics, ANOVA or Kruskal-Wallis tests, Kaplan-Meier method, and Log-rank test. RESULTS: The results revealed a significant correlation between hemoglobin levels and in-hospital mortality, as well as mortality rates at 30 days, 60 days, and 180 days (p < 0.001). Patients with lower hemoglobin levels exhibited higher mortality rates. However, once hemoglobin levels exceeded 7g/dL, no significant difference in mortality rates was observed (p = 0.557). Additionally, lower hemoglobin levels were associated with prolonged hospital stay, ICU admission time, and mechanical ventilation time (p < 0.001). Furthermore, hemoglobin levels were significantly correlated with complication risk, norepinephrine dosage, and red blood cell transfusion volume (p < 0.001). However, there was no significant difference among the groups in terms of major complications, specifically sepsis (p > 0.05). CONCLUSION: The study highlights the importance of managing hemoglobin levels in patients undergoing heart surgery with extracorporeal circulation. Hemoglobin levels can serve as valuable indicators for predicting clinical outcomes and guiding treatment decisions. Physicians should carefully consider hemoglobin levels to optimize transfusion strategies and improve postoperative patient outcomes. Further research and intervention studies are warranted to validate and implement these findings in clinical practice.

Stimulus-responsive proteins involved in multi-process regulation of storage substance accumulation during rice grain filling under elevated temperature.

BACKGROUND: The intensified global warming during grain filling deteriorated rice quality, in particular increasing the frequency of chalky grains which markedly impact market value. The formation of rice quality is a complex process influenced by multiple genes, proteins and physiological metabolic processes. Proteins responsive to stimulus can adjust the ability of plants to respond to unfavorable environments, which may be an important protein involved in the regulation of quality formation under elevated temperature. However, relatively few studies have hindered our further understanding of rice quality formation under elevated temperature. RESULTS: We conducted the actual field elevated temperature experiment and performed proteomic analysis of rice grains at the early stage of grain filling. Starting with the response to stimulus in GO annotation, 22 key proteins responsive to stimulus were identified in the regulation of grain filling and response to elevated temperature. Among the proteins responsive to stimulus, during grain filling, an increased abundance of signal transduction and other stress response proteins, a decreased abundance of reactive oxygen species-related proteins, and an increased accumulation of storage substance metabolism proteins consistently contributed to grain filling. However, the abundance of probable indole-3-acetic acid-amido synthetase GH3.4, probable indole-3-acetic acid-amido synthetase GH3.8 and CBL-interacting protein kinase 9 belonged to signal transduction were inhibited under elevated temperature. In the reactive oxygen species-related protein, elevated temperature increased the accumulation of cationic peroxidase SPC4 and persulfide dioxygenase ETHE1 homolog to maintain normal physiological homeostasis. The increased abundance of alpha-amylase isozyme 3E and seed allergy protein RA5 was related to the storage substance metabolism, which regulated starch and protein accumulation under elevated temperature. CONCLUSION: Auxin synthesis and calcium signal associated with signal transduction, other stress responses, protein transport and modification, and reactive oxygen species-related proteins may be key proteins responsive to stimulus in response to elevated temperature. Alpha-amylase isozyme 3E and seed allergy protein RA5 may be the key proteins to regulate grain storage substance accumulation and further influence quality under elevated temperature. This study enriched the regulatory factors involved in the response to elevated temperature and provided a new idea for a better understanding of grain response to temperature.

The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.

Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.

Comparison of anti-thymocyte globulin-based immunosuppressive therapy and allogeneic hematopoietic stem cell transplantation in patients with transfusion-dependent non-severe aplastic anaemia: a retrospective study from a single centre.

OBJECTIVES: The selection and timing of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA) pose significant clinical challenges. This study aims to compare the efficacy and long-term outcomes of the two treatments in TD-NSAA. METHODS: Patients who underwent ATG-based IST or allo-HSCT between July 2011 and December 2019 were reviewed. We gathered their clinical information, treatment response, survival data, and subsequently analysed the associated risk factors. RESULTS: A total of 97 TD-NSAA patients were reviewed, and 55 patients who underwent either ATG-based IST (n = 27) or allo-HSCT (n = 28) were enrolled. We observed a significant disparity in the 12-month overall response rate (ORR) (48.1% in IST vs 78.6% in HSCT, p < 0.05), but not in five-year overall survival (OS) and event-free survival (EFS). Multivariate Cox regression analysis identified the transfusion of ≥78.75 units of red blood cells (RBCs) as the sole independent risk factor for OS (HR: 17.04, p = 0.039) in the IST group. For the HSCT group, disease duration (DD) ≥20 months and transfusion of ≥78.75 units of RBCs predicted an adverse EFS. Frontline IST exhibited superior 12-month ORR (68.8% vs 18.2%, p = 0.018) and five-year EFS when compared to non-frontline. Patients with a DD ranging from 6 to 20 months displayed a better EFS (p = 0.016) in HSCT group than those in the ATG-based IST group. CONCLUSIONS: Prior treatment history, disease duration, and serum ferritin levels should be carefully weighed when making the choice between ATG-based IST and allo-HSCT for TD-NSAA.

