Objective:To evaluate the role of minimal residual disease (MRD) monitoring during early induction therapy for the treatment of childhood acute lymphoblastic leukemia (ALL).Methods:This was a multicenter retrospective cohort study. Clinical data of 1 164 ALL patients first diagnosed between October 2016 and June 2019 was collected from 16 hospitals in South China Children′s Leukemia Group. According to MRD assay on day 15 of early induction therapy, they were divided into MRD<0.10% group, MRD 0.10%-<10.00% group and MRD≥10.00% group. According to MRD assay on day 33, they were divided into MRD<0.01% group, MRD 0.01%-<1.00% group and MRD≥1.00% group. Age, onset white blood cell count, central nervous system leukemia (CNSL), molecular genetic characteristics and other data were compared between groups. Kaplan-Meier method was used for survival analysis. Cox regression model was used to analyze prognostic factors.Results:Of the 1 164 enrolled patients, there were 692 males and 472 females. The age of diagnosis was 4.7 (0.5, 17.4) years. The white blood cell count at initial diagnosis was 10.7 (0.4, 1 409.0) ×10 9/L. Among all patients, 53 cases (4.6%) had CNSL. The follow-up time was 47.6 (0.5, 68.8) months. The 5-year overall survival (OS) and 5-year relapse-free survival (RFS) rates were (93.1±0.8) % and (90.3±1.1) %. On day 15 of early induction therapy, there were 466 cases in the MRD<0.10% group, 523 cases in the MRD 0.10%-<10.00% group and 175 cases in the MRD≥10.00% group. The 5-year OS rates of the MRD<0.10% group, MRD 0.10%-<10.00% group and MRD≥10.00% group were (95.4±1.0) %, (93.3±1.1) %, (85.4±2.9) %, respectively, while the RFS rates were (93.2±1.6) %, (90.8±1.4) %, (78.9±4.3) %, respectively ( χ2=16.47, 21.06, both P<0.05). On day 33 of early induction therapy, there were 925 cases in the MRD <0.01% group, 164 cases in the MRD 0.01%-<1.00% group and 59 cases in the MRD≥1.00% group. The 5-year RFS rates in the MRD 0.01%-<1.00% group was lowest among three groups ((91.4±1.2) % vs. (84.5±3.2) % vs. (87.9±5.1) %). The difference between three groups is statistically significant ( χ2=9.11, P=0.010). Among ALL patients with MRD≥10.00% on day 15 of induction therapy, there were 80 cases in the MRD <0.01% group on day 33, 45 cases in the MRD 0.01%-<1.00% group on day 33 and 45 cases in the MRD≥1.00% group on day 33. The 5-year RFS rates of three groups were (83.9±6.0)%, (67.1±8.2)%, (83.3±6.9)% respectively ( χ2=6.90, P=0.032). Univariate analysis was performed in the MRD≥10.00% group on day 15 and the MRD 0.01%-<1.00% group on day 33.The 5-year RFS rate of children with CNSL was significantly lower than that without CNSL in the MRD≥10.00% group on day 15 ((50.0±20.4)% vs. (80.3±4.4)%, χ2=4.13, P=0.042). Patients with CNSL or MLL gene rearrangement in the MRD 0.01%-<1.00% group on day 33 had significant lower 5-year RFS rate compared to those without CNSL or MLL gene rearrangement ((50.0±25.0)% vs. (85.5±3.1)%, χ2=4.06, P=0.044;(58.3±18.6)% vs. (85.7±3.2)%, χ2=9.44, P=0.002). Multivariate analysis showed that age ( OR=0.58, 95% CI 0.35-0.97) and white blood cell count at first diagnosis ( OR=0.43, 95% CI 0.27-0.70) were independent risk factors for OS. The MRD level on day 15 ( OR=0.55,95% CI 0.31-0.97), ETV6-RUNX1 fusion gene ( OR=0.13,95% CI 0.03-0.54), MLL gene rearrangement ( OR=2.55,95% CI 1.18-5.53) and white blood cell count at initial diagnosis ( OR=0.52,95% CI 0.33-0.81) were independent prognostic factors for RFS. Conclusions:The higher the level of MRD in early induction therapy, the worse the OS. The MRD levels on day 15 is an independent prognostic factor for RFS.The MRD in early induction therapy guided accurate risk stratification and individualized treatment can improve the survival rate of pediatric ALL.

