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Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer’s disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

The impact of adjuvant radiotherapy in pT3N0 rectal cancer is controversial. We aimed to determine the risk factors for cancer‐specific survival (CSS) among these patients and to develop a risk‐stratification system to identify which of these patients would benefit from adjuvant radiotherapy. In this review of the Surveillance, Epidemiology, and End Results database (2010‐2014), we analyzed the data of pT3N0 rectal cancer patients who had not undergone neoadjuvant radiotherapy. Prognostic factors were identified using the Cox proportional hazards model, and risk scores were derived according to the β regression coefficient. A total of 1021 patients were identified from the database search. The overall 5‐year CSS was 86.31%. Multivariate analysis showed that age (P

BackgroundNoonan syndrome is an inherited disease involving multiple systems. More than 15 related genes have been discovered, among whichLZTR1was discovered recently. However, the pathogenesis and inheritance pattern ofLZTR1in Noonan syndrome have not yet been elucidated.Case presentationWe herein describe a family withLZTR1-related Noonan syndrome. In our study, the proband, sister, mother, maternal aunt and grandmother and female cousin showed the typical or atypical features of Noonan syndrome. Only 3 patients underwent the whole-exome sequencing analysis and results showed that the proband as well as her sister inherited the same heterozygousLZTR1variant (c.1149 + 1G > T) from their affected mother. Moreover, the proband accompanied by growth hormone deficiency without other associated variants.ConclusionIn a Chinese family with Noonan syndrome, we find that the c.1149 + 1G > T variant inLZTR1gene shows a different autosomal dominant inheritance from previous reports, which changes our understanding of its inheritance and improves our understanding of Noonan syndrome.

Background Melanoma is an aggressive malignant skin tumor endangering the health of patients. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been increasingly reported to be implicated in the carcinogenesis of melanoma. Long intergenic non-coding RNA 00665 (LINC00665) has been found to exert important regulatory roles in some cancers, yet its function in melanoma remains to be investigated. Methods QRT-PCR analysis was conducted to evaluate the relative expression of RNAs. Functional experiments in vitro including colony formation, EdU, wound-healing and transwell assays, as well as in vivo xenograft assays, were utilized to study the role of LINC00665 in melanoma. Mechanical experiments were implemented to probe into the molecular linkage of LINC00665, miR-224-5p and VMA21. Results LINC00665 was abnormally highly expressed in melanoma cells. Silencing LINC00665 could inhibit the proliferation and migration of melanoma cells. LINC00665 sponged miR-224-5p to up-regulate VMA21. VMA21 knockdown exerted similarly interfering effects on above biological processes in melanoma cells. However, VMA21 overexpression abolished the in vitro and in vivo outcomes of LINC00665 silencing. Conclusion LINC00665 promotes proliferative and migrating abilities of melanoma cells via targeting miR-224-5p/VMA21 axis.

Background Patients with cardiovascular comorbidities are at high risk of poor outcome from COVID-19. However, how the burden (number) of vascular risk factors influences the risk of severe COVID-19 disease remains unresolved. Our aim was to investigate the association of severe COVID-19 illness with vascular risk factor burden. Methods We included 164 (61.8 ± 13.6 years) patients with COVID-19 in this retrospective study. We compared the difference in clinical characteristics, laboratory findings and chest computed tomography (CT) findings between patients with severe and non-severe COVID-19 illness. We evaluated the association between the number of vascular risk factors and the development of severe COVID-19 disease, using a Cox regression model. Results Sixteen (9.8%) patients had no vascular risk factors; 38 (23.2%) had 1; 58 (35.4%) had 2; 34 (20.7%) had 3; and 18 (10.9%) had ≥4 risk factors. Twenty-nine patients (17.7%) experienced severe COVID-19 disease with a median (14 [7–27] days) duration between onset to developing severe COVID-19 disease, an event rate of 4.47 per 1000-patient days (95%CI 3.10–6.43). Kaplan-Meier curves showed a gradual increase in the risk of severe COVID-19 illness (log-rank P Conclusions Patients with increasing vascular risk factor burden have an increasing risk of severe COVID-19 disease, and this population might benefit from specific COVID-19 prevention (e.g., self-isolation) and early hospital treatment measures.

