Human amniotic mesenchymal stromal cell-derived exosomes promote neuronal function by inhibiting excessive apoptosis in a hypoxia/ischemia-induced cerebral palsy model: A preclinical study.

BACKGROUND: Cerebral palsy (CP) is a condition resulting from perinatal brain injury and can lead to physical disabilities. Exosomes derived from human amniotic mesenchymal stromal cells (hAMSC-Exos) hold promise as potential therapeutic options. OBJECTIVE: This study aimed to investigate the impact of hAMSC-Exos on neuronal cells and their role in regulating apoptosis both in vitro and in vivo. METHODS: hAMSC-Exos were isolated via ultracentrifugation and characterized via transmission electron microscopy, particle size analysis, and flow cytometry. In vitro, neuronal damage was induced by lipopolysaccharide (LPS). CP rat models were established via left common carotid artery ligation. Apoptosis levels in cells and CP rats were assessed using flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR), Western blotting, and TUNEL analysis. RESULTS: The results demonstrated successful isolation of hAMSC-Exos via ultracentrifugation, as the isolated cells were positive for CD9 (79.7%) and CD63 (80.2%). Treatment with hAMSC-Exos significantly mitigated the reduction in cell viability induced by LPS. Flow cytometry revealed that LPS-induced damage promoted apoptosis, but this effect was attenuated by treatment with hAMSC-Exos. Additionally, the expression of caspase-3 and caspase-9 and the Bcl-2/Bax ratio indicated that excessive apoptosis could be attenuated by treatment with hAMSC-Exos. Furthermore, tail vein injection of hAMSC-Exos improved the neurobehavioral function of CP rats. Histological analysis via HE and TUNEL staining showed that apoptosis-related damage was attenuated following hAMSC-Exo treatment. CONCLUSIONS: In conclusion, hAMSC-Exos effectively promote neuronal cell survival by regulating apoptosis, indicating their potential as a promising therapeutic option for CP that merits further investigation.

Dual inhibition of CYP17A1 and HDAC6 by abiraterone-installed hydroxamic acid overcomes temozolomide resistance in glioblastoma through inducing DNA damage and oxidative stress.

Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.

Correlation of Insulin-Like Growth Factor 1 With Cognitive Functions in Mild Traumatic Brain Injury Patients.

Mild traumatic brain injury (mTBI) is a prevalent health concern with variable recovery trajectories, necessitating reliable prognostic markers. Insulin-like growth factor 1 (IGF-1) emerges as a potential candidate because of its role in cellular growth, repair, and neuroprotection. However, limited studies investigate IGF-1 as a prognostic marker in mTBI patients. This study aimed to explore the correlation of IGF-1 with cognitive functions assessed using the Wisconsin Card Sorting Test (WCST) in mTBI patients. We analyzed data from 295 mTBI and 200 healthy control participants, assessing demographic characteristics, injury causes, and IGF-1 levels. Cognitive functions were evaluated using the WCST. Correlation analyses and regression models were used to investigate the associations between IGF-1 levels, demographic factors, and WCST scores. Significant differences were observed between mTBI and control groups in the proportion of females and average education years. Falls and traffic accidents were identified as the primary causes of mTBI. The mTBI group demonstrated worse cognitive outcomes on the WCST, except for the "Learning to Learn" index. Correlation analyses revealed significant relationships between IGF-1 levels, demographic factors, and specific WCST scores. Regression models demonstrated that IGF-1, age, and education years significantly influenced various WCST scores, suggesting their roles as potential prognostic markers for cognitive outcomes in mTBI patients. We provide valuable insights into the potential correlation of IGF-1 with cognitive functions in mTBI patients, particularly in tasks requiring cognitive flexibility and problem solving.

Mesenchymal Stem Cells Overexpressing FGF21 Preserve Blood-Brain Barrier Integrity in Experimental Ischemic Stroke.

