Characterization of genomic alterations in Chinese colorectal cancer patients with liver metastases.

BACKGROUND: The exploration of genomic alterations in Chinese colorectal liver metastasis (CRLM) is limited, and corresponding genetic biomarkers for patient's perioperative management are still lacking. This study aims to understand genome diversification and complexity that developed in CRLM. METHODS: A custom-designed IDT capture panel including 620 genes was performed in the Chinese CRLM cohort, which included 396 tumor samples from metastatic liver lesions together with 133 available paired primary tumors. RESULTS: In this Chinese CRLM cohort, the top-ranked recurrent mutated genes were TP53 (324/396, 82%), APC (302/396, 76%), KRAS (166/396, 42%), SMAD4 (54/396, 14%), FLG (52/396, 13%) and FBXW7 (43/396, 11%). A comparison of CRLM samples derived from left- and right-sided primary lesions confirmed that the difference in survival for patients with different primary tumor sites could be driven by variations in the transforming growth factor ß (TGF-ß), phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways. Certain genes had a higher variant rate in samples with metachronous CRLM than in samples with simultaneous metastasis. Overall, the metastasis and primary tumor samples displayed highly consistent genomic alterations, but there were some differences between individually paired metastases and primary tumors, which were mainly caused by copy number variations. CONCLUSION: We provide a comprehensive depiction of the genomic alterations in Chinese patients with CRLM, providing a fundamental basis for further personalized therapy applications.

Correlation Between the Evolution of Somatic Alterations During Lymphatic Metastasis and Clinical Outcome in Penile Squamous Cell Carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor survival after standard treatment. Although genomic alterations of PSCC have been characterized in several latest studies, the association between the formation of somatic landscape and regional lymph node metastasis (LNM), an important predictor for patient survival, has not been comprehensively investigated. Here, we collected formalin-fixed paraffin-embedded tumor tissue and matched normal samples of 32 PSCC patients, including 14 LNM patients and 18 clinically node-negative patients, to implement a whole-exome sequencing. Comparison of genomic features among different lymph node status subgroups was conducted after genomic profiling and its effects on patient survival were explored. Top-ranked recurrent gene mutants in our PSCC cohort were TP53 (13/32), NOTCH1 (12/32), CDKN2A (11/32), TTN (9/32) and FAT1 (8/32), mainly identified in the Notch, Hippo, cell cycle, TP53, RTK-RAS and PI3K pathways. While CDKN2A was confirmed to be the driver gene in all PSCC patients, certain gene mutants were significantly enriched in LNM involved patients, including TP53 (9/14 vs. 4/18, p = 0.029) and GBF1 (4/14 vs. 0/18, p = 0.028). Overall survival stratification of PSCC patients were found to be significantly correlated with mutations of three genes, including PIK3CA (Hazard ratio [HR] = 4.15, p = 0.029), CHD7 (HR = 4.82, p = 0.032) and LAMC3 (HR = 15.9, p < 0.001). PIK3CA and LAMC3 held a higher prevalence in patients with LNM compared to those without LNM (PIK3CA: 3/14 vs. 1/18, LAMC3: 2/14 vs. 1/18). Our finding demonstrated that genomic divergence exists across PSCC patients with different lymph node statuses, and it may be correlated with their survival outcome. It helps delineate somatic evolution during tumor progression and perfect potential therapeutic intervention in this disease.

Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases.

Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21-68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.

Melatonin promotes secondary hair follicle development of early postnatal cashmere goat and improves cashmere quantity and quality by enhancing antioxidant capacity and suppressing apoptosis.