Background Noonan syndrome (NS) is a multisystem disorder resulting from pathogenic mutations in more than 15 genes, among which LZTR1 is newly discovered. However, its role in NS pathogenesis remains unclear, including its inheritance pattern. Methods We herein report a family with LZTR-related NS. We collected clinical data of the proband and her families. Four of them completed the whole exon sequencing. Results Two children with NS inherited the same heterozygous LZTR1 variant, c.1149 + 1G > T, from their affected mother. Moreover, the proband was diagnosed as NS accompanied by growth hormone deficiency (GHD) without other associated gene mutations. Conclusion The variant c.1149 + 1G > T of LZTR1 was previously reported in autosomal recessive NS, but this is the first report of an autosomal dominant form. Our reported cases provided evidence for a more complex inheritance pattern resulting from LZTR1 c.1149 + 1G > T mutation. Occasionally, NS patients can have GHD.

Objectives: Enlarged perivascular spaces in the basal ganglia (BG-EPVS) share common vascular risk factors with atherosclerosis. However, little is known about the relationship between steno-occlusive middle cerebral artery (MCA) and BG-EPVS. In this cross-sectional study, we aimed to test the hypothesis that severe MCA stenosis or occlusion is associated with increased MRI-visible BG-EPVS.Methods: We retrospectively reviewed 112 patients with a steno-occlusive MCA from Fujian Medical University Union Hospital between January 2014 and December 2018. We rated BG-EPVS, white matter hyperintensities (WMH), and lacunes as markers of cerebral small vessel disease (CSVD) on magnetic resonance image (MRI). The severity of steno-occlusive MCA was assessed by computed tomography angiography (CTA) and was classified into moderate (50–69%), severe (70–99%), and occlusion (100%). We evaluated the association of steno-occlusive MCA for >10 BG-EPVS using logistic regression model adjusted for age, gender, hypertension, MR-visible WMH, and lacunes. We also compared the number of BG-EPVS between the affected side and unaffected side in patients with only unilateral steno-occlusive MCA.Results: In multivariable logistic regression analysis, age (OR = 1.07, 95%CI: 1.03–1.13, p = 0.003), hypertension (OR = 2.77, 95%CI: 1.02–7.51, p = 0.046), severe MCA stenosis (OR = 3.65, 95%CI: 1.12–11.87, p = 0.032), or occlusion (OR = 3.67, 95%CI: 1.20–11.27, p = 0.023) were significantly associated with >10 BG-EPVS. The number of BG-EPVS in the affected side was higher than the unaffected side in patients with severe MCA stenosis (12 [9−14] vs. 8 [6−11], p = 0.001) or occlusion (11 [7−14] vs. 8 [5−11], p = 0.028).Conclusions: BG-EPVS were more prevalent in patients with severe MCA atherosclerosis. Our findings suggest a biological link between severe steno-occlusive MCA and increased BG-EPVS. These results need confirmation in prospective studies.

Background: Medulloblastoma (MB) is a central nervous system malignancy that rarely affects adult. Epidemiological trends of adult MB are limited. This study aimed to explore population-level trends in the incidence of adult MB and to examine potential predictors for overall survival (OS). Methods: Data for patients from 1973 to 2015 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Age-adjusted incidence rates (AAIR) were calculated for groups divided on the basis of age, gender, and ethnicity. Propensity-score matching was used to compensate for potential selection biases. Cox proportional hazard models were used to examine potential predictors for OS. Results: AAIR was stable among MB patients ≥20 yr of age. The AAIR was slightly higher in males than that in females (0.065 vs. 0.049 per 100,000). Compared to whites, the incidence was nearly doubled in individuals of black ethnicity (0.063 vs. 0.033 per 100,000). Incidence was also lower among patients ≥40 yr of age, compared to those 20-39 yr of age (0.025 vs. 0.107 per 100,000). Multivariate Cox analysis indicated that age (p

