Objective To explore the expression profile of adenosine A1 receptor in the paraventricular thalamic nucleus(PVT)in wakefulness/sleep state and its role in regulating sleep.Methods Male C57BL/6J mice(6～12 weeks old,weighing 22～28 g)were randomly divided into ZT0,ZT6,ZT10,ZT12,and sleep deprivation and recover0y sleep groups(n=16 or n=4).RT-qPCR and fluorescence in situ hybridization were used to observe the changes of adenosine A1 receptor in PVT.Whole-cell patch-clamp recording was conducted to determine the effects of adenosine on the membrane potential and discharge frequency of PVT neurons.The experimental animals were divided into adenosine A1 receptor interference group(n=8)and interference control group(n=7).After RNA interference,electroencephalography(EEG)and electromyography(EMG)were applied simultaneously to observe the changes in wake and sleep time between the 2 groups during sleep deprivation for 6 h and sleep recovery for 4 h.Results RT-qPCR and fluorescence in situ hybridization confirmed that the expression of adenosine A1 receptor in PVT was affected by wakefulness/sleep state,with the level in the ZT0 group(active stage)significantly higher than that in the ZT12 group(non-active stage,P<0.05).Whole-cell patch clamp recording indicated that adenosine exerted inhibitory effects on PVT neurons through 2 distinct response types(P<0.05),and the inhibition was in a diminishing trend with a decrease in the expression level of adenosine A1 receptor.After sleep deprivation,the expression level of adenosine A1 receptor showed significant intergroup differences:the level was significantly higher in the sleep deprivation group than the recovery sleep group(P<0.05),while that of the recovery sleep group was higher than that of the ZT6 group and that of the ZT10 group(P<0.05).After knocking down adenosine A1 receptor(shRNA-A1R)in the PVT,the wakefulness timing of the shRNA-A1R group was significantly increased,while the sleep timing was significantly decreased within 1 h after sleep recovery when compared with the interference control group(P<0.05).Conclusion The expression of adenosine A1 receptor in the PVT is dynamically regulated by sleep pressure,which was increasing as sleep pressure rises.

BACKGROUND:Myelodysplastic syndrome has worse hazards of acute myeloid leukemia transformation,and some studies have revealed that immune infiltration plays a vital part in the two.Nevertheless,more studies are required to confirm the relationship between immune infiltration and related differentially expressed gene regulation. OBJECTIVE:To screen the differentially expressed genes with prognostic significance between myelodysplastic syndrome and acute myeloid leukemia by bioinformatics analysis and explore the possible roles and mechanisms among these differentially expressed genes and immune infiltration mechanisms in the occurrence and progression of diseases. METHODS:The differentially expressed genes were screened for bioinformatics analysis using the GEO datasets,and analyzed by DO,GO,KEGG and GSEA.The TCGA prognostic database was used to plot the K-M curves of differentially expressed genes and receiver operating characteristic curve analysis was applied to evaluate the clinical diagnostic performance.Finally,CIBERSORT analysis was used to intuitively demonstrate the correlation between critical prognostic genes and the distribution of immuno-infiltrated cells.RT-qPCR was employed to detect peripheral blood samples from healthy controls,myelodysplastic syndrome and acute myeloid leukemia patients so as to verify the crucial genes preliminarily. RESULTS AND CONCLUSION:(1)A total of 150 differentially expressed genes were obtained between myelodysplastic syndrome and acute myeloid leukemia,among which 16 genes were up-regulated and 134 were down-regulated.(2)The results of DO,GO,KEGG and GSEA analysis suggested that differentially expressed genes might promote the development of myelodysplastic syndrome to acute myeloid leukemia by regulating the immune response.CIBERSORT revealed the differences in immune infiltration between myelodysplastic syndrome and acute myeloid leukemia.The distribution of CD4+ T cells,monocytes,neutrophils and M1 macrophages decreased in acute myeloid leukemia patients.In contrast,the distribution of inflammatory suppressor cells M2 macrophages increased,suggesting that it may be related to the immunosuppression of acute myeloid leukemia.(3)K-M curve and receiver operating characteristic curve analysis of 150 differentially expressed genes screened out four genes relevant to immunity and prognosis with good diagnostic performance:MANSC1,FLT3,BMX and CXCR2.(4)The results of RT-qPCR exhibited that MANSC1,BMX and CXCR2 were low expressed,while FLT3 was highly expressed in acute myeloid leukemia patients.These findings verify that the differential expression of MANSC1,FLT3,BMX and CXCR2 in patients with myelodysplastic syndrome and acute myeloid leukemia is not only significantly correlated with the prognosis of patients but may also affect the occurrence and development of myelodysplastic syndrome and acute myeloid leukemia by regulating the immune infiltration of patients.They can be used as potential biomarkers and therapeutic targets of the transformation from myelodysplastic syndrome to acute myeloid leukemia,providing a new direction for clinical diagnosis and treatment of the transformation of myelodysplastic syndrome.

