[Association of Serine/Threonine Phosphoprotein Phosphatase 4C Expression With Prognosis of Gastric Cancer].

Objective To investigate the expression level of serine/threonine phosphoprotein phosphatase 4C(PPP4C)in gastric cancer,and analyze its relationship with prognosis and the underlying regulatory mechanism.Methods The clinical data of 104 gastric cancer patients admitted to the First Affiliated Hospital of Bengbu Medical College between January 2012 and August 2016 were collected.Immunohistochemical staining was employed to determine the expression levels of PPP4C and Ki-67 in the gastric cancer tissue.The gastric cancer cell lines BGC823 and HGC27 were cultured and transfected with the vector for PPP4C knockdown,the vector for PPP4C overexpression,and the lentiviral vector(control),respectively.The effects of PPP4C on the cell cycle and proliferation were analyzed and the possible regulatory mechanisms were explored.Results PPP4C was highly expressed in gastric cancer(P<0.001),and its expression promoted malignant progression of the tumor(all P<0.01).Univariate and Cox multivariate analysis clarified that high expression of PPP4C was an independent risk factor affecting the 5-year survival rate of gastric cancer patients(P=0.003).Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis suggested that PPP4C may be involved in the cell cycle.The correlation analysis showed that the expression of PPP4C was positively correlated with that of Ki-67 in gastric cancer(P<0.001).The up-regulation of PPP4C expression increased the proportion of tumor cells in the S phase,alleviated the G2/M phase arrest,and promoted the proliferation of gastric cancer cells and the expression of cyclin D1 and cyclin-dependent kinase 6(CDK6)(all P<0.05).The down-regulation of PPP4C decreased the proportion of gastric cancer cells in the S phase,promoted G2/M phase arrest,and inhibited cell proliferation and the expression of cyclin D1,CDK6,and p53(all P<0.05).p53 inhibitors promoted the proliferation of BGC823 and HGC27 cells in the PPP4C knockdown group(P<0.001,P<0.001),while p53 activators inhibited the proliferation of BGC823 and HGC27 cells in the PPP4C overexpression group(P<0.001,P=0.002).Conclusions PPP4C is highly expressed in gastric cancer and affects the prognosis of the patients.It may increase the proportion of gastric cancer cells in the S phase and alleviate the G2/M phase arrest by inhibiting p53 signaling,thereby promoting cell proliferation.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database.

Aims: We aimed to estimate the risk of drug-induced liver injury (DILI) from various antifungal treatments with azoles and echinocandins causing in real-world practice. Methods: We performed disproportionality and Bayesian analyses based on data from the first quarter in 2004 to the third quarter in 2021 in the Food and Drug Administration Adverse Event Reporting System to characterize the signal differences of antifungal drugs-related DILI. We also compared the onset time and mortality differences of different antifungal agents. Results: A total of 2943 antifungal drugs-related DILI were identified. Affected patients tended to be aged >45 years (51.38%), with more males than females (49.03% vs. 38.09%). Antifungal drug-induced liver injury is most commonly reported with voriconazole (32.45%), fluconazole (19.37%), and itraconazole (14.51%). Almost all antifungal drugs were shown to be associated with DILI under disproportionality and Bayesian analyses. The intraclass analysis of correlation between different antifungal agents and DILI showed the following ranking: caspofungin (ROR = 6.12; 95%CI: 5.36-6.98) > anidulafungin (5.15; 3.69-7.18) > itraconazole (5.06; 4.58-5.60) > voriconazole (4.58; 4.29-4.90) > micafungin (4.53; 3.89-5.27) > posaconazole (3.99; 3.47-4.59) > fluconazole (3.19; 2.93-3.47) > ketoconazole (2.28; 1.96-2.64). The onset time of DILI was significantly different among different antifungal drugs (p < 0.0001), and anidulafungin result in the highest mortality rate (50.00%), while ketoconazole has the lowest mortality rate (9.60%). Conclusion: Based on the Food and Drug Administration Adverse Event Reporting System database, antifungal drugs are significantly associated with DILI, and itraconazole and voriconazole had the greatest risk of liver injury. Due to indication bias, more clinical studies are needed to confirm the safety of echinocandins.

