Electrical micro flow cytometry with LSTM and its application in leukocyte differential.

This paper developed an electrical micro flow cytometry to realize leukocyte differentials leveraging a constrictional microchannel and a deep neural network. Firstly, purified granulocytes, lymphocytes or monocytes traveled through the constrictional microchannel with a cross-sectional area marginally larger than individual cells and produced large impedance variations by blocking focused electric field lines. By optimizing key elements (e.g., normalization, learning rate, batch size and neuron number) of the recurrent neural network (RNN), electrical results of purified leukocytes were analyzed to establish a leukocyte differential system with a classification accuracy of 95.2%. Then the leukocyte mixtures were forced to travel through the same constrictional microchannel, producing mixed impedance profiles which were classified into granulocytes, lymphocytes and monocytes based on the aforementioned differential system. As to the classification results, two leukocyte mixtures from the same donor were processed, producing comparable classification results, which were 57% versus 59% of granulocytes, 37% versus 34% of lymphocytes and 6% versus 7% of monocytes. These results validated the established classification system based on the constrictional microchannel and the recurrent neural network, providing a new perspective of differentiating white blood cells by electrical flow cytometry.

Leukocyte differential based on an imaging and impedance flow cytometry of microfluidics coupled with deep neural networks.

The differential of leukocytes functions as the first indicator in clinical examinations. However, microscopic examinations suffered from key limitations of low throughputs in classifying leukocytes while commercially available hematology analyzers failed to provide quantitative accuracies in leukocyte differentials. A home-developed imaging and impedance flow cytometry of microfluidics was used to capture fluorescent images and impedance variations of single cells traveling through constrictional microchannels. Convolutional and recurrent neural networks were adopted for data processing and feature extractions, which were then fused by a support vector machine to realize the four-part differential of leukocytes. The classification accuracies of the four-part leukocyte differential were quantified as 95.4% based on fluorescent images plus the convolutional neural network, 90.3% based on impedance variations plus the recurrent neural network, and 99.3% on the basis of fluorescent images, impedance variations, and deep neural networks. Based on single-cell fluorescent imaging and impedance variations coupled with deep neural networks, the four-part leukocyte differential can be realized with almost 100% accuracy.

Validation of the novel GLAS algorithm as an aid in the detection of liver fibrosis and cirrhosis based on GP73, LG2m, age, and sex.

BACKGROUND: Diagnosis of liver disease at earlier stages can improve outcomes and reduce the risk of progression to malignancy. Liver biopsy is the gold standard for diagnosis of liver disease, but is invasive and sample acquisition errors are common. Serum biomarkers for liver function and fibrosis, combined with patient factors, may allow for noninvasive detection of liver disease. In this pilot study, we tested and validated the performance of an algorithm that combines GP73 and LG2m serum biomarkers with age and sex (GLAS) to differentiate between patients with liver disease and healthy individuals in two independent cohorts. METHODS: To develop the algorithm, prototype immunoassays were used to measure GP73 and LG2m in residual serum samples collected between 2003 and 2016 from patients with staged fibrosis and cirrhosis of viral or non-viral etiology (n = 260) and healthy subjects (n = 133). The performance of five predictive models using combinations of age, sex, GP73, and/or LG2m from the development cohort were tested. Residual samples from a separate cohort with liver disease (fibrosis, cirrhosis, or chronic liver disease; n = 395) and healthy subjects (n = 106) were used to validate the best performing model. RESULTS: GP73 and LG2m concentrations were higher in patients with liver disease than healthy controls and higher in those with cirrhosis than fibrosis in both the development and validation cohorts. The best performing model included both GP73 and LG2m plus age and sex (GLAS algorithm), which had an AUC of 0.92 (95% CI: 0.90-0.95), a sensitivity of 88.8%, and a specificity of 75.9%. In the validation cohort, the GLAS algorithm had an estimated an AUC of 0.93 (95% CI: 0.90-0.95), a sensitivity of 91.1%, and a specificity of 80.2%. In both cohorts, the GLAS algorithm had high predictive probability for distinguishing between patients with liver disease versus healthy controls. CONCLUSIONS: GP73 and LG2m serum biomarkers, when combined with age and sex (GLAS algorithm), showed high sensitivity and specificity for detection of liver disease in two independent cohorts. The GLAS algorithm will need to be validated and refined in larger cohorts and tested in longitudinal studies for differentiating between stable versus advancing liver disease over time.

