Risk factors for cerebral palsy in children in Taiwan.

AIM: To determine the significant risk factors of cerebral palsy (CP) in Taiwanese children and the associations between infant-related and parent-related factors. METHOD: Data from 1 459 093 infants and their parents in Taiwan's national databases collected between 2009 and 2016 were used. The cohort with CP included children diagnosed with CP between birth and age 3 years; a total of 3254 children with CP were included in the final analysis. Hierarchical logistic regression models were used to estimate the odds ratio for the risk factors of CP. RESULTS: The hierarchical logistic regression models indicated that significant risk factors associated with CP are suburban location, low income, maternal and paternal diabetes mellitus, paternal substance abuse, paternal seizure disorder, male sex, birth by Cesarean section, singleton birth, low birthweight, being born extremely and very preterm, intraventricular hemorrhage, and periventricular leukomalacia, as well as tube feeding, ventilator use, and dopamine administration within 6 months of age. INTERPRETATION: In addition to common maternal and infant risk factors, we identified significant paternal risk factors associated with CP, including diabetes mellitus, seizure disorder, and substance abuse. The combination of maternal, paternal, and infant risk factors in CP holds great promise for early identification and intervention.

Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment.

We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis. Exome sequencing revealed compound heterozygous missense variants in SLC5A6, the gene encoding a cellular sodium-dependent multivitamin transporter (SMVT) responsible for transporting vitamins, including biotin (vitamin B7). We showed that the biotin deficiency was caused by the SLC5A6 variants resulting in defective B cell differentiation and antibody deficiency. Altered cellular metabolic profiles, including aberrant mitochondrial respiration and reliance on glycolysis, may underlie the failure in plasma cell maturation. Replenishment of biotin improved plasma cell maturation and recovered the antibody producing activity in the patient and in a CRISPR-Cas9 gene-edited mouse model bearing a patient-specific SLC5A6 variant. Our results demonstrate the critical role of metabolic reprogramming in the maturation of plasma cells and nominate SLC5A6 as a causative gene for immunodeficiency that may be treated by biotin replenishment.

Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by defects in the leukocyte NADP oxidase. We previously reported that sarcoplasmic/endoplasmic reticulum calcium pump (SERCA) inhibitors could be used to rescue mutant H338Y-gp91phox protein of a particular type of CGD with a CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T mutation on a Cybb knockout background and investigated the therapeutic effects of ER-targeted delivery of the SERCA inhibitor, curcumin, with poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs). We found that PLGA encapsulation improved the efficacy of curcumin as a SERCA inhibitor to induce ER calcium release. ER-targeting curcumin-loaded PLGA NPs reduced and delayed extracellular calcium entry and protected the cells from mitochondrial damage and apoptosis. In vivo studies showed that ER-targeting curcumin-loaded PLGA NPs treatment enhanced neutrophil gp91phox expression, ROS production and peritoneal bacterial clearance ability of the CybbC1024T transgenic Cybb -/- mice. Our findings indicate that ER-targeted delivery of curcumin not only rescues ER-retained H338Y-gp91phox protein, and hence leukocyte function, but also enhances the bioavailability and reduces cytotoxicity. Modulation of ER function by using organelle-targeted NPs may be a promising strategy to improve the therapeutic potential of curcumin as a treatment for CGD.

Increased ILC3s associated with higher levels of IL-1ß aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase.

The role of redox regulation in immune-mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte-derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL-1 family cytokines along with other cytokines relevant to ILC functions and development in serum-induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)-deficient Ncf1-/- mice. We found more severe serum-induced joint inflammation and increased NCR+ ILC3s in inflamed joints of Ncf1-/- mice. Furthermore, in vitro stimulation with IL-1ß on Tbet+ ILC1s from joints facilitated their differentiation into ROR-γt+ ILC3s. Moreover, treatment with IL-1 antagonists effectively lowered the proportions of NCR+ ILC3s and IL-17A producing ILC3s in Ncf1-/- arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential regulator of ILC transdifferentiation and may mediate this process in a redox-dependent manner through IL-1ß production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell-mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints.

Psychiatric Disorders After Attention-Deficit/Hyperactivity Disorder: A Nationwide Population-Based Study in Taiwan.

PURPOSE: To investigate the risk for psychiatric disorders in patients newly diagnosed with attention deficit hyperactive disorder (ADHD) from two longitudinal groups of children with and without ADHD. STUDY DESIGN: In total, 1,745 children newly diagnosed with ADHD and 6,980 participants without ADHD were identified from Taiwan's National Health Insurance Research Database in 2005 and followed until 2010. Risks for psychiatric disorders in the ADHD and non-ADHD groups were compared. RESULTS: The ADHD group was 3.82 times more likely to develop psychiatric disorders than their counterparts. The ADHD group showed the highest risk for oppositional defiant disorder, followed by adult ADHD and autism spectrum disorder. Moreover, the time effects of psychiatric disorders in the ADHD group were significant. Patients with ADHD subtypes had a significant risk for psychiatric disorders compared to their counterparts. CONCLUSIONS: A high risk for psychiatric disorders was revealed in this study among children with ADHD. Childhood ADHD, the duration after the ADHD diagnosis, and the ADHD subtype were associated with psychiatric disorders. CLINICAL RELEVANCE: Various psychiatric disorders were observed in children after they had been newly diagnosed with ADHD, indicating a need for integrated care that includes medical practitioners, family members, social workers, and early intervention workers for patients newly diagnosed with ADHD to decrease the risk for comprehensive psychiatric disorders.