Stevens-Johnson Syndrome Following Non-steroidal Anti-inflammatory Drugs: A Real-World Analysis of Post-marketing Surveillance Data.

Background: The Stevens-Johnson syndrome (SJS) is a severe skin reaction to non-steroidal anti-inflammatory drugs (NSAIDs), and can even be life-threatening. However, there are still few real-world studies to compare the specific differences in the adverse effects of skin and mucosal invasion. Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected SJS after using NSAIDs based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of antipyretic analgesic-associated SJS were also investigated. Results: A total of 1,868 reports of SJS adverse events were identified with NSAIDs. Among 5 NSAIDs monotherapies we studied (acetaminophen, ibuprofen, aspirin, diclofenac and celecoxib), ibuprofen had the highest association with SJS based on the highest reporting odds ratio (ROR = 7.06, 95% two-sided CI = 6.59-7.56), proportional reporting ratio (PRR = 6.98, χ2 = 4201.14) and empirical Bayes geometric mean (EBGM = 6.78, 95% one-sided CI = 6.40). However, ibuprofen-associated SJS had the lowest fatality rate (6.87%, p < 0.0001) and the highest hospitalization rate (79.27%, p < 0.0001). Celecoxib-associated SJS had the latest time to onset (317.56 days, p < 0.0001). Diclofenac-associated SJS cases appeared to be associated with the highest risk of death (25.00%, p < 0.0001). Conclusions: The analysis of FAERS data provides a more accurate profile of the incidence and prognosis of SJS after NSAIDs treatment, enabling continued surveillance and timely intervention in patients at risk of SJS following these NSAIDs.

Ruxolitinib treatment permits lower cumulative glucocorticoid dosing in children with secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: This study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH). METHODS: Eleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed. RESULTS: In group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2-2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up. CONCLUSION: Ruxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

Intestinal microbiota and juvenile idiopathic arthritis: current understanding and future prospective.

BACKGROUND: Juvenile idiopathic arthritis (JIA) characterized by arthritis of unknown origin is the most common childhood chronic rheumatic disease, caused by both host genetic factors and environmental triggers. Recent evidence has mounted to focus on the intestinal microbiota, a potentially recognized set of environmental triggers affecting JIA development. Here we offer an overview of recently published animal and human studies that support the impact of intestinal microbiota in JIA. DATA SOURCES: We searched PubMed for animal and human studies publications with the search terms "intestinal microbiota or gut microbiota" and "juvenile idiopathic arthritis or juvenile chronic arthritis or juvenile rheumatoid arthritis or childhood rheumatoid arthritis or pediatric rheumatoid arthritis". RESULTS: Several comparative studies have demonstrated that intestinal microbial alterations might be triggers in disease pathogenesis. Alternatively, a slice of studies has suggested environmental triggers in early life might disrupt intestinal microbial colonization, including cesarean section, formula feeding, and antibiotic exposure. Aberrant intestinal microbiota may influence the development of JIA by mediating host immune programming and by altering mucosal permeability. CONCLUSIONS: Specific microbial factors may contribute to the pathogenesis of JIA. Intensive studies, however, are warranted to investigate the causality between intestinal dysbiosis and JIA and the mechanisms behind these epidemiologic relationships. Studies are also needed to design the best interventional administrations to restore balanced intestinal microbial communities.

The Human Amniotic Mesenchymal Stem Cells (hAMSCs) Improve the Implant Osseointegration and Bone Regeneration in Maxillary Sinus Floor Elevation in Rabbits.

