简介：AbstractBackground:Traumatic brain injury, one of the leading causes of death in adults under 40 years of age in the world, is frequently caused by mechanical shock, resulting in diffuse neuronal damage and long-term cognitive dysfunction. Many existing TBI animal models revival with expensive equipment or special room are needed or the processes of operations are complex and not easy to be widely used. Therefore, a simpler TBI model needs to be designed.Methods:Our TBI model is an innovation of the modeling method through air guns shutting rubber bullets. A core facet is the application of our designed rubber bullet impact device. It could focus the hitting power to the fixed site of the brain, thus triggering a mild closed head injury. Moreover, the degree of damage can be adjusted by the times of shots.Results:Our model induced blood-brain barrier leakage and diffused neuronal damage. Besides, it led to an increased level of Tau phosphorylation and resulted in cognitive dysfunction within several weeks post-injury.Conclusion:Our TBI model is not only simple and time-saving but also can simulate mild brain injuries in clinical. It is suitable for exploring pathobiological mechanisms as well as a screening of potential therapies for TBI.

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简介：AbstractObjective:Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism and anti-inflammatory properties; however, limited information is available regarding its therapeutic potential in PCOS.Methods:Female C57BL/6 mice were randomly assigned into four groups (n = 6 mice/group): the control, letrozole or dehydroepiandrosterone-induced PCOS groups, PCOS + 20 mg/kg liquiritin group, and control + liquiritin groups. After 21 days of treatment, the mice were euthanized, and the associated metabolism indications were investigated. Ovarian histological examinations were performed, and serum hormone concentration was measured. The expression of key genes involved in steroid hormone synthesis, ovarian follicle development, and ovulation was assessed.Results:Liquiritin reduced fasting blood glucose levels and increased insulin sensitivity compared to the PCOS group. Liquiritin also significantly decreased serum levels of total testosterone (P < 0.001) and dehydroepiandrosterone sulfate (P < 0.05) in the PCOS group. Histomorphological inspection of ovaries from the liquiritin group revealed fewer cystic dilated follicles than in the PCOS group. Moreover, liquiritinsignificantly (P < 0.01) decreased Cyp17a1, Cyp19a1, Fshr, Hsd3b2, Runx2, and Ccn2 mRNA expression compared to letrozole-induced PCOS.Conclusion:Liquiritin may be safe and helpful in ameliorating PCOS-associated hyperandrogenemia and hyperglycemia. However, clinical trials investigating different liquiritin dosages are needed to confirm these findings.

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简介：AbstractObjective:To examine referral pattern, the timing of diagnostic/staging processes, and treatment initiation for new head and neck cancer patients in a community setting.Methods:Patients with a newly diagnosed previously untreated diagnosis of head neck cancer managed at Asplundh Cancer Pavilion/Abington Memorial Hospital from October 2018 to March 2020. Source of referral and preceding workup were examined as well as intervals between initial head and neck consult and various timepoints of treatment initiation.Results:One hundred and five patients were included in the study. The primary referral sources were external general otolaryngology (56.3%). Oral surgery and dermatology obtained tissue biopsy approximately 80% of the time before referral. The average time from the ordering of initial staging positron emission tomography/computed tomography to finalized results was 14 days (range: 10-25 days). Patients referred from dermatology and oral surgery were more likely to require single modality care, namely definitive surgical management. Time to treatment initiation average was 37 days (range: 29-41 days). Patients with longer treatment times noted significantly higher times to both radiation and medical oncology consults (48.42 vs. 18.13 days; P < 0.001).Conclusions:No notable differences in treatment initiation times were identified based on referral source or extent of workup performed before head/neck surgery consult. It appears the largest opportunities for improvement in terms of reducing overall treatment length exist in the optimization of radiation initiation time.

简介：AbstractBackground:Food-borne parasitic diseases decrease food safety and threaten public health. The snail species is an intermediate host for numerous human parasitic trematodes. Orientogalba ollula has been reported as intermediate hosts of many zoonotic trematodes. Here, we investigated the prevalence of zoonotic trematodes within O. ollula in Guangxi, China, and assessed their zoonotic potential.Methods:Snails were collected from 54 sites in 9 cities throughout Guangxi. The snail and trematode larvae species were determined by combining morphological characteristics and molecular markers. The trematodes prevalence and constituent ratio were calculated and compared among different habitat environments. Phylogenetic trees of the trematode species were constructed using the neighbor-joining method with nuclear internal transcribed spacer 2 (ITS2) sequences. The developmental cycles of the isolated trematodes were examined by experimental infection in ducks. The developmental characteristics of Echinostoma revolutum was recorded by dissecting infected ducklings from 1-day post infection (dpi) to 10 dpi.Results:The overall prevalence of trematode larvae was 22.1% (1818/8238) in O. ollula from 11 sample sites. Morphological together with molecular identification, showed that E. revolutum, Australapatemon sp., Hypoderaeum conoideum, Pharyngostomum cordatum, and Echinostoma sp. parasitized O. ollula, with the highest infection rate of E. revolutum (13.0%). However, no Fasciola larvae were detected. The trematodes prevalence and constituent ratio varied in two sub-biotypes (P < 0.01). A neighbor-joining tree analysis of ITS2 sequences resulted in distinct monophyletic clades supported by sequences from isolated larvae with high bootstrap values. Ducklings exposed to O. ollula infected with Echinostoma sp., E. revolutum, and H. conoideum larvae were successfully infected. The animal model for Echinostoma revolutum was successfully established. E. revolutum matured from larvae to adult at 10 dpi in the intestine of the duck, and the developmental characteristics of E. revolutum were characterized by the maturation of the reproductive and digestive organs at 6-8 dpi.Conclusions:This study revealed a high prevalence of zoonotic trematodes in O. ollula from Guangxi, China. Existing trematodes infection in animals and human clinical cases, coupled with the wide geographical distribution of O. ollula, necessitate further evaluations of the potential risk of spillover of zoonotic infection from animal to human and vice versa.