Blood-brain barrier (BBB) disruption is a prominent pathophysiological mechanism in stroke. Transplantation of mesenchymal stem cells (MSCs) preserves BBB integrity following ischemic stroke. Fibroblast growth factor 21 (FGF21) has been shown to be a potent neuroprotective agent that reduces neuroinflammation and protects against BBB leakage. In this study, we assessed the effects of transplantation of MSCs overexpressing FGF21 (MSCs-FGF21) on ischemia-induced neurological deficits and BBB breakdown. MSCs-FGF21 was injected into the rat brain via the intracerebroventricular route 24 h after middle cerebral artery occlusion (MCAO) surgery. The behavioral performance was assessed using modified neurological severity scores and Y-maze tests. BBB disruption was measured using Evans blue staining, IgG extravasation, and brain water content. The levels of tight junction proteins, aquaporin 4, and neuroinflammatory markers were analyzed by western blotting and immunohistochemistry. The activity of matrix metalloproteinase-9 (MMP-9) was determined using gelatin zymography. At day-5 after MCAO surgery, intraventricular injection of MSCs-FGF21 was found to significantly mitigate the neurological deficits and BBB disruption. The MCAO-induced loss of tight junction proteins, including ZO-1, occludin, and claudin-5, and upregulation of the edema inducer, aquaporin 4, were also remarkably inhibited. In addition, brain infarct volume, pro-inflammatory protein expression, and MMP-9 activation were effectively suppressed. These MCAO-induced changes were only marginally improved by treatment with MSCs-mCherry, which did not overexpress FGF21. Overexpression of FGF21 dramatically improved the therapeutic efficacy of MSCs in treating ischemic stroke. Given its multiple benefits and long therapeutic window, MSC-FGF21 therapy may be a promising treatment strategy for ischemic stroke.

Listeria monocytogenes: a promising vector for tumor immunotherapy.

Cancer receives enduring international attention due to its extremely high morbidity and mortality. Immunotherapy, which is generally expected to overcome the limits of traditional treatments, serves as a promising direction for patients with recurrent or metastatic malignancies. Bacteria-based vectors such as Listeria monocytogenes take advantage of their unique characteristics, including preferential infection of host antigen presenting cells, intracellular growth within immune cells, and intercellular dissemination, to further improve the efficacy and minimize off-target effects of tailed immune treatments. Listeria monocytogenes can reshape the tumor microenvironment to bolster the anti-tumor effects both through the enhancement of T cells activity and a decrease in the frequency and population of immunosuppressive cells. Modified Listeria monocytogenes has been employed as a tool to elicit immune responses against different tumor cells. Currently, Listeria monocytogenes vaccine alone is insufficient to treat all patients effectively, which can be addressed if combined with other treatments, such as immune checkpoint inhibitors, reactivated adoptive cell therapy, and radiotherapy. This review summarizes the recent advances in the molecular mechanisms underlying the involvement of Listeria monocytogenes vaccine in anti-tumor immunity, and discusses the most concerned issues for future research.

Therapeutic Effect of Human Adipocyte-derived Stem Cell-derived Exosomes on a Transgenic Mouse Model of Parkinson's Disease.

BACKGROUND/AIM: Stem cell therapy and regenerative medicine are promising for treating Parkinson's disease (PD) not only for the potential for cell replacement but also for the paracrine effect of stem cell secretion, especially proteins and nucleotide-enriched exosomes. This study investigated the neuroprotective effect of exosomes secreted from human adipocyte-derived stem cells (hADSCs) on PD. MATERIALS AND METHODS: hADSCs were isolated from the visceral fat tissue of individuals without PD who underwent bariatric surgery and were validated using surface markers and differentiation ability. Exosomes were isolated from the culture medium of hADSCs through serial ultracentrifugation and validated. Condensed exosomes were administered intravenously to 12-week-old MitoPark mice, transgenic parkinsonism mouse model with conditional knockout of mitochondrial transcription factor A in dopaminergic neurons, monthly for 3 months. Motor function, gait, and memory were assessed monthly, and immunohistochemical analysis of neuronal and inflammatory markers was performed at the end of the experiments. RESULTS: The hADSC-derived exosome-treated mice exhibited better motor function in beam walking and gait analyses than did the untreated mice. In the novel object recognition tests, the exosome-treated mice retained better memory function. Immunohistochemical analysis revealed that although exosome treatment did not prevent the loss of dopaminergic neurons in the substantia nigra of mice, it down-regulated microglial activation and neuroinflammation in the midbrain. CONCLUSION: hADSC-derived exosomes were neuroprotective in this in vivo mouse model of PD, likely because of their anti-inflammatory effect. Use of hADSC-derived exosomes may offer several beneficial effects in stem cell therapy. Since they can also be produced at an industrial level, they are a promising treatment option for PD and other neurodegenerative diseases.