Diabetic cardiomyopathy is a myocardial complication associated with abnormal glucose metabolism and dyslipidiaemia, which increases the risk of death and heart failure in diabetic patients. Mitochondrial dysfunction is involved in the occurrence and development of diabetic cardiomyopathy. Recent studies have confirmed that scavenging damaged mitochondria in cardiomyocytes through mitophagy can restore mitochondrial homeostasis, reduce oxidative stress and improve diabetic cardiomyopathy. Therefore, this article provides a comprehensive review of the mechanisms and characteristics of mitochondrial autophagy in diabetic cardiomyopathy. It aims to offer new insights and theoretical basis for the prevention and treatment of diabetic cardiomyopathy.

Hypoglycemia is the most common complication of the treatment for diabetes mellitus. Current studies suggest that recurrent hypoglycemia induces impaired awareness of hypoglycemia in diabetes by the failure of sympathetic nerve response or other mechanisms, which increases the risk of severe hypoglycemia and hypoglycemic fear in diabetics. Therefore, exploring the pathogenesis and preventive measures of impaired awareness of hypoglycemia is expected to provide new ideas for reducing severe hypoglycemia events and conducting subsequent studies.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Objective:To improve the efficiency and success rate of human adenovirus 3 (HAdV-3) whole genome sequencing, a high-throughput sequencing method for the whole genome of HAdV-3 based on multiplex PCR was established.Methods:Multiplex PCR primers suitable for the whole genome amplification of HAdV-3 were designed. The whole genome sequence of HAdV-3 was amplified by multiplex PCR, and the specificity of the amplification product was preliminarily verified by agarose gel electrophoresis. High-throughput sequencing of the multiplex PCR products was performed using Illumina second-generation sequencing. After obtaining the sequence, software such as CLC and IGV were used to analyze the effective data amount, average sequencing depth, and whole genome coverage obtained by high-throughput sequencing, then the sequencing quality was evaluated. Based on the whole genome sequencing result, a phylogenetic tree was constructed to confirm the virus type and analyze homology of the sequences, and then the accuracy of this method was evaluated.Results:A total of 70 (35 pairs) multiplex PCR amplification primers for the whole genome of HAdV-3 were designed, with amplicon size of approximately 1 200 bp. And the expected whole genome coverage could reach 99.8% (with a total genome length of approximately 35 240 bp). Agarose gel electrophoresis analysis showed that the size of the multiplex PCR products was consistent with expectations, and the amplification specificity was high. The high-throughput sequencing result showed that the whole genome sequences obtained by this method were complete and intact, and the genome coverage was consistent with expectations. Sequence quality analysis showed that the high-throughput sequencing method based on multiplex PCR could obtain more effective data and greater sequencing depth, resulting in more uniform whole genome coverage. Phylogenetic analysis showed that the evolutionary typing result of viral DNA sequenced after multiplex PCR amplification were consistent with those of viral DNA sequenced directly and had high homology, indicating that the multiplex PCR method had high amplification fidelity and the results obtained in combination with high-throughput sequencing were accurate.Conclusions:A high-throughput sequencing method for the whole genome of HAdV-3 based on multiplex PCR was established in this study successfully. This method could improve the efficiency and success rate of HAdV-3 whole genome sequencing, aiming to provide better technical support and reference for HAdV-3 pathogen surveillance and epidemic source-tracing based on whole genome sequencing.