Diagnostic potential of site-specific serotransferrin N-glycosylation in discriminating different liver diseases.

BACKGROUND: Altered glycosylation modulates the structure and function of disease-related proteins. The associations between serotransferrin (STF) N-glycosylation and liver diseases (LDs) have been revealed. However, how intact N-glycopeptides vary among different types of liver diseases remains unclear. METHODS: Intact STF N-glycopeptides from patients with chronic liver disease (CLD, n = 92), primary liver cancer (PLC, n = 123), metastatic liver cancer (MLC, n = 57), and healthy controls (HCs, n = 59) were determined using high-resolution mass spectrometry. RESULTS: Significant changes were displayed in STF glycosylation among 4 groups. The LD screening model, including Asn432 G1S/G2S, Asn432 G2S/G2S2, and Asn630 G2NS2/G2FNS2, was constructed to differentiate LDs from HCs, with a AUC of 0.92. The liver cancer (LC) diagnostic model, a combination of Asn432 G1-N/G1S-N, Asn432 G1/G2, Asn432 G2FS/G2FS2, and Asn630 G1S-N /G1S, showed good performance in discriminating LC from CLD (AUC = 0.93). Moreover, AFP-negative LC patients (93 %) were successfully predicted by the LC diagnostic model. Furthermore, the MLC triage model, composed of Asn432 G1/G2, Asn432 G3F/G3FS, Asn630 G2/G2S, Asn630 G2S2/G2NS2, and Asn630 G3FS/G3FS2, yielded an AUC of 0.98 between PLC and MLC. CONCLUSIONS: STF N-glycosylation is a potential biomarker for the accurate classification of different LDs.

Proteomic Profiling of Cryoglobulinemia.

Objective: We aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls (HCs). Methods: The tandem mass tag (TMT)-labeled serum quantitative proteomics approach was used to identify differentially expressed proteins between the CGE and DC groups. Ingenuity pathway analysis was used for functional annotation of differentially expressed proteins. Biomarker candidates were validated in another cohort using the parallel reaction monitoring (PRM) method. Apolipoprotein A1 (APOA1), apolipoprotein CIII (APOC3), adiponectin, and proprotein convertase subtilisin/kexin type-9 (PCSK9), which represent key proteins involved in the cholesterol metabolism pathway, were further verified in an increased number of samples by enzyme-linked immunosorbent assay (ELISA). Results: A total of 1004 proteins were identified, of which 109 proteins were differentially expressed between the CGE and DC groups. These differentially expressed proteins were primarily involved in hepatic fibrosis/hepatic stellate cell activation and immune/inflammation-related pathways. In the disease and biofunction analysis, these proteins were mainly associated with the adhesion of blood cells, leukocyte migration, cholesterol transport, and transport of lipids. Twelve candidate biomarkers were validated by PRM-based proteomics, and proteins involved in the cholesterol metabolism pathway were further verified. APOA1, APOC3, adiponectin and PCSK9 concentrations were increased in CGE patients compared with healthy controls (P=0.0123, 0.1136, 0.5760, and 0.0019, respectively). Conclusion: This report describes the first application of a TMT-PRM-ELISA workflow to identify and validate CGE-specific biomarkers in serum. APOA1 and PCSK9 have been confirmed to be increased in CGE patients, demonstrating that proteins involved in cholesterol metabolism are also implicated in the development of CGE. These findings contribute to pathogenesis research and biomarker discovery in CGE.

Epidemiological and clinical characteristics of cancer patients with COVID-19: A systematic review and meta-analysis of global data.