Cognitive-adaptive Functioning Gap and Mediating Factors that Impact Adaptive Functioning in Chinese Preschool-aged Children with Autism Spectrum Disorder.

This study aimed to investigate the gap between adaptive functioning and cognitive functioning, especially verbal and nonverbal intelligence quotient (IQ) in Chinese children with ASD. We systematically explored cognitive functioning, ASD severity, early signs of developmental abnormalities, and socioeconomic factors as mediating factors of adaptive functioning. We enrolled 151 children (age: 2.5?6 years) with ASD and categorized them into one group with IQ ≥ 70 and another with IQ < 70. The two groups were calibrated for age, age at diagnosis, and IQ, and the relationship of adaptive skills with vocabulary acquisition index (VAI) and nonverbal index (NVI) were separately analyzed. Results show that the gap between IQ and adaptive functioning was significant in children with ASD having IQ ≥ 70, with both VAI and NVI showing statistically significant differences (all P < 0.001). VAI correlated positively with scores for overall adaptive skills and specific domains, whereas NVI had no significant correlations with adaptive skill scores. Age of first walking unaided had an independent positive correlation (all P < 0.05) with scores of adaptive skills and specific domains. IQ-adaptive functioning gap is significant in children with ASD having IQ ≥ 70, suggesting that defining "high-functioning autism" merely on the basis of IQ is not appropriate. Verbal IQ and early signs of motor development are specific and possible predictors of adaptive functioning in children with ASD, respectively.

Brain-derived neurotrophic factor contributes to neurogenesis after intracerebral hemorrhage: a rodent model and human study.

Background and purpose: Intracerebral hemorrhage (ICH) enhances neurogenesis in the subventricular zone (SVZ); however, the mechanism is not fully understood. We investigated the role of brain-derived neurotrophic factor (BDNF) in post-ICH neurogenesis in a rodent model and in patients with ICH using cerebrospinal fluid (CSF). Methods: A rat model of ICH was constructed via stereotaxic injection of collagenase into the left striatum. Patients with ICH receiving an external ventricular drain were prospectively enrolled. CSF was collected from rats and patients at different post-ICH times. Primary cultured rat neural stem cells (NSCs) were treated with CSF with or without BDNF-neutralized antibody. Immunohistochemistry and immunocytochemistry were used to detect NSC proliferation and differentiation. The BDNF concentration in CSF was quantified using enzyme-linked immunosorbent assays (ELISA). Results: In the rat model of ICH, the percentage of proliferating NSCs and neuroblasts in SVZ was elevated in bilateral hemispheres. The cultured rat NSCs treated with CSF from both rats and patients showed an increased capacity for proliferation and differentiation toward neuroblasts. BDNF concentration was higher in CSF collected from rats and patients with ICH than in controls. Blocking BDNF decreased the above-noted promotion of proliferation and differentiation of cultured NSCs by CSF treatment. In patients with ICH, the BDNF concentration in CSF and the neurogenesis-promoting capacity of post-ICH CSF correlated positively with ICH volume. Conclusion: BDNF in CSF contributes to post-ICH neurogenesis, including NSC proliferation and differentiation toward neuroblasts in a rat model and patients with ICH.

Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of ß-catenin.

Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic (n = 182) and extrahepatic (n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with ß-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear ß-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA.

Efficacy and moderating factors of the Early Start Denver Model in Chinese toddlers with autism spectrum disorder: a longitudinal study.

BACKGROUND: Several studies have shown the effectiveness of the Early Start Denver Model (ESDM), but few studies have explored the long-term efficacy of ESDM. This study aimed to explore the efficacy and moderating factors of ESDM in Chinese toddlers with autism spectrum disorder (ASD) in a longitudinal way. METHODS: A total of 60 toddlers with ASD were recruited and randomly divided into two groups: ESDM group all received 24 weeks intervention; Control group were waiting for intervention. Baseline assessment (T0) was conducted before intervention, including Gesell Developmental Scale (GDS) and Psycho-educational Profile-3rd Edition (PEP-3). All toddlers with ASD were examined in the first assessment (T1) at 6 months and in the second assessment (T2) at 12 months. RESULTS: In T1 assessment, the increments in speech and personal communication development quotient in GDS were significantly larger in the ESDM group than in the control group (P = 0.010, 0.047). In T2 assessment, the ESDM group had higher elevation in cognitive verbal/preverbal (CVP), social reciprocity and characteristic verbal behaviors assessed by PEP-3 (P = 0.021, 0.046, 0.014). In addition, the severity of stereotyped behavior was negatively associated with improvement in CVP. Family income was positively associated with improvement in speech and CVP (all P < 0.05). CONCLUSIONS: ESDM can effectively improve speech and communication in toddlers with ASD after 24-week intervention. More importantly, ESDM can promote cognition and social interaction and can reduce stereotyped verbal behavior in toddlers with ASD in longitudinal observation. The severity of stereotyped behavior and family ecological factors may be considered as affecting the efficacy of ESDM.