Insufficient bone height in the posterior maxilla is a challenging problem in dental implantation. Bio-Oss, though routinely used in maxillary sinus floor elevation (MSFE), is not osteoinductive. Human amniotic mesenchymal cells (hAMSCs) isolated from placental tissues have potential for multidifferentiation and immunomodulatory properties and can be easily obtained without the need for invasive procedures and without ethical concerns. This is the first study to use hAMSCs to improve implant osseointegration and bone regeneration after MSFE. Human AMSCs were loaded into a fibrin gel and injected into rabbit MSFE models. The rabbits were assigned to four groups (n = 3 per group), i.e., the control group, the hAMSC group, the Bio-Oss group, and the hAMSC/Bio-Oss group. The animals were sacrificed at postsurgery for four and twelve weeks and evaluated by histology and immunohistochemistry. Bone volume, bone volume/tissue volume, bone-to-implant contact ratio, and vessel-like structures in the hAMSC/Bio-Oss group were significantly better than those in other groups in the peri-implant and augmented areas. Immunofluorescence staining showed that alkaline phosphatase (ALP) activities of two hAMSC groups were higher than those of the other two groups. Sequential fluorescent labeling was performed in all of the 12-week groups. Observations showed that hAMSCs accelerated mineralized deposition rates on implant surfaces and in bone-augmented areas. These data demonstrated that hAMSCs could enhance implant osseointegration and bone regeneration after MSFE and might be used to optimize dental implantation in the future.

Reports of three cases with the initial presentation of mesenteric vasculitis in children with system lupus erythematous.

We reviewed three cases of systemic lupus erythematosus (SLE) in children with mesenteric vasculitis (LMV) as initial presentation and analysed their clinical characteristics to improve the understanding of this disease. Three patients with SLE were admitted to our hospital and initially presented with gastrointestinal symptoms. We retrospectively analysed their clinical data, including clinical presentations, laboratory results, images and short- and long-term treatment outcomes. (1) All three children were school-age girls. The patients were presented to our hospital with vomiting and abdominal pain as initial symptoms. The patients also had urinary symptoms, including proteinuria in three cases, ureteropelvic dilatation in two cases and hydronephrosis in one case. (2) The patients had various positive autoantibodies and a low complement level. Two of the patients had blood system involvement, and one had central nervous system symptoms. (3) All of the patients had active SLE (SLEDAI-2K score ≥ 5 points and moderate to severe degree 10-24). (4) Abdominal CT scans with contrast showed the 'target sign' of the intestinal wall in case 1, a slightly thickened intestinal wall and blurry mesentery in case 2, and the 'comb sign' of the margin mesenteric blood vessels in case 3. (5) All three patients responded promptly to steroid therapy. The patients' symptoms improved rapidly after treatment. LMV is a rare SLE complication. The lack of comprehensive understanding of LMV's clinical presentation makes it considerably challenging to diagnose. LMV is also a serious complication of SLE that is often accompanied by concurrent damage to other organs. LMV often occurs with active SLE but responds rapidly to glucocorticoid therapy. Therefore, in order to make early diagnosis and treatment, we suggest checking autoantibodies and abdominal CT scans with contrast when children present with gastrointestinal symptoms and the involvement of other organs, especially the urinary system.

[A study of maxillary sinus lateral wall thickness of Han population in Jiangsu region using cone-beam CT].