There are minimal data regarding the prevalence of cancer in patients with coronavirus disease 2019 (COVID-19), as well as the incidence of severe illness and rate of mortality in COVID-19 patients with cancer. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched, from database inception to July 15, 2020, for studies of patients with COVID-19 that included information regarding comorbid cancer. In total, 109 eligible global studies were included in this systematic review. Ninety studies with 94,845 COVID-19 patients, among which 4106 exhibited comorbid cancer, were included in the meta-analysis regarding prevalence of comorbid cancer. Twenty-three studies with 71,969 COVID-19 patients, among which 4351 with comorbid cancer had severe illness or death, were included in the meta-analysis. The overall prevalence of cancer among COVID-19 patients was 0.07 (95% CI 0.05-0.09). The cancer prevalence in COVID-19 patients was higher in Europe (0.22, 95% CI 0.17-0.28) than in the Asia-Pacific region (0.04, 95% CI 0.03-0.06) or North America (0.05, 95% CI 0.04-0.06). The cancer prevalence in COVID-19 patients aged >60 years was 0.10 (95% CI 0.07-0.14), while the prevalence among patients aged ≤60 years was 0.05 (95% CI 0.03-0.06). The pooled prevalence of severe illness among COVID-19 patients with cancer was 0.34 (95% CI 0.26-0.42) and the pooled mortality rate of COVID-19 patients with cancer was 0.20 (95% CI 0.16-0.25). Pooled incidences of severe illness among COVID-19 patients with cancer from Asia Pacific, Europe, and North America were 0.38 (95% CI 0.24-0.52), 0.39 (95% CI 0.25-0.53), and 0.26 (95% CI 0.20-0.31), respectively; pooled mortality rates from the Asia-Pacific region, Europe, and North America were 0.17 (95% CI 0.10-0.24), 0.26 (95% CI 0.18-0.35), and 0.19 (95% CI 0.13-0.25), respectively.

The seroprevalence and kinetics of IgM and IgG in the progression of COVID-19.

BACKGROUND: SARS-CoV-2 is a novel coronavirus first recognized in late December 2019 that causes coronavirus disease 19 (COVID-19). Due to the highly contagious nature of SARS-CoV-2, it has developed into a global pandemic in just a few months. Antibody testing is an effective method to supplement the diagnosis of COVID-19. However, multicentre studies are lacking to support the understanding of the seroprevalence and kinetics of SARS-CoV-2 antibodies in COVID-19 epidemic regions. METHOD: A multicentre cross-sectional study of suspected and confirmed patients from 4 epidemic cities in China and a cohort study of consecutive follow-up patients were conducted from 29/01/2020 to 12/03/2020. IgM and IgG antibodies elicited by SARS-CoV-2 were tested by a chemiluminescence assay. Clinical information, including basic demographic data, clinical classification, and time interval from onset to sampling, was collected from each centre. RESULTS: A total of 571 patients were enrolled in the cross-sectional study, including 235 COVID-19 patients and 336 suspected patients, each with 91.9%:2.1% seroprevalence of SARS-CoV-2 IgG and 92.3%:5.4% seroprevalence of SARS-CoV-2 IgM. The seroprevalence of SARS-CoV-2 IgM and IgG in COVID-19 patients was over 70% less than 7 days after symptom onset. Thirty COVID-19 patients were enrolled in the cohort study and followed up for 20 days. The peak concentrations of IgM and IgG were reached on the 10th and 20th days, respectively, after symptom onset. The seroprevalence of COVID-19 IgG and IgM increased along with the clinical classification and treatment time delay. CONCLUSION: We demonstrated the kinetics of IgM and IgG SARS-CoV-2 antibodies in COVID-19 patients and the association between clinical classification and antibodies, which will contribute to the interpretation of IgM and IgG SARS-CoV-2 antibody tests and in predicting the outcomes of patients with COVID-19.

Deletion of Krüppel-like factor-4 promotes axonal regeneration in mammals.

Axonal regeneration plays an important role in functional recovery after nervous system damage. However, after axonal injury in mammals, regeneration is often poor. The deletion of Krüppel-like factor-4 (Klf4) has been shown to promote axonal regeneration in retinal ganglion cells. However, the effects of Klf4 deletion on the corticospinal tract and peripheral nervous system are unknown. In this study, using a mouse model of sciatic nerve injury, we show that the expression of Klf4 in dorsal root ganglion sensory neurons was significantly reduced after peripheral axotomy, suggesting that the regeneration of the sciatic nerve is associated with Klf4. In vitro, dorsal root ganglion sensory neurons with Klf4 knockout exhibited significantly enhanced axonal regeneration. Furthermore, the regeneration of the sciatic nerve was enhanced in vivo following Klf4 knockout. Finally, AAV-Cre virus was used to knockout the Klf4 gene in the cortex. The deletion of Klf4 enhanced regeneration of the corticospinal tract in mice with spinal cord injury. Together, our findings suggest that regulating KLF4 activity in neurons is a potential strategy for promoting axonal regeneration and functional recovery after nervous system injury. This study was approved by the Animal Ethics Committee at Soochow University, China (approval No. SUDA20200316A01).