Xueqing Zhang,1,* Jinluan Li,1,* Qingqin Peng,2 Yunxia Huang,1 Lirui Tang,1 Qingyang Zhuang,1 Feifei Lin,1 Xijin Lin,1 Kaixin Du,3 Junxin Wu1 1Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China; 2Department of Radiation Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou 362000, China; 3Department of Radiation Oncology, Xiamen Humanity Hospital, Xiamen 361000, China *These authors contributed equally to this work Purpose: The inflammatory status of patients with cancer appears to affect cancer progression and patient prognosis. We examined the characteristics of cancer-associated systemic and local inflammation and its impact on the overall survival (OS) of patients with locally advanced rectal cancer (LARC) who received neoadjuvant radiotherapy (nRT). Patients and methods: Seventy-six consecutive LARC patients who received nRT from February 2012 to September 2015 were retrospectively analyzed. The peripheral neutrophil-to-lymphocyte ratio (NLR) was determined at diagnosis, and the CD8+ T-cell count was determined from surgical specimens. Factors associated with OS were identified by univariate and multivariate Cox regression. Results: The median follow-up time was 23.0 months (range: 2–59), and the overall 5-year OS rate was 68.6% (95% CI =46.06–91.14). Patients with a high NLR (≥2.0) and a low CD8+ T-cell count (

Purpose To characterize the pattern of post-mastectomy supraclavicular lymph node (LN) metastases in patients with breast cancer (BC) and to provide insights for individualized clinical target volume delineation for radiotherapy. Methods We retrospectively analyzed 88 patients with BC who developed post-mastectomy regional LN metastases. The affected regional LNs were categorized as the ipsilateral medial supraclavicular LN area (IMSC-LN), ipsilateral lateral supraclavicular LN area (ILSC-LN), ipsilateral infraclavicular LN area (IIC-LN), and ≥2 groups in the ipsilateral clavicular LN area (MMIC-LN). Clinical characteristics were included in a multivariate analysis to identify risk factors for clavicular LN metastases. Results The ILSC-LNs (68.2%) were the most common metastatic site. IMSC-LN metastases showed a significant association with estrogen-receptor (ER) negative status, left-sided BC, and positive axillary LNs. Tumor size ≥2.4 cm and Her2 type were predictors of ILSC-LN metastases. Additionally, tumor size ≥2.4 cm, and level I ipsilateral axillary metastases were associated with MMIC-LN metastasis. Conclusion ILSC-LN was the most frequently affected group of supraclavicular lymph nodes. ER-negative status, left-sided BC, tumor size, and positive ipsilateral axillary LNs are potentially associated with the pattern of supraclavicular LN metastatic involvement.

To evaluate whether high biologically effective dose (BED) radiotherapy improves local control and survival outcomes for patients with brain metastases (BMs) from small-cell lung cancer (SCLC) and to determine possible prognostic factors. From January 1998 to June 2018, 250 patients with BM from SCLC were retrospectively analyzed. The Cutoff Finder program was used to classify patients by BED. Overall survival (OS) and BM progression-free survival (BM-PFS) were analyzed using the Kaplan-Meier method and log-rank test. A Cox regression model was used to calculate the hazard ratio and 95% CI for prognostic factors for OS among the study population and propensity score (PS)–matched patients. A BED of 47.4 was taken as the optimal cutoff value. Both OS and BM-PFS were significantly improved in the high-BED (>47.4 Gy) than in the low-BED (≤47.4 Gy) group (median OS: 17.5 months vs 9.5 months, P < .001, median BM-PFS: 14.4 months vs 8.3 months, P < .001). Biologically effective dose ( P < .001), Eastern Cooperative Oncology Group performance status ( P = .047), smoking ( P = .005), and pleural effusion ( P = .004) were independent prognostic factors for OS. Propensity score matching with a ratio of 1:2 resulted in 57 patients in the high-BED group and 106 patients in the low-BED group. In the PS-matched cohort, OS and BM-PFS were significantly prolonged in the high-BED group compared with the low-BED group ( P < .001). Biologically effective dose >47.4 Gy improves survival among patients with BM from SCLC. Eastern Cooperative Oncology Group score, smoking, and pleural effusion independently affect OS of SCLC patients with BM.