简介：AbstractBackground:Despite advances in decompressive craniectomy (DC) for the treatment of traumatic brain injury (TBI), these patients are at risk of having a poor long-term prognosis. The aim of this study was to predict 1-year mortality in TBI patients undergoing DC using logistic regression and random tree models.Methods:This was a retrospective analysis of TBI patients undergoing DC from January 1, 2015, to April 25, 2019. Patient demographic characteristics, biochemical tests, and intraoperative factors were collected. One-year mortality prognostic models were developed using multivariate logistic regression and random tree algorithms. The overall accuracy, sensitivity, specificity, and area under the receiver operating characteristic curves (AUCs) were used to evaluate model performance.Results:Of the 230 patients, 70 (30.4%) died within 1 year. Older age (OR, 1.066; 95% CI, 1.045-1.087; P < 0.001), higher Glasgow Coma Score (GCS) (OR, 0.737; 95% CI, 0.660-0.824; P < 0.001), higher D-dimer (OR, 1.005; 95% CI, 1.001-1.009; P = 0.015), coagulopathy (OR, 2.965; 95% CI, 1.808-4.864; P < 0.001), hypotension (OR, 3.862; 95% CI, 2.176-6.855; P < 0.001), and completely effaced basal cisterns (OR, 3.766; 95% CI, 2.255-6.290; P < 0.001) were independent predictors of 1-year mortality. Random forest demonstrated better performance for 1-year mortality prediction, which achieved an overall accuracy of 0.810, sensitivity of 0.833, specificity of 0.800, and AUC of 0.830 on the testing data compared to the logistic regression model.Conclusions:The random forest model showed relatively good predictive performance for 1-year mortality in TBI patients undergoing DC. Further external tests are required to verify our prognostic model.

简介：AbstractBackground:Tourette syndrome (TS) is a neuropsychiatric disorder with onset in childhood that warrants effective therapies. Gut microbiota can affect central physiology and function via the microbiota-gut-brain axis. Therefore, the gut microbiota plays an important role in some mental illnesses. A small clinical trial showed that fecal microbiota transplantation (FMT) may alleviate TS symptoms in children. Herein, FMT effects and mechanisms were explored in a TS mouse model.Methods:TS mice model (TSMO) (n = 80) were established with 3,3＇-iminodipropionitrile, and 80 mice were used as controls. Mice were grouped into eight groups and were subjected to FMT with feces from children or mice with or without TS, or were given probiotics. Fecal specimens were collected 3 weeks after FMT. 16S rRNA sequencing, behavioral observation, and serum serotonin (5-HT) assay were performed. Differences between groups were analyzed using Mann-Whitney U test and Kolmogorov-Smirnov (KS) tests.Results:A total of 18 discriminative microbial signatures (linear discriminant analysis score > 3) that varied significantly between TS and healthy mice (CONH) were identified. A significant increase in Turicibacteraceae and Ruminococcaceae in TSMO after FMT was observed (P < 0.05). Compared with non-transplanted TSMO, the symptoms of those transplanted with feces from CONH were alleviated (W = 336, P = 0.046). In the probiotic and FMT experiments, the serum 5-HT levels significantly increased in TSMO that received probiotics (KS = 1.423, P = 0.035) and in those transplanted with feces from CONH (W= 336.5, P = 0.046) compared with TSMO without transplantation.Conclusions:This study suggests that FMT may ameliorate TS by promoting 5-HT secretion, and it provides new insights into the underlying mechanisms of FMT as a treatment for TS.