Objective:To investigate soft-and hard-tissue changes after simultaneously labial and lingual augmented corticotomy in patients with insufficient alveolar bone thickness of lower anterior teeth both in labial and lingual side during orthodontic treatment.Methods:From January 2021 to June 2022, 10 patients [2 males and 8 females, (26.2±3.1) years old] who received orthodontic and orthognathic combined treatment from the Fourth Clinical Division, Peking University School and Hospital of Stomatology were selected. The alveolar bone thickness of lower anterior teeth both in labial and lingual side in these patients was less than 0.5 mm according to cone-beam CT examination before or during treatment, and 60 lower anterior teeth were included. The 10 patients were treated with simultaneously labial and lingual augmented corticotomy. The differences in gingival recession, papilla index and the differences in labial and lingual alveolar bone thickness of lower anterior teeth were compared.Results:Six months after surgery, the alveolar bone thicknesses at the 4 mm under cemento-enamel junction (CEJ), 8 mm under CEJ and at the apical level [labial side: (1.02±0.39), (2.22±0.89) and (4.87±1.35) mm; lingual side: (1.07±0.46), (2.31±1.04) and (3.91±1.29) mm] were significantly higher than that before surgery [labial side: (0.02±0.09), (0.06±0.21) and (2.71±1.33) mm]; lingual side: (0.14±0.29), (0.40±0.52) and (2.13±1.02) mm] ( P<0.001), respectively. The increases in alveolar bone thickness of central incisors [apical level on labial side: (2.53±1.20) mm, 8 mm under CEJ on lingual side: (2.27±1.24) mm, apical level on lingual side: (2.66±1.49) mm] and lateral incisors [apical level on labial side: (2.42±1.30) mm, 8 mm under CEJ on lingual side: (2.28±0.92) mm, apical level on lingual side: (1.94±1.15) mm] were significantly higher than that of canines [apical level on labial side: (1.52±1.47) mm, 8 mm under CEJ on lingual side: (1.17±1.09) mm,apical level on lingual side: (0.74±1.37) mm] ( P<0.01). There were no significant differences in the degree of gingival recession [labial side before surgery: (0.72±0.88) mm, lingual side before surgery: (0.80±1.09) mm; labial side 6 months after surgery: (0.72±0.81) mm,lingual side 6 months after surgery: (0.89±0.21) mm] and gingival papilla index [before surgery: 1.00(0.75, 2.00); 6 months after surgery: 1.00(1.00, 2.00) ] between pre-operation and 6 months after surgery ( P>0.05). No serious complications occurred. Conclusions:The method used in this article for simultaneously labial and lingual augmented corticotomy was safe and feasible. This surgery has positive clinical significance for the stability of the periodontal tissue in orthodontic treatment for patients with alveolar bone thickness less than 0.5 mm of lower anterior teeth both in labial and lingual side.