Rifaximin Modifies Gut Microbiota and Attenuates Inflammation in Parkinson's Disease: Preclinical and Clinical Studies.

Patients with Parkinson's disease (PD) exhibit distinct gut microbiota, which may promote gut-derived inflammation. Rifaximin is a nonabsorbable antibiotic that can modify gut microbiota. The present study investigated the effect of rifaximin on gut microbiota and inflammation status in PD. The study examined the effect of long-term rifaximin treatment on in vivo transgenic PD mice (MitoPark) and short-term rifaximin treatment on patients with PD. Rifaximin treatment caused a significant change in gut microbiota in the transgenic PD mice; in particular, it reduced the relative abundance of Prevotellaceae UCG-001 and increased the relative abundance of Bacteroides, Muribaculum, and Lachnospiraceae UCG-001. Rifaximin treatment attenuated serum interleukin-1ß, interleukin-6 and tumor necrosis factor-α, claudin-5 and occludin, which indicated the reduction of systemic inflammation and the protection of the blood-brain barrier integrity. The rifaximin-treated MitoPark mice exhibited better motor and memory performance than did the control mice, with lower microglial activation and increased neuronal survival in the hippocampus. In the patients with PD, 7-day rifaximin treatment caused an increase in the relative abundance of Flavonifractor 6 months after treatment, and the change in plasma proinflammatory cytokine levels was negatively associated with the baseline plasma interleukin-1α level. In conclusion, the present study demonstrated that rifaximin exerted a neuroprotective effect on the transgenic PD mice by modulating gut microbiota. We observed that patients with higher baseline inflammation possibly benefited from rifaximin treatment. With consideration for the tolerability and safety of rifaximin, randomized controlled trials should investigate the disease-modification effect of long-term treatment on select patients with PD.

LncRNA CRNDE is involved in radiation resistance in hepatocellular carcinoma via modulating the SP1/PDK1 axis.

Hepatocellular carcinoma (HCC) is defined as a universal malignancy while radiation therapy is the effective treatment for it. This study validated the mechanism of long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed gene (CRNDE) in radiation resistance in HCC. LncRNA CRNDE upregulation was detected in HCC cells. The radiation-resistant cell strains Huh7R and SNU-387R were established. After silencing lncRNA CRNDE, the cell colony formation ability, cell activity, apoptosis, cell cycles, and γ-H2AX positive rate in Huh7R and SNU-387R were detected. Silencing lncRNA CRNDE decreased the cell activity, colony formation ability, and cell number in the G2 phase and facilitated DNA damage and apoptosis. The binding relations of specificity protein 1 (SP1) with lncRNA CRNDE and 3-phosphoinositide dependent protein kinase 1 (PDK1) were verified. LncRNA CRNDE regulated PDK1 transcription by binding to transcription factor SP1. PDK1 overexpression partially reversed the inhibition of silencing lncRNA CRNDE on radiation resistance in HCC cells. The transplanted tumor mouse model was established and showed that silencing lncRNA CRNDE decreased tumor volume and weight and Ki67-positive cells in HCC mice in vivo. Collectively, lncRNA CRNDE was upregulated in HCC cells and promoted PDK1 transcription by binding to SP1, thus enhancing radiation resistance in HCC cells.

3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.

(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-ß levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6'- and 1,6'-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6'-DP did not lower Ikaros, Aiolos or SALL4 levels-critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6'-DP and 1,6'-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays -critical FDA regulatory tests. Finally, 3,6'- and 1,6'-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6'-DP and 1,6'-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

Therapeutic Effect of Rapamycin on TDP-43-Related Pathogenesis in Ischemic Stroke.