简介：AbstractBackground:Despite improvements in disease diagnosis, treatment, and prognosis, breast cancer is still a leading cause of cancer death for women. Compelling evidence suggests that targeting cancer stem cells (CSCs) have a crucial impact on overcoming the current shortcomings of chemotherapy and radiotherapy. In the present study, we aimed to study the effects of T cells and a critical anti-tumor cytokine, interferon-gamma (IFN-γ), on breast cancer stem cells.Methods:BALB/c mice and BALB/c nude mice were subcutaneously injected with 4T1 tumor cells. Tumor growth and pulmonary metastasis were assessed. ALDEFLOURTM assays were performed to identify aldehyde dehydrogenasebright (ALDHbr) tumor cells. ALDHbr cells as well as T cells from tumor-bearing BALB/c mice were analyzed using flow cytometry. The effects of CD8+ T cells on ALDHbr tumor cells were assessed in vitro and in vivo. The expression profiles of ALDHbr and ALDHdim 4T1 tumor cells were determined. The levels of plasma IFN-γ were measured by enzyme-linked immunosorbent assay, and their associations with the percentages of ALDHbr tumor cells were evaluated. The effects of IFN-γ on ALDH expression and the malignancy of 4T1 tumor cells were analyzed in vitro.Results:There were fewer metastatic nodules in tumor-bearing BALB/c mice than those in tumor-bearing BALB/c nude mice (25.40 vs. 54.67, P < 0.050). CD8+ T cells decreased the percentages of ALDHbr 4T1 tumor cells in vitro (control vs. effector to target ratio of 1:1, 10.15% vs. 5.76%, P < 0.050) and in vivo (control vs. CD8+ T cell depletion, 10.15% vs. 21.75%, P < 0.001). The functions of upregulated genes in ALDHbr 4T1 tumor cells were enriched in the pathway of response to IFN-γ. The levels of plasma IFN-γ decreased gradually in tumor-bearing BALB/c mice, while the percentages of ALDHbr tumor cells in primary tumors increased. IFN-γ at a concentration of 26.68 ng/mL decreased the percentages of ALDHbr 4T1 tumor cells (22.88% vs. 9.88%, P < 0.050) and the protein levels of aldehyde dehydrogenase 1 family member A1 in 4T1 tumor cells (0.86 vs. 0.49, P < 0.050) and inhibited the abilities of sphere formation (sphere diameter <200 μm, 159.50 vs. 72.0; ≥200 μm, 127.0 vs. 59.0; both P < 0.050) and invasion (89.67 vs. 67.67, P < 0.001) of 4T1 tumor cells.Conclusion:CD8+ T cells and IFN-γ decreased CSC numbers in a 4T1 mouse model of breast cancer. The application of IFN-γ may be a potential strategy for reducing CSCs in breast cancer.

简介：AbstractBackground:Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s dementia. Mitochondrial dysfunction is involved in the pathology of PD. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was identified as associated with autosomal dominant PD. However, the mechanism of CHCHD2 in PD remains unclear.Methods:Short hairpin RNA (ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma (SHSY5Y) and HeLa cells. Blue-native polyacrylamide gel electrophoresis (PAGE) and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system (MICOS). Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10. Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were used to examine the influence of CHCHD2 in vivo.Results:We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model. Furthermore, we identified that CHCHD2 interacted with Mic10, and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment, while knockdown of CHCHD2 impaired the stability of MICOS.Conclusion:This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex, which contributes to protecting mitochondrial function in PD.

简介：AbstractBackground:Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods:A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen-activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope.Results:First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N-terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions:Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.

简介：AbstractBackground:Breast cancer with low-positive human epidermal growth factor receptor 2 (HER2) expression has triggered further refinement of evaluation criteria for HER2 expression. We studied the clinicopathological features of early-stage breast cancer with low-positive HER2 expression in China and analyzed prognostic factors.Methods:Clinical and pathological data and prognostic information of patients with early-stage breast cancer with low-positive HER2 expression treated by the member units of the Chinese Society of Breast Surgery and Chinese Society of Surgery of Chinese Medical Association, from January 2015 to December 2016 were collected. The prognostic factors of these patients were analyzed.Results:Twenty-nine hospitals provided valid cases. From 2015 to 2016, a total of 25,096 cases of early-stage breast cancer were treated, 7642 (30.5%) of which had low-positive HER2 expression and were included in the study. After ineligible cases were excluded, 6486 patients were included in the study. The median follow-up time was 57 months (4-76 months). The disease-free survival rate was 92.1% at 5 years, and the overall survival rate was 97.4% at 5 years. At the follow-up, 506 (7.8%) cases of metastasis and 167 (2.6%) deaths were noted. Multivariate Cox regression analysis showed that tumor stage, lymphvascular invasion, and the Ki67 index were related to recurrence and metastasis (P < 0.05). The recurrence risk prediction model was established using a machine learning model and showed that the area under the receiving operator characteristic curve was 0.815 (95% confidence interval: 0.750-0.880).Conclusions:Early-stage breast cancer patients with low-positive HER2 expression account for 30.5% of all patients. Tumor stage, lymphvascular invasion, and the Ki67 index are factors affecting prognosis. The recurrence prediction model for breast cancer with low-positive HER2 expression based on a machine learning model had a good clinical reference value for predicting the recurrence risk at 5 years.Trial registration:ChiCTR.org.cn, ChiCTR2100046766.