Serum Occludin as a Biomarker to Predict the Severity of Acute Ischemic Stroke, Hemorrhagic Transformation, and Patient Prognosis.

Blood-brain barrier (BBB) damage plays an important role in overall brain injury following acute ischemic stroke (AIS). We investigated the potential utility of serum occludin, a BBB damage biomarker, in predicting the severity of AIS, hemorrhagic transformation (HT) and patient prognosis. A total of 243 patients, suspected of suffering an AIS and admitted to the emergency room at Xuanwu Hospital between November 2018 to March 2019, were enrolled in this study. Serum occludin levels were measured by enzyme linked immunosorbent assay and clinical data were collected from each patient. Receiver operating characteristic curves (ROC) were used to analyze the relationship between serum occludin and AIS. Multiple logistic regression analysis was used to analyze the relationship between serum occludin and stroke prognosis. Serum occludin levels were significantly elevated in acute stroke cases compared with those with stroke-like symptoms (P<0.001). In the moderate and severe cerebral infarction (CI) groups, serum occludin levels were significantly higher than those in the mild CI group (P<0.001). Patients with HT had higher occludin levels than non-HT patients (P<0.05). In addition, serum occludin level of patients with poor prognosis was significantly higher than that of the patients with good prognosis for non-reperfusion therapy. The ROC curve showed that serum occludin could reasonably predict HT and poor prognosis. Moreover, serum occludin were independently associated with 90-day poor prognosis. These findings suggest that the serum occludin levels could be used to identify early acute stroke cases and may predict the severity of AIS and HT as well as the prognosis at 90 days.

Clinicopathological study of mixed cryoglobulinemic glomerulonephritis secondary to hepatitis B virus infection.

BACKGROUND: Cryoglobulinemic glomerulonephritis (CryoGn) caused by hepatitis B virus (HBV) infection was rarely reported. Our study aimed to investigate the clinical features, renal pathology findings, and prognosis in patients with HBV related CryoGn. METHODS: This was a retrospective study including seven Chinese patients with HBV related CryoGn in a tertiary referral hospital from April 2016 to March 2019. The clinical and pathological data were collected and analyzed. RESULTS: Age at renal biopsy was 47 ± 12 years, with female/male ratio 3/4. Urine protein was 5.6 (3.0, 6.6) g/d and five cases presented with nephrotic syndrome. The baseline eGFR was 23.5 (20.2, 46.3) ml/min per 1.73m2. The extrarenal manifestations included purpura (n = 6), arthralgia (n = 1), peripheral neuropathy (n = 1), and cardiomyopathy (n = 1). Six cases had type II cryoglobulinemia with IgMκ, the other one had type III. The median cryocrit was 4.0 (1.0, 15.0) %. Renal pathologic findings on light microscopy: endocapillary proliferative glomerulonephritis (Gn) (n = 3), membranoproliferative Gn (n = 3), and mesangial proliferative Gn (n = 1). On immunofluorescence microscopy, the predominant type of immunoglobulin deposits was IgM (n = 5). HBsAg and HBcAg deposits were found in one case. Ultrastructural studies showed granular subendothelial and mesangial electron-dense deposits in all patients and microtubules in one case. All patients received antiviral medications. They were given corticosteroid alone (n = 2) or combined with cyclophosphamide (n = 4) or mycophenolate mofetil (n = 1). Two patients received plasmapheresis. The median follow-up time was 18 (6, 37) months. Four patients got remission, two patients died of pneumonia, and one progressed to end-stage renal disease (ESRD). At endpoint of follow-up, 24hUP was 2.1 (0.8-5.2) g/d, and eGFR was 55.3 (20.7, 111.8) ml/min per 1.73m2. The median cryocrit decreased to 1.0 (0, 5.75) %. CONCLUSIONS: The etiology of mixed CryoGn should be screened for HBV infection. Endocapillary proliferative Gn and membranoproliferative Gn were the common pathologic patterns. Diagnosis and treatment in early stage benefit patients' renal outcomes. Immunosuppressive therapy should be considered for severe renal disease, based on efficient antiviral therapy.

Antiphospholipid Antibodies in Critically Ill Patients With COVID-19.