Animals ; Mice ; Motor Neurons/physiology* ; Spinal Cord

Objective:To explore the role of transgelin(TAGLN) in the occurrence and development of papillary thyroid carcinoma (PTC) and its possible signal pathway.Methods:One hundred cases of PTC tissues and corresponding paracancerous normal thyroid tissues were collected. Realtime quantitative PCR (RT-qPCR), Western blotting, and immunohistochemistry were used to analyze the expression of TAGLN in PTC tissues and corresponding paracancerous normal thyroid tissues. PTC cells were transfected with plasmid and shRNA lentivirus vector respectively to up-regulate or down-regulate the expression of TAGLN in order to detect the effects of them on the proliferation, invasion, and migration by cell proliferation assay(cell counting kit-8, CCK-8)and cell invasion and migration assays (Transwell). The effects of TAGLN on mitogen-activated protein kinase (MAPK)/extracellular-signal regulating kinase (ERK) signal pathway was detected with Western blotting.Results:RT-qPCR showed that there was no difference in the expression of TAGLN mRNA between PTC and corresponding paracancerous normal thyroid tissues ( P>0.05); Western blotting demonstrated that the expression of TAGLN protein in PTC tissues was significantly lower than that in corresponding paracancerous normal thyroid tissues ( P<0.01). Immunohistochemical results revealed that the expression of TAGLN in PTC tissues was significantly lower than that in corresponding paracancerous normal thyroid tissues. Overexpression of TAGLN inhibited the proliferation, invasion, and migration of PTC cells ( P<0.01), but knockdown of TAGLN promoted the proliferation, invasion, and migration of PTC cells ( P<0.01). Overexpression of TAGLN decreased the expression of phosphorylated ERK ( P<0.05), whereas silencing TAGLN increased phosphorylated ERK level in PTC cells( P<0.01). Conclusion:The expression of TAGLN in PTC is significantly decreased. It is related to the occurrence and development of PTC, and its mechanism may be related to MAPK/ERK signal pathway.

Objective: To explore the clinical value of contrast-enhanced ultrasound combined with modified labeled method in labeling sentinel lymph nodes of breast cancer in comparison with nano-carbon stained method. Methods: Eighty female breast cancer patients who underwent surgery in the First Affiliated Hospital of Soochow University between July 2017 and April 2019 were enrolled. Sentinel lymph nodes in all patients were labeled by contrast-enhanced ultrasound combined with modified labeled method and nano-carbon stained method, respectively. The consistency of first lymph node labeled by the two methods was judged, the number of SLNs labeled by two methods was counted, and the pathology of the labeled SLN was compared with that after axillary dissection. Results: The two methods have good consistency in locating sentinel lymph nodes of breast cancer(Kappa=0.749, P=0.000). The number of SLNs labeled by modified labeling method was significantly less than that labeled by stained method(Z=-7.434, P=0.000). The pathology of lymph nodes labeled by both the modified labeling method and stained method coincided well with that of axillary dissection(Kappa=0.941, 0.943; P=0.000, 0.000), and diagnostic efficiency was comparable(AUC=0.964, 0.967). Conclusions Contrast-enhanced ultrasound combined with modified labeling method is simple and accurate in labeling sentinel lymph nodes of breast cancer. Accurate assessment of axillary lymph node staging can be made by precise biopsy of 1-2 SLNs.

OBJECTIVE: To explore the impact of dietary sodium-intake on residual renal function in patients undergoing peritoneal dialysis (PD). METHODS: Thirty-three patients on PD with stable dialysis were regularly followed up for 12 months. The daily sodium intake of the patients was calculated based on the 3-day dietary record. Based on the mean daily sodium intake, the patients enrolled were divided into low-salt group (sodium intake≤3.0 g/day, 19 patients) and high-salt group (sodium intake>3.0 g/day, 14 patients). The baseline data of the patients were recorded, and the indicators of residual renal function and peritoneal function were regularly tested. The patients were followed-up at 3-month intervals, and their urine volume, peritoneal ultrafiltration volume and other clinical indicators were recorded and the biochemical indexes were detected to evaluate the changes in the residual renal function and peritoneal function. RESULTS: There was a positive correlation between the total sodium excretion and dietary sodium intake in these patients (=0.536, =0.0013), and sodium excretion by dialysis was positively correlated with their sodium intake (=0.901, =0.000). Regression analysis suggested that the total sodium excretion was correlated with dietary sodium intake (β=0.416, 95% : 0.170-0.666; < 0.0018); sodium excretion by dialysis was associated with dietary sodium intake (β=0.489, 95% : 0.395-0.582; < 0.001). The residual renal function was reduced by 17.48±11.22 L /(w·1.73 m) in the low-salt group, as compared to 30.20±18.30 L /(w·1.73 m) in the high-salt group (=0.032). The reduction in the residual renal function was correlated with sodium intake in the PD patients (=0.409, =0.018). Multivariate regression analysis showed that sodium intake was an independent factor contributing to the reduction of residual renal function (β=14.646, 95% CI 7.426-21.866, < 0.001). CONCLUSIONS Sodium excretion by PD in patients with continuous ambulatory PD is positively correlated with their dietary sodium intake, which contribute to the decrease of residual renal function. A high dietary sodium intake may accelerate the reduction of residual renal function in these patients.
Humans ; Kidney ; Peritoneal Dialysis ; Prospective Studies ; Sodium, Dietary