Stroke is a major cause of death and disability across the world, and its detrimental impact should not be underestimated. Therapies are available and effective for ischemic stroke (e.g., thrombolytic recanalization and mechanical thrombectomy); however, there are limitations to therapeutic interventions. Recanalization therapy has developed dramatically, while the use of adjunct neuroprotective agents as complementary therapies remains deficient. Pathological TAR DNA-binding protein (TDP-43) has been identified as a major component of insoluble aggregates in numerous neurodegenerative pathologies, including ALS, FTLD and Alzheimer's disease. Here, we show that increased pathological TDP-43 fractions accompanied by impaired mitochondrial function and increased gliosis were observed in an ischemic stroke rat model, suggesting a pathological role of TDP-43 in ischemic stroke. In ischemic rats administered rapamycin, the insoluble TDP-43 fraction was significantly decreased in the ischemic cortex region, accompanied by a recovery of mitochondrial function, the attenuation of cellular apoptosis, a reduction in infarct areas and improvements in motor defects. Accordingly, our results suggest that rapamycin provides neuroprotective benefits not only by ameliorating pathological TDP-43 levels, but also by reversing mitochondrial function and attenuating cell apoptosis in ischemic stroke.

Screening for Poor Self-Reported Sleep Quality at 12 Weeks in Post-Mild Traumatic Brain Injury Patients Using the HF-Age-Gender (HAG) Index.

To identify a screening tool for poor self-reported sleep quality at 12 weeks according to non-invasive measurements and patients' characteristics in the first week after mild traumatic brain injury (mTBI), data from 473 mTBI participants were collected and follow-ups were performed at 12 weeks. Patients with previous poor self-reported sleep quality prior to the injury were excluded. Patients were then divided into two groups at 12 weeks according to the Pittsburgh Sleep Quality Index based on whether or not they experienced poor sleep quality. The analysis was performed on personal profiles and heart rate variability (HRV) for 1 week. After analyzing the non-invasive measurements and characteristics of mTBI patients who did not complain of poor sleep quality, several factors were found to be relevant to the delayed onset of poor sleep quality, including age, gender, and HRV measurements. The HRV-age-gender (HAG) index was proposed and found to have 100% sensitivity (cut-off, 7; specificity, 0.537) to predicting whether the patient will experience poor sleep quality after mTBI at the 12-week follow-up. The HAG index helps us to identify patients with mTBI who have no sleep quality complaints but are prone to developing poor self-reported sleep quality. Additional interventions to improve sleep quality would be important for these particular patients in the future.

Mesenchymal Stem/Stromal Cell Therapy in Blood-Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects.

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood-brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

The distribution of hepatitis C virus infection in Shanghai, China: a time-spatial study.

BACKGROUND: Shanghai, as a pilot city of China to achieve the goal of eliminating hepatitis C, its strategy of allocating medical resources is a pressing problem to be solved. This study aims to infer the time-spatial clustering patterns of HCV-infected cases, and grasp the dynamic genotype distribution of HCV, thereby inform elimination strategies of HCV with efficacy and efficiency. METHODS: Reported HCV cases including their demographic information in Shanghai city from 2005 to 2018 were released from the National Infectious Disease Reporting Information System, population data at community scale, geographical layers of hospitals, communities and districts were gathered from former research. Blood samples of HCV-infected individuals were collected during 2014-2018 from 24 sentinel hospitals, HCV-antibody test, qualitative nucleic acid test and NS5B/5'UTR gene amplification were performed accordingly to determine the genotypes of the specimen. Furthermore, global and local spatial self-correlation analysis of both acute and chronic HCV infections were conducted at community scale year by year, then time-spatial clusters of acute and chronic HCV infections and HCV genotype distribution of specimen collected from sentinel hospitals by districts were mapped by using Arcmap10.1. RESULTS: A total of 2631 acute HCV cases and 15,063 chronic HCV cases were reported in Shanghai from 2005 to 2018, with a peak in 2010 and 2017, respectively. The mean age of chronic HCV patients was 49.70 ± 14.55 years, 3.34 ± 0.32 years older than the acute (t = 10.55, P-value < 0.01). The spatial distribution of acute HCV infection formed one primary cluster (Relative Risk = 2.71), and the chronic formed one primary cluster and three secondary clusters with Relative Risk ranged from 1.94 to 14.42, meanwhile, an overlap of 34 communities between acute and chronic HCV clusters were found with time period spans varied from 6 to 12 years. Genotype 1 (N = 257, 49.71%) was the most prevalent HCV genotype in Shanghai, genotype 3 infections have increased in recent years. Baoshan district presented cluster of acute HCV and the highest proportion of genotype 2, Pudong new area was the cluster of chronic HCV and occupied the highest proportion of genotype 3. CONCLUSIONS: Despite the low prevalence of HCV infection, it is still needed to push forward the elimination process in Shanghai, as there is a certain amount of HCV infected people waiting to be treated. The time-spatial clustering patterns and the dynamic of HCV genotype distribution together indicated a changing constitution of different transmission routes of HCV infection, thus, a focused strategy may be needed for high-risk population related to genotype 3 infection like drug users, in addition to an enforcement of the existing measures of preventing the iatrogenic and hematogenic transmission of HCV.