OBJECTIVE: Coagulopathy is one of the characteristics observed in critically ill patients with coronavirus disease 2019 (COVID-19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, though their role in COVID-19 remains unclear. This study was undertaken to determine the prevalence and characteristics of aPLs in patients with COVID-19. METHODS: Sera collected from 66 COVID-19 patients who were critically ill and 13 COVID-19 patients who were not critically ill were tested by chemiluminescence immunoassay for anticardiolipin antibodies (aCLs), anti-ß2 -glycoprotein I (anti-ß2 GPI) (IgG, IgM, and IgA), and IgG anti-ß2 GPI-domain 1 (anti-ß2 GPI-D1) and IgM and IgG anti-phosphatidylserine/prothrombin (anti-PS/PT) antibodies were detected in the serum by enzyme-linked immunosorbent assay. RESULTS: Of the 66 COVID-19 patients in critical condition, aPLs were detected in 31 (47% ). Antiphospholipid antibodies were not present among COVID-19 patients who were not in critical condition. The IgA anti-ß2 GPI antibody was the most commonly observed aPL in patients with COVID-19 and was present in 28.8% (19 of 66) of the critically ill patients, followed by IgA aCLs (17 of 66, or 25.8%) and IgG anti-ß2 GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti-ß2 GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti-ß2 GPI + IgA aCL + IgG anti-ß2 GPI (10 of 66, or 15.2%). Antiphospholipid antibodies emerge ~35-39 days after disease onset. A dynamic analysis of aPLs revealed 4 patterns based on the persistence or transient appearance of the aPLs. Patients with multiple aPLs had a significantly higher incidence of cerebral infarction compared to patients who were negative for aPLs (P = 0.023). CONCLUSION: Antiphospholipid antibodies were common in critically ill patients with COVID-19. Repeated testing demonstrating medium to high titers of aPLs and the number of aPL types a patient is positive for may help in identifying patients who are at risk of developing cerebral infarction. Antiphospholipid antibodies may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID-19 may trigger the development of an autoimmune condition similar to the antiphospholipid syndrome (APS), referred to as "COVID-19-induced APS-like syndrome." Long-term follow-up of COVID-19 patients who are positive for aPLs would be of great importance in understanding the pathogenesis of this novel coronavirus.

Case study of an autoantibody panel for early detection of lung cancer and ground-glass nodules.

PURPOSE: Increasing lung cancer incidence in China with a high death rate due to late diagnosis highlights the need for biomarkers, such as panels of autoantibodies (AAbs), for prediction and early lung cancer diagnosis. We conducted a study to further evaluate the clinical performance of an AAb diagnostic kit. METHODS: Using enzyme-linked immunosorbent assay, levels of seven AAbs in serum samples from 121 patients with newly diagnosed lung cancer, 84 controls (34 healthy individuals and 50 patients with benign lung disease), and 100 indeterminate solid nodules, were measured. Participants were followed up until 6 months after a positive test result to confirm lung cancer diagnosis. RESULTS: The seven AAb concentration was significantly higher in lung cancer patients than in controls (P < 0.05). The seven AAb sensitivity and specificity for newly diagnosed lung cancer were 45.5% and 85.3%, respectively, while the seven AAb combined area under the curve (in lung cancer patients versus controls) was 0.660. Of the 28 patients with solid nodules with positive test results, 8 and 3 were diagnosed with lung cancer and benign lung disease, respectively, during follow-up. The positive predictive value of the experiment was 72.7%. CONCLUSION: Positive AAb test results were associated with a high risk of lung cancer. The seven-AAb panel also had a high predictive value for detecting lung cancer in patients with solid nodules. Our seven lung cancer autoantibody types can provide an important early warning sign in the clinical setting.

Prevalence of metabolic syndrome among ethnic groups in China.

BACKGROUND: Metabolic syndrome (MetS) is common in China, which has a multi-ethnic population of 1·3 billion. We set out to determine the prevalence of MetS and its components in different ethnic groups. METHODS: This nationwide cross-sectional survey involved 24,796 participants from eight ethnicities in six provinces in China from 2008 to 2011. MetS was defined using the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Results were analysed using SPSS version 22·0 in 2018. Logistic regression was used for deriving odds ratios and 95% confidence intervals of risk factors for the MetS. RESULTS: The prevalence of MetS increased with age from 3·60% to 21·68%. After age standardization, the prevalence of MetS, in descending order, was 35·42% (Korean), 22·82% (Hui), 19·80% (Han), 13·72% (Miao), 12·90% (Tujia), 12·04% (Li), 11·61% (Mongolian), 6·17% (Tibetan). Korean ethnicity was associated with a higher prevalence in five components of MetS, while Tibetan ethnicity was associated with lower prevalence except decreased HDL cholesterol. Logistic regression analyses showed that age, drinking and being non-Tibetan were associated with a higher risk of MetS. CONCLUSIONS: Within one country, albeit a large one, the prevalence of MetS can vary greatly. Chinese of Korean ethnicity had a much higher prevalence than Tibetan ethnicity. Measures to tackle MetS should be tailored to the ethnic groups within a population.