OBJECTIVETo evaluate the safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (mFOLFOXIRI) for patients with advanced colorectal cancer (CRC).

METHODSData of 312 CRC patients confirmed by pathology receiving triplet drug alone or combined with target therapy between October 2012 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. CRC patients who had previously completed adjuvant therapy (or neoadjuvant therapy) within 6 months or palliative chemotherapy were excluded, meanwhile those with poor general condition (ECOG score > 2) or grade 2 neuropathy and allergy to oxaliplatin were excluded as well. Regimen of mFOLFOXIRI: oxaliplatin 85 mg/m² dissolved in 5% glucose solution 500 ml by intravenous infusion for 2 h; irinotecan 150 to 165 mg/m² dissolved in 0.9% sodium chloride 250 ml by intravenous infusion for 90 min; following intravenous infusion of leucovorin 400 mg/m² for 2 h, day 1; 5-FU 2800 mg/m², 48-h continuous intravenous infusion; once every 2 weeks. Therapy could be combined with a targeted drug, bevacizumab 5 mg/kg every two weeks; cetuximab 500 mg/m² every two weeks. Side effect was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0.3). The objective response rate was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) after administering at least four cycles of chemotherapy.

RESULTSThe median age was 52 years (range 16-73) in the whole group; 113 patients (36.2%) had locally advanced CRC, and 199 (63.8%) had metastatic CRC. Most patients (274/312, 87.8%) did not receive any treatment earlier. There were a total of 1651 chemotherapy cycles in the whole group, with a median of 6(1-19) cycles. Of these 1651 cycles, 124 cycles of chemotherapy(7.5%) were dose-adjusted; 176 cycles of chemotherapy(10.7%) were delayed for median 5(3-13) days; 124 cycles(7.5%) required dose decrease. The overall relative dose intensity was >90%; the specific drug dose intensity was 93.6%(2620 mg×m⁻²×d⁻¹) for fluorouracil, 97.8%(83 mg×m⁻²×d⁻¹) for oxaliplatin, and 94.2%(155 mg×m⁻²×d⁻¹) for irinotecan. Twenty-three patients (7 of intestinal perforation, 7 of intestinal obstruction, 1 of grade 4 hematologic toxicity, and 8 of grade 3 fatigue) refused subsequent chemotherapy due to intolerable toxicity. Main grade 3 or 4 adverse events in patients were neutropenia in 69 cases (22.1%), fatigue in 35 cases (11.2%), and anemia in 28 cases (8.9%). Twenty serious adverse events (6.4%) occurred, including 13 patients of febrile neutropenia (4.2%), 7 patients of intestinal perforation (2.2%, 4 patients in upper rectum, 2 in sigmoid colon, and 1 in transverse colon cancer), and 9 of them had subsequent sepsis (2.9%). All the patients with intestinal perforation underwent emergency operation. No treatment-related deaths occurred. In 199 patients with metastatic CRC, because 22 patients did not receive image evaluation, the preliminary efficacy of 177 patients was actually evaluated. A total of 113 objective response events were observed. The overall response rate was 63.8%(113/177), partial response rate was 61.6%(109/177), clinically complete response rate was 2.3%(4/177), stable disease was 29.9% (53/177), progressive disease was 6.2%(11/177), and the disease control rate was 93.8%(166/177). In 127 patients receiving triplet drug, objective response rate was 40.9% for those with less than four cycles and 81.1% for those with more than four cycles (P<0.001).