Development of secondary hair follicles in early postnatal cashmere goats may be adversely affected by reactive oxygen species which cause oxidative stress. Because melatonin is a potent antioxidant and scavenger of free radicals, this study explored the effects of melatonin on secondary hair follicle development and subsequent cashmere production. It was found that the initiation of new secondary follicles in early postnatal Inner Mongolian cashmere goats of both melatonin-treated and control goats occurred in the first 10 weeks of age. Melatonin promoted the initiation and maturation of secondary follicles and increased their population. Importantly, the beneficial effect of melatonin on secondary follicle population remained throughout life. As a result, melatonin increased cashmere production and improved its quality in terms of reduced fiber diameter. The mechanisms underlying the role of melatonin on secondary follicle development included the enhancement of activities of antioxidant enzymes, for example, superoxide dismutase and glutathione peroxidase (GSH-Px), elevated total antioxidant capacity, and upregulated anti-apoptotic Bcl-2 expression and downregulated expression of the pro-apoptotic proteins, Bax and caspase-3. These results reveal that melatonin serves to promote secondary hair follicle development in early postnatal cashmere goats and expands our understanding of melatonin application in cashmere production. Melatonin treatment led to an increase in both the quantity and quality of cashmere fiber. This increased the textile value of the fibers and provided economic benefit.

Prohibitin as a novel autoantigen in rheumatoid arthritis.

THE AIM OF THIS STUDY: The aim of this study was to verify whether prohibitin is a novel autoantigen in rheumatoid arthritis. MATERIAL AND METHODS: First, recombinant human prohibitin (rhPHB) protein was cloned, expressed, and purified. Then the anti-prohibitin autoantibodies were detected by western blotting by using rhPHB protein to incubate sera from patients with rheumatoid arthritis (RA). Next, immunoprecipitation was employed to further illustrate whether anti-prohibitin antibodies exist in RA patients. And finally, autoantibodies against the rhPHB protein were investigated using a homemade ELISA kit through the assessment of 258 real clinical samples. RESULTS: It was revealed that anti-prohibitin antibodies existed in the sera of patients with RA. Reactivity of serum IgG against rhPHB was detected in 26 of 86 RA patients (30.3%), 7 of 86 systemic lupus erythematosus (SLE) patients (8.1%), and 1 of 86 apparently healthy donors (HC) (1.2%). CONCLUSIONS: Prohibitin was proved to be a novel autoantigen and the corresponding anti-prohibitin autoantibodies were present in the RA patients' blood circulation.

[Clinical features and risk factors of co-morbid tic disorder in children with attention deficit hyperactivity disorder].

OBJECTIVE: To study the clinical features and risk factors of co-morbid tic disorder (TD) in children with attention deficit hyperactivity disorder (ADHD). METHODS: A total of 312 children with ADHD were involved in this study. Subtypes of co-morbid TD, incidences of TD in different subtypes of ADHD (ADHD-I, ADHD-HI and ADHD-C) were observed. Thirteen potential factors influencing the comorbidity rate of TD in ADHD were evaluated by univariate analysis and multiple logistic regression analysis. RESULTS: Forty-two of 312 children with ADHD suffered from co-morbid TD (13.5%). Comorbidity rate of TD in children with ADHD-C (24.1%) was significantly higher than in those with ADHD-HI (10.9%) and ADHD-I (8.8%) (P<0.05). There were 21 cases (50.0%) of transient TD, 12 cases (28.6%) of chronic TD, and 9 cases (21.4%) of Tourette syndrome. The univariate analysis revealed 6 factors associated with comorbidity: addiction to mobile phone or computer games, poor eating habits, infection, improper family education, poor relationship between parents and poor relationship with schoolmates. Multiple logistic analysis revealed two independent risk factors for comorbidity: improper family education (OR=7.000, P<0.05) and infection (OR=2.564, P<0.05). CONCLUSIONS: The incidence of co-morbid TD in children with ADHD is influenced by many factors, and early interventions should be performed based on the main risk factors.

Multiple correlations of mRNA expression and protein abundance in human cytokine profile.

With the development of genomic study, researchers found that it is insufficient to predict protein expression from quantitative mRNA data in large scale, which is contrary to the traditional opinion that mRNA expression correlates with protein abundance at the single gene level. To try to solve the apparent conflicting views, here we set up a series of research models and chose soluble cytokines as targets. First, human peripheral blood mononuclear cell (PBMC) from one health donor was treated with 16 continuously changing conditions, the protein and mRNA profile were analyzed by multiplex Luminex and genomic microarray, respectively. Among the tested genes, around half mRNA correlated well with their corresponding proteins (ρ > 0.8), however if we put all the genes together, the correlation coefficient for the 16 conditions varied from 0.29 to 0.71. Second, PBMC from 14 healthy donors were stimulated with the same condition and it was found that the correlation coefficient went down (ρ < 0.6). Third, 28 rheumatoid arthritis (RA) patients were tested for their response to the same external stimuli and it turned out different individual displayed different protein expression pattern as expect. Lastly, autoimmune disease cohorts (8 diseases including RA, 103 patients in total) were assayed on the whole view. It was observed that there was still some similarity in the protein profile among patients from the single disease type although completely different patterns were displayed across different disease categories. This study built a good bridge between single gene analysis and the whole genome study and may give a reasonable explanation for the two conflicting views in current biological science.