OBJECTIVES: During pregnancy, pregnant women are prone to stress reactions due to external stimuli, affecting their own health and fetal development. At present, there is no good treatment for the stress reactions from pregnant women during pregnancy. This study aims to explore the effect of probiotics on abnormal behavior and hippocampal injury in pregnant stressed offspring. METHODS: SD pregnant rats were divided into a control group, a stress group, and a probiotics group, with 6 rats in each group. The control group was untreated; the stress group was given restraint stress on the 15th-20th day of pregnancy; the probiotics group was given both bifidobacterium trisporus capsules and restraint stress on the 15th-20th day of pregnancy, and the offspring continued to be fed with probiotics until 60 days after birth (P60). The offspring rats completed behavioral tests such as the open field test, the elevated plus maze test, the new object recognition test, and the barnes maze test at 60-70 d postnatally. Nissl's staining was used to reflect the injury of hippocampal neurons; immunohistochemical staining was used to detect the expression of microglia marker ionized calcium binding adapter molecule 1 (IBA-1) which can reflect microglia activation; ELISA was used to detect the content of plasma TNF-α and IL-1β; Western blotting was used to detect the expression of Bax, Bcl-2, and caspase-3. RESULTS: The retention time of offspring rats in the stress group in the central area of the open field was significantly less than that in the control group (P<0.01), and the retention time of offspring rats in the probiotic group in the central area of the open field was significantly more than that in the stress group (P<0.05). The offspring rats in the stress group stayed in the open arm for a shorter time than the control group (P<0.05) and entered the open arm less often than the control group (P<0.01); the offspring rats in the probiotic group stayed in the open arm for a longer time than the stress group and entered the open arm more often than the stress group (both P<0.05). The discrimination ratio for new to old objects in the offspring rats of the stress group was significantly lower than that of the control group (P<0.01), and the discrimination ratio for new to old objects in the offspring rats of the probiotic group was significantly higher than that of the stress group (P<0.05). The offspring rats in the stress group made significantly more mistakes than the control group (P<0.05), and the offspring rats in the probiotic group made significantly fewer mistakes than the stress group (P<0.05). Compared with the control group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly reduced in the offspring rats of the stress group (all P<0.001), the number of activated microglia in DG area of hippocampus was significantly increased (P<0.01), the contents of TNF-α and IL-1β in peripheral blood were significantly increased (P<0.05 or P<0.01), the protein expression level of Bcl-2 was significantly down-regulated, and the protein expression levels of Bax and caspase-3 were significantly up-regulated (all P<0.001). Compared with the stress group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly increased in the probiotic group offspring rats (P<0.001, P<0.01, P<0.05), the number of activated microglia in the DG area of hippocampus was significantly reduced (P<0.05), and the TNF-α and IL-1β levels in peripheral blood were significantly decreased (both P<0.05), the protein expression level of Bcl-2 was significantly up-regulated, and the protein expression levels of Bax and caspase-3 were significantly down-regulated (all P<0.001). CONCLUSIONS Probiotic intervention partially ameliorated anxiety and cognitive impairment in rats offspring of pregnancy stress, and the mechanism may be related to increasing the number of neurons, inhibiting the activation of hippocampal microglia, and reducing inflammation and apoptosis.