The selection and timing of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) present notable clinical challenges for individuals with transfusion-dependent non-severe aplastic anaemia (TD-NSAA).In terms of treatment outcomes, allo-HSCT exhibited a higher 12-month overall response rate (ORR) in comparison to ATG-based IST among TD-NSAA patients. Nevertheless, comparable rates of 5-year overall survival (OS) and event-free survival (EFS) were observed between the two therapeutic approaches.Several factors warrant consideration when deliberating between ATG-based IST and allo-HSCT for TD-NSAA. These factors include the patient's prior treatment history, disease duration, number of packed red cell transfusions received, and serum ferritin levels.

FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3ß/GLI1 pathway.

Triple-negative breast cancer (TNBC) lacks effective therapeutic targets and has a poor prognosis, easy recurrence and metastasis. It is urgent and important to explore TNBC treatment targets. Through mass spectrometry combined with qRT-PCR validation in luminal A cells and TNBC cells, high-content screening and clinical sample analysis, FUNDC2 was discovered as a novel target. The function of the outer mitochondrial membrane protein FUNDC2 in breast cancer is still unclear. In this study, we find that FUNDC2 expression in TNBC tissues is significantly higher than that in luminal subtype breast cancer tissues. FUNDC2 silencing in TNBC cells significantly reduces cell proliferation, migration and invasion. As demonstrated in vivo using subcutaneous tumor xenografts in mice, FUNDC2 suppression significantly inhibits tumor growth. The underlying mechanism might be mediated by inactivating its downstream signal AKT/GSK3ß and GLI1, a key factor of the Hedgehog signaling pathway. Therefore, FUNDC2 may promote TNBC progression and provide a therapeutic target for treating TNBC.

Prolonged haematologic toxicity in CAR-T-cell therapy: A review.

Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies. With increasing use, our understanding of immune-mediated side effects such as cytokine release syndrome and neurotoxicity has improved; nevertheless, prolonged haematologic toxicity (PHT), with a high incidence rate, remains underrecognized. Owing to heterogeneity in populations, the CAR-T cells used and diseases treated as well as differences in the definition of PHT, its rate, risk factors and management vary across studies. In this review, we provide a narrative of PHT occurring in patients following CAR-T-cell therapy; evidence of PHT treatment strategies is also presented, with the aim of contributing to systematic understanding of PHT.

Mitigating the adverse effect of warming on rice canopy and rhizosphere microbial community by nitrogen application: An approach to counteract future climate change for rice.

The adverse impact of climate change on crop production continues to increase, necessitating the development of suitable strategies to mitigate these effects and improve food security. Several studies have revealed how global warming negatively impacts the grain-filling stage of rice and that this effect could be mitigated by nitrogen; however, the impact of nitrogen application on rice canopy and rhizosphere microbial communities remains unclear. We conducted a study using an open-field warming system. Results showed that warming influenced rice canopy by decreasing aboveground biomass and harvest index, whereas nitrogen application had positive effect on rice production under warming conditions by increasing the plant nitrogen content, biomass, harvest index and soil fertilities. Moreover, soil ammonium nitrogen (NH4+-N) and nitrate nitrogen (NO3--N) contents were significantly decreased under warming, which were higher after nitrogen application. Notably, warming and nitrogen fertilizer caused 19 % (P < 0.01) and 7 % (P < 0.05) variations, respectively, in the ß diversity of the microbial community, respectively. The impact of warming was significant on NH4+-N-related microorganisms; however, this impact was weakened by nitrogen application for microbes in the rhizosphere. This study demonstrated that enhanced nitrogen fertilizer can alleviate the adverse impact of warming by weakening its effects on rhizosphere microbes, improving soil fertility, promoting rice nitrogen uptake, and increasing the aboveground biomass and harvest index. These findings provide an important theoretical basis for developing practical, responsive cultivation strategies.

Multiple regulators were involved in glutelin synthesis and subunit accumulation in response to temperature and nitrogen during rice grain-filling stage.