CONCLUSIONThe mFOLFOXIRI regimen with reduced dose can be safely used in advanced CRC and has achieved promising results in terms of short-term efficacy.

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Camptothecin ; administration & dosage ; analogs & derivatives ; Colorectal Neoplasms ; drug therapy ; Fluorouracil ; administration & dosage ; Humans ; Leucovorin ; administration & dosage ; Middle Aged ; Organoplatinum Compounds ; administration & dosage ; Retrospective Studies ; Treatment Outcome ; Young Adult

PURPOSE: Vascular endothelial growth factor (VEGF) signal transduction mainly depends on its binding to VEGF receptor 2 (VEGFR-2). VEGF downstream signaling proteins mediate several of its effects in cancer progression, including those on tumor growth, metastasis, and blood vessel formation. The activation of VEGFR-2 signaling is a hallmark of and is considered a therapeutic target for breast cancer. Here, we report a study of the regulation of the VEGFR-2 signaling pathway by a small molecule, isomangiferin. METHODS: A human breast cancer xenograft mouse model was used to investigate the efficacy of isomangiferin in vivo. The inhibitory effect of isomangiferin on breast cancer cells and the underlying mechanism were examined in vitro. RESULTS: Isomangiferin suppressed tumor growth in xenografts. In vitro, isomangiferin treatment inhibited cancer cell proliferation, migration, invasion, and adhesion. The effect of isomangiferin on breast cancer growth was well coordinated with its suppression of angiogenesis. A rat aortic ring assay revealed that isomangiferin significantly inhibited blood vessel formation during VEGF-induced microvessel sprouting. Furthermore, isomangiferin treatment inhibited VEGF-induced proliferation of human umbilical vein endothelial cells and the formation of capillary-like structures. Mechanistically, isomangiferin induced caspase-dependent apoptosis of breast cancer cells. Furthermore, VEGF-induced activation of the VEGFR-2 kinase pathway was down-regulated by isomangiferin. CONCLUSION: Our findings demonstrate that isomangiferin exerts anti-breast cancer effects via the functional inhibition of VEGFR-2. Pharmaceutically targeting VEGFR-2 by isomangiferin could be an effective therapeutic strategy for breast cancer.
Angiogenesis Inhibitors ; Animals ; Apoptosis ; Blood Vessels ; Breast Neoplasms ; Cell Proliferation ; Heterografts ; Human Umbilical Vein Endothelial Cells ; Humans ; In Vitro Techniques ; Mice ; Microvessels ; Neoplasm Metastasis ; Phosphotransferases ; Rats ; Receptors, Vascular Endothelial Growth Factor* ; Signal Transduction ; Vascular Endothelial Growth Factor A* ; Vascular Endothelial Growth Factor Receptor-2*

Objective To explore the relationship between the polymorphisms of the primary gout predisposing gene (BCAS3) rs11653176 locus and the incidence of gout in Han Chinese men in coastal areas of Shandong Province. Methods One hundred and fifty-two cases of patients with gout remission,68 cases of acute stage,252 patients with hyperuricemia, and 280 healthy subjects, total males, were enrolled. Genotyping the rs11653176 locus of BCAS3 gene by TaqMan probe technique. The expression level of BCAS3 gene mRNA in each PBMC was measured by RT-qPCR. The levels of tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-18(IL-18)in serum were measured by ELISA. Results The change of allele frequency of rs11653176 locus in BCAS3 gene was associated with gout(P<0.01). BCAS3 mRNA in patients with gout was significantly higher than that of healthy people and patients with hyperuricemia(P<0.01). In gout patients, the expression level of BCAS3 gene containing C allele was higher than that of T allele(mRNA,P<0.05). The inflammatory factors in the acute phase of gout were significantly higher than those in phases of remission and hyperuricemia(P<0. 01). Conclusion Changes in the allele frequency of BCAS3 alleles rs11653176(high C, low T)may contribute to the expression of this gene,and lead to gout. And the onset of gout is closely related to the production of inflammatory factors.