Animals ; Caspase 3/metabolism* ; Female ; Hippocampus/physiopathology* ; Humans ; Pregnancy ; Probiotics/therapeutic use* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Rats ; Stress, Psychological/therapy* ; Tumor Necrosis Factor-alpha/metabolism* ; bcl-2-Associated X Protein/metabolism*

Objective:To observe the clinical characteristics of patients with visual impairment caused by fungal sphenoid sinusitis and analyze the influencing factors related to visual prognosis.Methods:A retrospective clinical study. From January 2006 to December 2020, 44 patients (55 eyes) with visual impairment caused by fungal sphenoid sinusitis confirmed by imaging and pathological examination in the Department of Ophthalmology of Beijing Tongren Hospital were included in the study. Patients was first diagnosed in the Department of Ophthalmology due to monocular or binocular vision loss, or binocular diplopia, limited eye movement and ptosis. All patients underwent visual acuity examination and fundus color photography. CT examination of paranasal sinus or orbit was performed in 37 cases; magnetic resonance imaging (MRI) of paranasal sinus, brain or orbit was performed in 34 cases. All patients underwent endoscopic sinus opening combined with intrasinus lesion clearance; 14 cases were treated with antifungal drugs after operation. The average follow-up time was 59.61±37.70 months. Comparison of clinical characteristics between invasive and non-invasive fungal sphenoid sinusitis were by χ 2 test or Fisher exact test. The influencing factors with P<0.2 in univariate analysis were selected for multivariate regression analysis. Results:Among the 44 patients, there were 19 males and 25 females; the ratio of male to female was 1:1.3; the average age of visual symptoms was 61.48 ± 12.17 years; 23 cases (52.3%, 23/44) suffered from immune dysfunction, including 21 cases of diabetes mellitus. The visual acuity decreased in 33 cases (44 eyes) (75.0%, 33/44). There were 15 cases of binocular diplopia with eye movement disorder (34.0%, 15/44), including 6 cases with visual impairment. The visual acuity of the affected eye was no light perception-0.8. There were 35 cases with headache (79.5%, 35/44). Nasal symptoms were found in 14 cases (31.8%, 14/44). There were 40 and 4 cases of Aspergillus and Mucor infection in sphenoid sinus, respectively. Among the 37 cases who underwent CT examination of paranasal sinus or orbit, there were soft tissue filling in the sinus cavity, including 19 cases of high-density calcification in the sinus cavity (51.4%, 19/37); bone defect of sinus wall were in 24 cases (64.9%, 24/37). There were 26 cases (70.3%, 26/37) of sinus wall osteosclerosis. MRI of paranasal sinus, brain or orbit was performed in 34 cases. T1WI of sphenoid sinus lesions showed low signal, high signal and equal signal in 14, 10 and 9 cases, respectively; T2WI showed high signal, low signal and equal signal in 13, 16 and 2 cases respectively. After enhancement, the lesions were strengthened in 11 cases, no obvious enhancement in 23 cases, and the surrounding mucosa was thickened and strengthened. The lesions involved the orbital apex and cavernous sinus in 18 and 16 cases, respectively; orbital apex and cavernous sinus were involved in 12 cases. Six months after operation, visual acuity was significantly improved in 27 eyes (65.9%, 27/41); visual acuity did not improve in 14 eyes (34.1%, 14/41). Multivariate regression analysis showed that the change of sinus wall osteosclerosis was associated with higher visual acuity improvement rate (odds ratio= 0.089, 95% confidence interval 0.015-0.529, P=0.008). Conclusions:Fungal sphenoid sinusitis related visual impairment is relatively common in elderly female patients with low immune function; monocular vision loss with persistent headache is the most common clinical symptom; imaging findings of sphenoid sinus lesions are an important basis for diagnosis. Sphenoid sinus opening combined with sinus lesion clearance is an effective treatment. After operation, the visual acuity of most patients can be improved. The prognosis of visual acuity was relatively good in patients with hyperplasia and sclerosis of sphenoid sinus wall bone.

Retrospective analysis was performed on 1 child with silent inactivation (SI) of asparaginase (ASNas) who was diagnosed with acute lymphoblastic leukemia (ALL) and treated in the First Affiliated Hospital, Sun Yat-Sen University in October 2019.The patient was a 9 years and 3 months old boy who was diagnosed as ALL accompanied with late bone marrow relapse.After pegylated Escherichia coli-Asparaginase (PEG-ASNase) was given, he did not have the expected treatment-related adverse reactions, including hyperammonemia, hypofibrinogenemia, and the low activation of antithrombin Ⅲ (ATⅢ). The plasma asparagine (ASN) concentration failed to meet the depletion criteria and the ASNase activity was 64.5 U/L.Therefore, the SI of ASNase was confirmed.Erwinase was used to replace PEG-ASNase, the lowest level of ATⅢ was 33%, and the lowest level of fibrinogen was 1.20 g/L.Hyperammonemia and decreased ASN were also observed, and the ASNase activity was 1 813.0 U/L.All the above suggested that when, SI occurred, the replacement by Erwinase was effective.The ASNase activity should be monitored in ALL patients who were treated with ASNase.Monitoring the treatment-related adverse reactions such as hyperammonia and coagulation disorders closely has important implications to the SI of ASNase when the detection of ASNase activity was unavailable.