Vancomycin-associated acute kidney injury in Hong Kong in 2012-2016.

BACKGROUND: To study the incidence of vancomycin-associated acute kidney injury (VA-AKI) in Hong Kong and identify risk factors for VA-AKI. METHOD: Patients with vancomycin prescription and blood level measurement in 2012-2016 were identified using the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. Acute kidney injury was defined using KDIGO criteria. Patients without creatinine measurements, steady-state trough vancomycin level or who had vancomycin treatment < 3 days were excluded. Results were analyzed using SPSS version 22.0. Logistic regression was used to identify the predictors for VA-AKI. Odds ratio and 95% confidence interval were estimated. RESULTS: One thousand four hundred fifty patients were identified as VA-AKI from 12,758 records in Hong Kong in 2012-2016. The incidence was respectively 10.6, 10.9, 11.3, 12.2, 11.2% from 2012 to 2016. The incidence of VA-AKI was 16.3, 12.2, 11.3 and 6.2% in patients aged 1-12, 12-60, elderly aged > 60 and newborn and infants, respectively. Baseline creatinine, serum trough vancomycin level, systematic disease history including respiratory failure, hypertension, congestive heart failure, chronic renal failure, anemia and type II diabetes, and concomitant diuretics, piperacillin-tazobactam (PTZ) and meropenem prescription were significantly higher in VA-AKI patients older than 12 years. Logistic regression showed that older age group, higher baseline creatinine, serum trough vancomycin level, respiratory failure, chronic renal failure and congestive heart failure, concomitant diuretics, PTZ and meropenem prescription, and longer hospital stay were all associated with increased risk of VA-AKI. CONCLUSION: The incidence of VA-AKI in Hong Kong is low but shows no decline. Patients with higher baseline creatinine, multi-organ diseases and multiple drugs administration should have their vancomycin level monitored to decrease the risk of VA-AKI.

c-Myc controls the fate of neural progenitor cells during cerebral cortex development.

The anatomical structure of the mammalian cerebral cortex is the essential foundation for its complex neural activity. This structure is developed by proliferation, differentiation, and migration of neural progenitor cells (NPCs), the fate of which is spatially and temporally regulated by the proper gene. This study was used in utero electroporation and found that the well-known oncogene c-Myc mainly promoted NPCs' proliferation and their transformation into intermediate precursor cells. Furthermore, the obtained results also showed that c-Myc blocked the differentiation of NPCs to postmitotic neurons, and the expression of telomere reverse transcriptase was controlled by c-Myc in the neocortex. These findings indicated c-Myc as a key regulator of the fate of NPCs during the development of the cerebral cortex.

Association between blood circulating vitamin D and colorectal cancer risk in Asian countries: a systematic review and dose-response meta-analysis.

OBJECTIVES: To assess the association between blood circulating vitamin D levels and colorectal cancer risk in the Asian population. DESIGN: This is a systematic review and dose-response meta-analysis of observational studies that investigated the relationship between blood circulating vitamin D levels and colorectal cancer risk in the Asian population. DATA SOURCES: Relevant studies were identified through a literature search in Medline, Embase and Web of Science from 1st January 1980 to 31st January 2019. Eligibility criteria: original studies published in peer-reviewed journals investigating the association between blood circulating vitamin D levels and the risk of colorectal cancer and/or adenoma in Asian countries. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted data and assessed the quality of included studies. Study-specific ORs were pooled using a random-effects model. A dose-response meta-analysis was performed with generalised least squares regression. We applied the Newcastle-Ottawa Scale quality assessment to evaluate the quality of the selected studies. RESULTS: The eight included studies encompassed a total of 2916 cases and 6678 controls. The pooled ORs of colorectal cancer for the highest versus lowest categories of blood circulating vitamin D levels was 0.75 (95% CI 0.58 to 0.97) up to 36.5 ng/mL in the Asian population. There was heterogeneity among the studies (I2=53.9%, Pheterogeneity=0.034). The dose-response meta-analysis indicated a significant linear relationship (Pnon-linearity=0.11). An increment of 16 ng/mL in blood circulating vitamin D level corresponded to an OR of 0.79 (95% CI 0.64 to 0.97). CONCLUSIONS: The results of this meta-analysis indicate that blood circulating vitamin D level is associated with decreased risk of colorectal cancer in Asian countries. The dose-response meta-analysis shows that the strength of this association among the Asian population is similar to that among the Western population. Our study suggests that the Asian population should improve nutritional status and maintain a higher level of blood circulating vitamin D.