PURPOSE: To evaluate maxillary sinus lateral wall thickness by use of cone-beam computed tomography (CBCT), in order to provide anatomical basis for preoperative risk assessment and operation guidance of maxillary sinus lifting. METHODS: Using SimPlant software, the 3D images were reconstructed with CBCT images from 412 subjects and the thickness of maxillary sinus lateral wall were evaluated at measurement plane. The data was analyzed with SPSS17.0 software package. RESULTS: Among 412 subjects (824 sides), the mean thickness of maxillary sinus lateral wall at the second premolar (P2), the first molar (M1) and the second molar (M2) was 2.23±1.07 mm, 2.19±1.45 mm and 1.41±0.81 mm, respectively. The thickness of maxillary sinus lateral wall on the left side were significantly different from that on the right side at P2 (P<0.01). Significant gender differences on the thickness of maxillary sinus lateral wall were demonstrated at P2 and M2 (P<0.05), and the thickness in men were thicker than that in women. The thickness of maxillary sinus lateral wall at M1 and M2 were significantly different among different age groups (P<0.05). There was no significant difference on the lateral wall thickness with respect to presence or absence of tooth. CONCLUSIONS: CBCT can accurately measure the thickness of maxillary sinus lateral wall. The mean thickness of lateral wall changes at different reference points. The value at premolar region is greater than that at molar region, and the maxillary sinus lateral wall is the thinnest at M2. There are significant differences in the mean thickness of the lateral wall with respect to age, gender, and side of maxillay sinus. Supported by National Natural Science Foundation of China (81271109), Priority Academic Development Program of Jiangsu Higher Education Institutions (2011-137).

[Comparative study on the morphology of crown, alveolar ridge crest and gingival in maxillary anterior region].

OBJECTIVE: To investigate the correlation among the morphology of crown, alveolar ridge crest and gingiva in maxillary anterior region of adults and to provide anatomical basis for clinical implant esthetics. METHODS: Sixty Han-Chinese with healthy peridontium were selected in this study. The curvature of labial alveolar crest, the length and height of inter-proximal bone were measured on 3-D model reconstructed from cone-beam CT (CBCT) images, and the curvature of free gingiva, the width and height of inter-dental papilla and central incisor crown were evaluated on casts. The ratio of crown width to height was ranked and the 10 ranked highest were categorized as group Short-Wide (SW), the 10 ranked lowest were selected as group Long-Narrow (LN). RESULTS: In maxillary anterior region, the curvature angle of both alveolar crest and marginal gingiva were significantly different among different tooth regions, but the alveolar and gingival curvature was significantly correlated in the same region (P < 0.05). The morphology of inter-proximal bone and papilla was significantly correlated (P < 0.01), except the region between central and lateral incisors (P = 0.625, P > 0.05). Compared to group SW, group LN formed a pronounced scalloped contour of gingival margin (P = 0.002) and slender inter-dental papilla (P = 0.000). CONCLUSIONS: The free gingival curvature and inter-dental papillary morphology are significantly correlated with the morphology of crown and alveolar ridge crest in maxillary anterior region of Han-Chinese. Individuals with long-narrow crown, pronounced scalloped marginal gingiva and slender inter-dental papilla are susceptible to risk implant esthetics.

[An anatomical study of maxillary sinus septum of Han population in Jiangsu region using cone-beam CT].

PURPOSE: To examine the anatomical variation of maxillary sinus septum of Han nationality in Jiangsu region by using cone-beam computed tomography (CBCT) combined with Simplant software in order to provide anatomical basis and operation instruction for oral implants after maxillary sinus lifting. METHODS: CBCT image data were collected from 424 patients for analysis of maxillary sinus septa. Digital imaging and communications in medicine (Dicom) image files were fed into the computer-aided Simplant software and used to analyze the prevalence, location, height, orientation, and morphology of maxillary sinus septa through three-dimensional reconstruction. The data was analyzed with SPSS17.0 software package. RESULTS: The proportion of the occurrence of maxillary sinus septa in 424 subjects was 44.81% and 21.23% of the subjects (n=90) had multiple sinus septa, while 20.52% had bilateral sinus septa (n=87). Totally 848 maxillary sinuses were observed in this study and 277 sinuses had septa with a proportion of 32.67%. The prevalence of septa was not significantly related to gender, age, and the presence or absence of teeth. Septa were located most frequently in the middle of maxillary sinus (59.94%). The mean height of sinus septa was (5.90±3.65) mm and (5.54±2.87) mm in the right and left maxillary sinus, respectively. The mean length of sinus septa was (8.15±2.40) mm and (7.88±2.73) mm in the right and left maxillary sinus, respectively. CONCLUSIONS: Nearly 44.81% of Han population in Jiangsu region have maxillary sinus septa. The CBCT imaging technique can provide comprehensive and accurate quantitative analysis of maxillary sinus septa and is meaningful to provide anatomical basis and clinical guidance before sinus augmentation procedures.