Rice glutelin is sensitive to temperature and nitrogen, however, the regulatory mechanism of glutelin response to temperature and nitrogen is unclear. In this study, we conducted the open field warming experiment by the Free-air temperature enhancement facility and application of nitrogen during grain filling. In three-year field warming experiments, glutelin relative content was significantly increased under elevated temperature and application of nitrogen. Temperature and nitrogen and their interaction increased the glutelin accumulation rate in the early and middle grain filling stages (10-25d after flowering), but decreased the glutelin accumulation rate in the middle and late grain filling stages (25-45d after flowering). Elevated temperature promoted pro-glutelin levels whereas application of nitrogen under warming increased the amount of α-glutelin. At the transcriptional level, the expression levels of the glutelin-encoding genes and protein disulphide isomerase-like enzyme (PDIL1-1), glutelin precursor accumulation 4 (GPA4), glutelin precursor mutant 6 (GPA2), glutelin precursor accumulation 3 (GPA3) and vacuolar processing enzyme (OsVPE1) of glutelin folding, transport and accumulation-related genes were up-regulated by nitrogen under natural temperature as early as 5d after flowering. However, elevated temperature up-regulated glutelin-encoding genes before 20d after flowering, and the expression of endoplasmic reticulum chaperone (OsBip1), OsPDIL1-1, small GTPase gene (GPA1), GPA2-GPA4 and OsVPE1 were significantly increased post 20d after flowering under warming. In addition, the increase in glutelin content worsened grain quality, particularly chalkiness and eating quality. Overall, the results were helpful to understand glutelin accumulation and provide a theoretical basis for further study the relationship between rice quality and glutelin under global warming.

[Clinical Characteristics and Survival Analysis of Carbapenem-Resistant Pseudomonas Aeruginosa Colonized or Infected Patients with Hematological Disorders].

OBJECTIVE: To observe the clinical characteristics and impact on mortality of carbapenem-resistant Pseudomonas aeruginosa (CRPA) colonized or infected patients with hematological disorders in order to provide evidence for the prevention and treatment of CRPA. METHODS: The patients who were colonized or infected with CRPA in the Department of Hematology of The First Affiliated Hospital of Zhejiang Chinese Medical University from January 2020 to March 2021 were selected as the research subjects, the clinical data such as hospitalization time, primary disease treatment regimen, granulocyte count, previous infection and antibiotic regimen of these patients were analyzed, meanwhile, antibiotic regimen and efficacy during CRPA infection, 30-day and long-term survival were also analyzed. RESULTS: A total of 59 patients were included in this study, and divided into CRPA infection group (43 cases) and CRPA colonization group (16 cases). Univariate logistic regression analysis showed that ECOG score (P =0.003), agranulocytosis (P <0.001), and exposure to upper than 3rd generations of cephalosporins and tigecycline within 30 days (P =0.035, P =0.017) were the high-risk factors for CRPA infection. Multivariate logistic regression analysis showed that ECOG score of 3/4 ( OR=10.815, 95%CI: 1.260-92.820, P =0.030) and agranulocytosis ( OR=13.82, 95%CI: 2.243-85.176, P =0.005) were independent risk factors for CRPA infection. There was a statistically significant difference in cumulative survival rate between CRPA colonization group and CRPA infection group ( χ2=14.134, P < 0.001). Kaplan-Meier survival analysis showed that the influencing factors of 30-day survival in patients with CRPA infection were agranulocytosis (P =0.022), soft tissue infection (P =0.03), and time of hospitalization before CRPA infection (P =0.041). Cox regression analysis showed that agranulocytosis was an independent risk factor affecting 30-day survival of patients with CRPA infection (HR=3.229, 95%CI :1.093-3.548, P =0.034). CONCLUSIONS: Patients with hematological disorders have high mortality and poor prognosis after CRPA infection. Bloodstream infection and soft tissue infection are the main causes of death. Patients with high suspicion of CRPA infection and high-risk should be treated as soon as possible.

Eltrombopag plus cyclosporine in refractory immune thrombocytopenia: a single-center study.

Background: With the development of thrombopoietin receptor agonists, the prognosis of immune thrombocytopenia (ITP) in patients in whom there was a poor response to first-line treatment has greatly improved. However, there are still some patients who are refractory to eltrombopag. Objectives: To explore the efficacy and safety of eltrombopag combined with low-dose cyclosporine in the management of patients with refractory ITP. Methods: A total of 21 participants with ITP who failed to respond to multiple lines of therapy (including a daily dose of 75 mg of eltrombopag for at least 30 days) treated at The First Affiliated Hospital of Zhejiang Chinese Medical University between January 2018 and August 2022 were included. All enrolled patients subsequently received 50 mg of eltrombopag daily and low-dose cyclosporine (3 mg/kg/d, with an initial target concentration of 75-120 ng/mL). The efficacy and safety of the combined therapies were evaluated. Results: A total of 76.2% (16/21) of the patients responded to the combination of cyclosporine and eltrombopag, with a median time to response of 14.5 (range, 5-37) days. A complete response (platelet count ≥ 100 × 109/L) was observed in 81.3% (13/16) of the patients, among whom 1 patient experienced relapse due to self-reduction in eltrombopag. During a median follow-up of 180 days, there were no relapses, and 70% (7/10) of the patients successfully stopped or decreased concomitant ITP medications. One patient had both a catheter-related deep vein thrombosis and a venous cerebral thrombotic event later; no other severe drug-related adverse events were observed. Conclusion: Combining low-dose cyclosporine with eltrombopag may be an effective alternative for multirefractory ITP that is nonresponsive to eltrombopag alone.