Neonatal hyperoxia induces gut dysbiosis and behavioral changes in adolescent mice.

BACKGROUND: Supplemental oxygen is often required to treat preterm infants with respiratory disorders. Experimental studies have demonstrated that hyperoxia results in the disruption of intestinal and neuronal plasticity and myelination of the brain. The association between the neonatal hyperoxia and changes of phenotypes in gut microbiota and in behaviors is not clear to date. METHODS: We designed an animal experiment that C57BL/6 mice pups were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 7. From postnatal days 8 to 42, the mice were reared in RA. Intestinal microbiota was sampled from the lower gastrointestinal tract on postnatal days 7 and 42, and behavioral tests were performed and brain tissues were collected on postnatal day 42. RESULTS: Neonatal hyperoxia decreased intestinal tight junction protein expression and altered intestinal bacterial composition and diversity on postnatal day 7. Among the concrete discriminative features, Proteobacteria and Epsilonbacteraeota were significantly elevated in hyperoxia-reared mice on postnatal days 7 and 42, respectively. Hyperoxia-reared mice exhibited significantly reduced sociability and interest in social novelty and impaired motor coordination compared with RA-reared mice on postnatal day 42. Hyperoxia-reared mice also exhibited significantly reduced myelination and a significantly higher number of apoptotic cells in the brain compared with RA-reared mice on postnatal day 42. CONCLUSION: Neonatal hyperoxia during the first week of life altered gut microbiota and reduced brain myelination that might associate with the deficits of social interaction and motor coordination in adolescent mice.

Single probe PCR melting curve analysis MTHFR C677T SNP sites.

BACKGROUND: The detection and analysis of methylene tetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP) from blood samples is time-consuming and costly. We aimed to establish a method to detect these SNPs by direct whole blood PCR and without DNA extraction. METHODS: Probes modified by different fluorescent groups on the same sequence were designed. Various MTHFR genotypes from direct blood PCR experiments were used to verify the similarity of the obtained and sequencing results. The SNP sites adjacent to the MTHFR C677T SNP were used to verify whether the method can accurately distinguish these sites. RESULTS: The ROX probe was found to be the most suitable for this study. We tested 291 samples with 1 µL whole blood as a template, and obtained 126, 43, and 122 cases of C677C, C677T, and C677 C/T genotypes, respectively. The melting curve was consistent with the sequencing results. The detection limit was approximately 1000 white blood cells/µL. Through PCR and the melting curve method, the adjacent sites were accurately distinguished. CONCLUSION: We established a reliable, simple, rapid, and low-cost direct blood PCR method for the detection of MTHFR C677T SNPs. This could also be used as a potential diagnostic tool for a variety of diseases.

Worsening of Dizziness Impairment Is Associated with Bone Marrow Kinase on Chromosome X Level in Patients after Mild Traumatic Brain Injury.

Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. Bone marrow kinase on chromosome X (BMX), a member of the TEC family of nonreceptor tyrosine kinases, is up-regulated after traumatic neural injury in a rat model of mTBI. The aim of this investigation was to determine whether BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between 13 and 15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks postinjury. The participant was asssigned to the case group if the subject's complaints of dizziness became worse at the sixth week assessment; otherwise, the participant was assigned to the control group. A receiver operating characteristic curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve for prediction of change in DHI postinjury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score, and 0.66 for functional score. Specificities were between 0.69 and 0.77 for total score and emotional score, respectively. Therefore, BMX demonstrates potential as a candidate serum biomarker of exacerbating dizziness post-mTBI.