[An epidemiological survey of attention deficit hyperactivity disorder in school-age children in Shenzhen].

OBJECTIVE: To investigate the prevalence of attention deficit hyperactivity disorder (ADHD) and behavior problems among school-age children in Shenzhen City of Guangdong. METHODS: A total of 10553 students in Grades 1-6 from different primary schools in Shenzhen City were assessed by Conners Parent Symptom Questionnaire (PSQ) and Conners Teacher Rating Scale (TRS). Children showing abnormalities according to PSQ or TRS were further assessed according to the diagnostic standard for ADHD as laid out in the diagnostic and statistical manual for mental disorders- 4th edition (DSM-Ⅳ). RESULTS: A total of 8193 PSQ and TRS assessments were completed. The children were aged from 7 to 13 years. The total prevalence rate was 7.60% by PSQ and 5.59 % by TRS. Four hundred and forty-two children were diagnosed having ADHD by DSM-Ⅳ, with a prevalence rate of 5.39%. There were significant differences in the prevalence rate of ADHD among children aged 7 to 13 years (χ2=21.613, P<0.05). In children aged 7 to 9 years, the prevalence rate was higher (above 6%). The prevalence rate of ADHD in boys was significantly higher than in girls (6.65% vs 3.12%; P<0.05). Impulsion and hyperactivity (79.6%), learning (60.6%) and conduct disorders (52.0%) were the main behavioral problems in children with ADHD. The prevalence of learning disorders was higher in girls than in boys. Conclusions The prevalence rate of ADHD in children from primary schools in Shenzhen City is 5.39%, and it is higher in children aged 7 to 9 years. Boys have a higher prevalence rates of ADHD than girls. Impulsion and hyperactivity, learning and conduct disorders are common problems in children with ADHD.

[Clinical features of various subtypes of attention deficit hyperactivity disorders in children].

OBJECTIVE: To study the features of various subtypes of attention deficit hyperactivity disorders (ADHD) in children. METHODS: Sex composition, risk factors, comorbidities, intelligence quotient and behavioral problems were investigated in 175 children with ADHD who met the Diagnostic Statistical Manual of Mental Disorder Criteria (DSM-IV). The children were classified into three groups: ADHD predominantly inattentive (ADHD-I, n=82), ADHD predominantly hyperactive-impulsive (ADHD-HI, n=24) and ADHD combined type (ADHD-C, n=69). RESULTS: There were no significant differences in the sex composition among the three groups. The rates of birth abnormality in the ADHD-I and the ADHD-C groups were higher than those in the ADHD-HI group. Negative parenting practices were noted more frequently in the ADHD-HI and the ADHD-C groups than the ADHD-I group. There were no significant differences in the performance intelligence quotient (PIQ), verbal intelligence quotient (VIQ) and full intelligence quotient (FIQ) among the three groups. However, the incidence of imbalance between VIQ and PIQ in the ADHD-I group was higher than the other two groups. The rate of comorbidities with oppositional defiant disorder (ODD) and tic disorder (TD) in the ADHD-C and the ADHD-HI groups was higher than that in the ADHD-I group. Both the ADHD-I and the ADHD-C groups had a higher rate of comorbidities with learning disorder (LD) than the ADHD-HI group. The impulsive/hyperactive and conduct problems were more severe and the hyperactivity index was higher in the ADHD-C and the ADHD-HI groups than those in the ADHD-I group, while the learning difficulties in the ADHD-I group were the most severe. CONCLUSIONS: The children with ADHD-C or ADHD-HI have higher incidences of comorbidities with ODD and TD than those with ADHD-I who the learning difficulties and the imbalance between VIQ and PIQ are more severe.