Background Medulloblastoma (MB) is a rare central nervous system malignancy in adult. For its rarity, most previous studies are limited on patient populations and ascertainment bias. We aimed to explore the population-level trends in incidence and assess potential predictors of overall survival (OS). Methods We utilized the Surveillance, Epidemiology and End Results Program (SEER) database between 1973 and 2015, to estimate the epidemiological trends of adult MB in the United States. Propensity-score matching was used to balance potential selection biases and Cox proportional hazard modeling was used to determine predictors of OS. Results The age-adjusted incidence was stable in MB patients aged 20 years old and elder in total (annual percent change (APC)=0.15). The age-adjusted incidence rate in males was slightly higher than that in females (0.065 vs. 0.049 per 100,000). Compared to whites, the rate was nearly doubled to blacks (0.063 vs. 0.033 per 100,000). There was obvious differ between the younger group and the elder group (aged 20-39: 0.107 vs. aged≥40: 0.025 per 100,000). According to multivariable Cox analysis, age (P Conclusions From the SEER database, race, gender and age disparities were found in incidence of adult MB patients. The survival analysis demonstrated the benefits of the GTR and younger patients. As for patients without GTR, radiotherapy and chemotherapy may improve the long-term survival. Legal entity responsible for the study Feifei, Lin. Funding The Fujian Province Natural Science Foundation (2017J01260), Joint Funds for the Innovation of Science and Technology, Fujian province (2017Y9074), and the Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing (2017 Open Project-9). Disclosure All authors have declared no conflicts of interest.

Background HIV related stigma is a recognized barrier to early detection of HIV and causes great suffering for those affected. However, data regarding HIV related stigma among female sex workers (FSW) in China was limited, with none for comparison between FSW and general migrant women (GMW). Therefore, the aim of this study was to examine HIV related stigma among FSW and GMW in Shanghai, China. Methods A community based cross-sectional study with face-to-face interviews was conducted in Shanghai (September 2011 through December 2012), using a structured questionnaire.HIV related stigma scores were examined graphically using boxplot. A logistic regression analysis with the proportional odds model was employed to identify factors affecting HIV related stigma scores. Results A total of 1,396 subjects, including 721 FSW and 675 GMW, were recruited in the present study. Both groups had substantial misconceptions about HIV/AIDS, although FSW had slightly higher scores on average. Both groups showed a medium level of HIV related stigma (38.34 ± 6.21 and 38.35 ± 6.86 for FSW and GMW, respectively). For the FSW, higher levels of stigma were observed for those who were in the older age groups (age 26-35 years, OR, 2.06, 95% CI 1.06-4.01), those who were married (OR, 1.62, 95% CI 1.03-2.54), and those who were working at lower-level sex service sites (OR, 1.60, 95% CI 1.06-2.43). Conversely, HIV knowledge was inversely associated with the level of HIV related stigma (OR, 0.93, 95% CI 0.87-0.98).Among GMW participating in the study, those age in the 26-35 years were more likely to show higher level of stigma (OR, 2.61, 95% CI 1.03-2.54), and HIV knowledge was found to be inversely associated with the HIV related stigma level as well (OR, 0.89, 95% CI 0.84-0.95). Conclusions The present study suggests that there is an urgent need for the development of appropriate education strategies to reduce HIV related stigma among FSW and GMW in Shanghai, China. In particular, older women, less educated women, and women that have lived in Shanghai a relatively long time should be targeted in future stigma reduction programs. Electronic supplementary material The online version of this article (doi:10.1186/s12905-014-0160-3) contains supplementary material, which is available to authorized users.

The aim was to investigate the relationship between apparent diffusion coefficient (ADC) values measured by diffusion-weighted magnetic resonance imaging (DW MRI) and the split glomerular filtration rate (GFR) in infants with congenital hydronephrosis. Diffusion-weighted imaging (DWI) (b = 0 and 700 seconds/mm(2)) was performed with a General Electric Company (GE) Signa 1.5T MR unit in 46 infants suffering single congenital hydronephrosis and in 30 healthy infants as normal control group. The ADCs were calculated with regions of interest (ROIs) positioned in the renal parenchyma. The 46 obstructed kidneys were classified into four groups according to the GFR level: renal dysfunction compensated group, renal dysfunction decompensated group, renal failure group, and uremia group. The renal ADCs in six groups (normal kidneys in control group, contralateral kidneys, and four groups of hydronephrotic kidneys) were compared statistically using analysis of variance (ANOVA), and the correlative relationship between ADCs and GFR was examined by Pearson's correlation test. There were statistically significant differences in renal ADCs among the six groups. The ADCs of hydronephrotic kidneys were lower than that of the normal kidneys. There was a moderate positive correlation between the ADCs of hydronephrotic kidneys and split GFR (r = 0.744). This study indicated that the ADCs of congenital hydronephrotic kidneys were lower than that of normal renal parenchyma, and there was a positive correlation between the ADCs and split renal GFR, which demonstrates that the ADCs can reflect the filtration function of hydronephrotic kidneys and may provide some reference to help clinical physician to explore a novel noninvasive approach to evaluate the single renal function.