Women′s health is the cornerstone of national health. During the 70 years since the founding of New China, under the leadership of the Communist Party of China, a legal system and related policies including more than 100 laws and regulations have been established to fully protect women′s rights and health, and women′s rights and health throughout their life cycle have been effectively protected. The health status of Chinese women has been significantly improved, the form and accessibility of women′s health care services have been continuously improved, and the building of women′s health care teams has been continuously strengthened. All of these achievements demonstrate the original intention of the Communist Party of China to put people′s health first and action of forging ahead.

Objective:To discuss the role of ataxia telangiectasia and Rad3-related kinase (ATR) /check point kinase 1 (CHK1) signaling pathway in the occurrence and development of epithelial ovarian cancer.Methods:Human epithelial ovarian cancer cells OVCAR3 cells were cultured in vitro, siRNA and VE-822 were used to interfere with ATR in OVCAR3 cells, the effectiveness of interference with ATR expression was detected by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot, the cell proliferation inhibition was detect by CCK-8 method, cell cycle and apoptosis were detected by flow cytometry (FCM) , the mRNA expressions of Caspase-3, B-cell lymphoma-2 (Bcl-2) , Bcl-2-associated X protein (Bax) were detected by qRT-PCR, Western blot was used to detect the expression of ATR/CHK1 pathway related proteins.Results:After siRNA-ATR transfection and VE-822 intervention, compared with those in NC group and siRNA-sc group, the expression level of ATR mRNA [ (1.55±0.12) , (1.51±0.13) , (0.71±0.11) , (0.73±0.12) , (0.49±0.09) ] in OVCAR3 cells in siRNA-ATR group, VE-822 group and siRNA-ATR + VE-822 group was significantly lower ( P<0.05) , the inhibition rate of cell proliferation [ (0.00±0.00) %, (0.00±0.00) %, (32.84±1.08) %, (30.75±1.44) %, (43.90±1.57) %], ratio of G0/G1 phase [ (40.08±2.57) , (36.35±3.44) , (53.28±4.34) , (56.37±5.03) , (70.63±3.81) ], apoptosis rate [ (4.28±0.67) %, (5.35±0.94) %, (23.63±1.13) %, (24.57±1.20) %, (35.86±1.09) %], expression of Caspase-3 and Bax mRNA were significantly higher ( P<0.05) , and the cell proportions in S phase [ (32.93±3.02) , (35.35±2.82) , (25.79±3.61) , (23.74±3.54) , (18.04±2.37) ] and G2/M phase [ (26.99±2.84) , (28.30±2.72) , (20.93±3.01) , (19.98±2.87) , (11.33±2.11) ], Bcl-2 mRNA, ATR, p-CHK1/CHK1, cell division cycle protein 25C (CDC25C) and cyclin B1 protein expression were significantly lower ( P<0.05) . Compared with those in siRNA-ATR group, the expression of ATR mRNA in siRNA-ATR + VE-822 group was further decreased ( P<0.05) , the inhibition rate of cell proliferation, apoptosis, expression of Caspase-3 and Bax mRNA were further increased ( P<0.05) , and the expression of Bcl-2 mRNA, ATR, p-CHK1/CHK1, CDC25C and cyclin B1 protein was decreased continuously ( P<0.05) . Conclusion:ATR/CHK1 signaling pathway is activated during the proliferation of epithelial ovarian cancer OVCAR3 cells. Inhibition of ATR/CHK1 signaling pathway can inhibit the proliferation of epithelial ovarian cancer cells and induce G1/S cell cycle arrest and apoptosis.