[Rituximab therapy for severe pediatric systemic lupus erythematosus].

OBJECTIVE: To analyze the safety and efficacy of anti-CD20 monoclonal antibody in treatment of severe pediatric systemic lupus erythematosus (PSLE). METHOD: The diagnosis of PSLE was made according to the criteria for the classification of systemic lupus erythematosus revised by the American College of Rheumatology in 1997. Severe cases with PSLE was selected by the following criteria: age ≤ 16 years, number of important organs involved > 1, SLEDAI score > 10 points and poor response to conventional immunosuppressive treatment. These patients received 2 doses of 375 mg/m(2) rituximab (RTX), 2 weeks apart. Clinical, laboratory findings and drug side effects were recorded at RTX initiation, 2 weeks, 1 month, 3, 6 and 12 months after infusion. RESULT: A total of 20 patients. Male to female ratio was 1:3, were enrolled. They were 5-16 years old. The course of disease was (3.0 ± 2.5) years (range: 1 month-7 years), patients were followed up for 12 - 36 months [median: (27.0 ± 7.8) months]. Delirium and cognitive disorders were significantly improved in 10 cases of lupus encephalopathy after 1 month. Lupus nephritis in children were eased slowly, 14/15 patients with lupus nephritis were improved after 2-3 months. Four cases of lupus pneumonia were significantly improved within 1 month. Decreased blood cells counts were relieved at 1 month in 16/18 cases. Cellular immune function was assessed 2 weeks after application of anti-CD20 monoclonal antibody; we found B-cell clearance in 19 patients (95%). B lymphocyte count of 18 patients (90%) was restored within one year. SLEDAI score was reduced obviously. Dose of corticosteroid ranged from (45.0 ± 4.7) mg/m(2) before drug use to (12.0 ± 2.7) mg/m(2) 12 months later (P < 0.001). After the drug use, 5 patients had pneumonia within 6 months; 2 cases who suffered from aspergillus pneumonia and Pneumocystis carinii pneumonia respectively were severe. They accepted mechanical ventilation and anti-inflammatory support after being transferred to the intensive care unit, and their conditions improved at last. No death occurred. In 2 patients the disease recurred with B-cell recovery after 15 months and 18 months. Administration of another cycle of rituximab resulted in remission again in one case but not in the other. CONCLUSION: Anti-CD20 monoclonal antibody is effective and safe in treatment of severe PSLE. But severe infections may occur in some cases. Focusing on prevention and early treatment can reduce the probability of adverse reactions.

In vitro degradation of biodegradable blending materials based on poly(p-dioxanone) and poly(vinyl alcohol)-graft-poly(p-dioxanone) with high molecular weights.

Amphiphilic biodegradable graft copolymer, poly(vinyl alcohol)-graft-poly(p-dioxanone) (PVA-g-PPDO), was used to prepare a new biodegradable material by blending with poly(p-dioxanone) (PPDO). The in vitro degradation properties of the copolymer and blends with different contents of PVA-g-PPDO were studied in phosphate buffer at 37 degrees C. The degradation processes of the PVA-g-PPDO and its blends with the PPDO were monitored by weight loss, viscosimetry, water uptake, differential scanning calorimetry (DSC), and scanning electron microscopy. The results of inherent viscosity and weight loss reveal that the PVA-g-PPDO has a different in vitro degradation behavior from that of PPDO, and the introducing of copolymer into the blending system may enhance the degradability of PPDO when the contents of copolymer is higher than 5%. The change of the degree of crystallization (Dc) of copolymer and blends derived from the DSC also shows that the copolymer and blends have faster degradation rates than the neat PPDO during the testing period. A degradation mechanism of the blends was postulated based on the results of the weight retention, inherent viscosity measurement, and DSC.