Background Limited information on epidemiologic patterns of KSHV, with none focusing on heterosexual transmission, is available in mainland China. To clarify this, a cross-sectional study was conducted among a group of female sex workers (FSW) and general population women (GW) in Shanghai, China. Methods An anonymous questionnaire interview was administrated among 600 FSW and 600 GW. Blood samples were collected and tested for antibodies to KSHV, HSV-2, HIV, syphilis and HBsAg. Correlates of KSHV and HSV-2 were examined using multiple logistic regression analysis. Results None of the study participants were tested positive for HIV. The seroprevalence of KSHV, HSV-2 , HBV and syphilis was 10.0%, 52.2%, 12.3% and 10.5%, respectively for FSW, and was 11.0%, 15.3%, 9.8% and 2.8%, respectively for GW. KSHV seropositivity was not associated with syphilis and HSV-2 infection as well as sexual practices among either FSW or GW. Nevertheless, HSV-2 infection among FSW was independently associated with being ever married (OR = 1.59; 95%CI: 1.04-2.45), >5 years of prostitution (OR = 2.06; 95%CI: 1.16-3.68) and being syphilis positive (OR = 2.65; 95%CI: 1.43-4.93). HSV-2 infection among GW was independently associated with an age of >35 years (OR = 2.29; 95%CI: 1.07-4.93), having had more than 2 sex partners in the prior 12 months (OR = 6.44; 95%CI: 1.67-24.93) and being syphilis positive (OR = 3.94; 95%CI: 1.38-11.23). A gradual increase of prevalence with the prostitution time group was also detected for HSV-2 and syphilis, but not for KSHV. Conclusions KSHV is moderately and equivalently prevalent among FSW and GW. Heterosexual contact is not a predominant route for KSHV transmission among Chinese women.

Background This study was performed to determine whether injury induced by cerebral ischemia could be further improved by transplantation with bone marrow-derived mesenchymal stem cells (MSCs) modified by Survivin (SVV). Methods MSCs derived from bone marrow of male Sprague-Dawley rats were infected by the self-inactive lentiviral vector GCFU carrying green fluorescent protein (GFP) gene and SVV recombinant vector (GCFU-SVV). In vitro, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were detected in infected MSCs supernatants under hypoxic conditions by ELSIA. In vivo, experiments consisted of three groups, one receiving intravenous injection of 500 μl of phosphate-buffered saline (PBS) without cells (control group) and two groups administered the same volume solution with either three million GFP-MSCs (group GFP) or SVV/GFP-MSCs (group SVV). All animals were submitted to 2-hour middle cerebral artery occlusion (MCAO) and then reperfusion. Differentiation and survival of the transplanted MSCs were determined by confocal microscope. Western blot was used to detect the expression of VEGF and bFGF in ischemic tissue. A 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to assess the infarct volume. Evaluation of neurological function was performed using a modified Neurological Severity Score (mNSS). Results In vitro, modification with SVV further increased secretion of VEGF and bFGF under hypoxic condition. In vivo, only very few transplantated cells co-expressed GFP and NeuN. The survival transplanted cells in the group SVV was 1.3-fold at 4 days after transplantation and 3.4-fold higher at 14 days after transplantation, respectively, when compared with group GFP. Expression of VEGF and bFGF in the ischemic tissue were further up-regulated by modification with SVV. Moreover, modification with SVV further reduced the cerebral infarct volume by 5.2% at 4 days after stroke and improved post-stroke neurological function at 14 days after transplantation. Conclusion Modification with SVV could further enhance the therapeutic effects of MSCs possibly through improving the MSCs survival capacity and up-regulating the expression of protective cytokines in the ischemic tissue.