Regulation of adult mammalian intrinsic axonal regeneration by NF-κB/STAT3 signaling cascade.

The inflammatory response is a critical regulator for the regeneration of axon following nervous system injury. Nuclear factor-kappa B (NF-κB) is characteristically known for its ubiquitous role in the inflammatory response. However, its functional role in adult mammalian axon growth remains elusive. Here, we found that the NF-κB signaling pathway is activated in adult sensory neurons through peripheral axotomy. Furthermore, inhibition of NF-κB in peripheral sensory neurons attenuated their axon growth in vitro and in vivo. Our results also showed that NF-κB modulated axon growth by repressing the phosphorylation of STAT3. Furthermore, activation of STAT3 significantly promoted adult optic nerve regeneration. Taken together, the findings of our study indicated that NF-κB/STAT3 cascade is a critical regulator of intrinsic axon growth capability in the adult nervous system.

Calcium/calmodulin-dependent protein kinase II regulates mammalian axon growth by affecting F-actin length in growth cone.

While axon regeneration is a key determinant of functional recovery of the nervous system after injury, it is often poor in the mature nervous system. Influx of extracellular calcium (Ca2+ ) is one of the first phenomena that occur following axonal injury, and calcium/calmodulin-dependent protein kinase II (CaMKII), a target substrate for calcium ions, regulates the status of cytoskeletal proteins such as F-actin. Herein, we found that peripheral axotomy activates CaMKII in dorsal root ganglion (DRG) sensory neurons, and inhibition of CaMKII impairs axon outgrowth in both the peripheral and central nervous systems (PNS and CNS, respectively). Most importantly, we also found that the activation of CaMKII promotes PNS and CNS axon growth, and regulatory effects of CaMKII on axon growth occur via affecting the length of the F-actin. Thus, we believe our findings provide clear evidence that CaMKII is a critical modulator of mammalian axon regeneration.

Establishing reference intervals for sex hormones and SHBG in apparently healthy Chinese adult men based on a multicenter study.

BACKGROUND: Measuring sex hormones is essential in diagnosing health issues such as testicular dysfunction, male infertility and feminization syndrome. However, there are no reports on reference intervals (RIs) in Chinese men. We conducted a nationwide multicenter study to establish RIs for seven sex hormones (luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin [PRL], total testosterone [TT], free testosterone [FT], bioavailable testosterone [BAT] and estrogen [E2]), as well as sex hormone-binding globulin (SHBG). METHODS: In 2013, 1043 apparently healthy adult men from five representative cities in China (Beijing, Hangzhou, Guangzhou, Dalian and Urumqi) were recruited; hormones were measured using an automated immunoassay analyzer. Multiple regression analysis (MRA) was performed to identify sources of variation (SVs) that might influence the hormone serum levels. RIs were computed using the parametric method. RESULTS: Dalian and Hangzhou had significantly higher E2 values than other cities; age was a major source of variation for FSH, LH, PRL, SHBG, FT and BAT. FSH, LH and SHBG increased significantly with age, while PRL, FT and BAT decreased with age. TT showed no significant age-related changes. Median (RIs) derived without partition by age were as follows: FSH, 5.6 (1.9-16.3) IU/L; LH, 4.2 (1.6-10.0) IU/L; PRL, 189 (88-450) mIU/L; E2, 85 (4.7-195) pmol/L; SHBG, 29.4 (11.5-66.3) nmol/L; TT, 15.6 (7.4-24.5) nmol/L; FT, 0.31 (0.16-0.52) nmol/L; and BAT, 8.0 (3.7-13.2) nmol/L. RIs were also derived in accordance with between-city and between-age differences. CONCLUSIONS: RIs were established for sex hormones and SHBG in apparently healthy Chinese men in consideration of age.