Yoga for asthma.

BACKGROUND: Asthma is a common chronic inflammatory disorder affecting about 300 million people worldwide. As a holistic therapy, yoga has the potential to relieve both the physical and psychological suffering of people with asthma, and its popularity has expanded globally. A number of clinical trials have been carried out to evaluate the effects of yoga practice, with inconsistent results. OBJECTIVES: To assess the effects of yoga in people with asthma. SEARCH METHODS: We systematically searched the Cochrane Airways Group Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched PEDro. We searched ClinicalTrials.gov and the WHO ICTRP search portal. We searched all databases from their inception to 22 July 2015, and used no restriction on language of publication. We checked the reference lists of eligible studies and relevant review articles for additional studies. We attempted to contact investigators of eligible studies and experts in the field to learn of other published and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared yoga with usual care (or no intervention) or sham intervention in people with asthma and reported at least one of the following outcomes: quality of life, asthma symptom score, asthma control, lung function measures, asthma medication usage, and adverse events. DATA COLLECTION AND ANALYSIS: We extracted bibliographic information, characteristics of participants, characteristics of interventions and controls, characteristics of methodology, and results for the outcomes of our interest from eligible studies. For continuous outcomes, we used mean difference (MD) with 95% confidence interval (CI) to denote the treatment effects, if the outcomes were measured by the same scale across studies. Alternatively, if the outcomes were measured by different scales across studies, we used standardised mean difference (SMD) with 95% CI. For dichotomous outcomes, we used risk ratio (RR) with 95% CI to measure the treatment effects. We performed meta-analysis with Review Manager 5.3. We used the fixed-effect model to pool the data, unless there was substantial heterogeneity among studies, in which case we used the random-effects model instead. For outcomes inappropriate or impossible to pool quantitatively, we conducted a descriptive analysis and summarised the findings narratively. MAIN RESULTS: We included 15 RCTs with a total of 1048 participants. Most of the trials were conducted in India, followed by Europe and the United States. The majority of participants were adults of both sexes with mild to moderate asthma for six months to more than 23 years. Five studies included yoga breathing alone, while the other studies assessed yoga interventions that included breathing, posture, and meditation. Interventions lasted from two weeks to 54 months, for no more than six months in the majority of studies. The risk of bias was low across all domains in one study and unclear or high in at least one domain for the remainder.There was some evidence that yoga may improve quality of life (MD in Asthma Quality of Life Questionnaire (AQLQ) score per item 0.57 units on a 7-point scale, 95% CI 0.37 to 0.77; 5 studies; 375 participants), improve symptoms (SMD 0.37, 95% CI 0.09 to 0.65; 3 studies; 243 participants), and reduce medication usage (RR 5.35, 95% CI 1.29 to 22.11; 2 studies) in people with asthma. The MD for AQLQ score exceeded the minimal clinically important difference (MCID) of 0.5, but whether the mean changes exceeded the MCID for asthma symptoms is uncertain due to the lack of an established MCID in the severity scores used in the included studies. The effects of yoga on change from baseline forced expiratory volume in one second (MD 0.04 litres, 95% CI -0.10 to 0.19; 7 studies; 340 participants; I(2) = 68%) were not statistically significant. Two studies indicated improved asthma control, but due to very significant heterogeneity (I(2) = 98%) we did not pool data. No serious adverse events associated with yoga were reported, but the data on this outcome was limited. AUTHORS' CONCLUSIONS: We found moderate-quality evidence that yoga probably leads to small improvements in quality of life and symptoms in people with asthma. There is more uncertainty about potential adverse effects of yoga and its impact on lung function and medication usage. RCTs with a large sample size and high methodological and reporting quality are needed to confirm the effects of yoga for asthma.

Interleukin-2 as maintenance therapy for children and adults with acute myeloid leukaemia in first complete remission.

BACKGROUND: Acute myeloid leukaemia (AML) is a malignant cancer of hematopoietic stem cells. The treatment of AML consists of two treatment phases: the remission induction phase to achieve a rapid, complete remission (CR) and the consolidation phase to achieve a durable molecular remission. People in CR are at risk of AML relapse, and people with relapsed AML have poor survival prospects. Thus, there is a continuous need for treatments to further improve prognosis. Interleukin-2 (IL-2), an immune-stimulatory cytokine, is an alternative to standard treatment for people with AML to maintain the efficacy after consolidation therapy. Maintenance therapy is not an integral part of the standard treatment for AML. Studies have been conducted to evaluate the efficacy of IL-2 as maintenance therapy for people with AML in first CR, but the effect of IL-2 is not yet fully established. OBJECTIVES: To evaluate the efficacy and safety of IL-2 as maintenance therapy for children and adults with AML who have achieved first CR and have not relapsed. SEARCH METHODS: We systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 8), MEDLINE (1950 to August 2015), EMBASE (1950 to August 2015), LILACS (1982 to August 2015), CBM (1978 to August 2015), relevant conference proceedings (2000 to 2015), and metaRegister of Controlled Trials (since inception to August 2015) of ongoing and unpublished trials. In addition, we screened the reference lists of relevant trials and reviews. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) comparing IL-2 with no treatment in people with AML who had achieved first CR and had not relapsed. We did not identify studies comparing IL-2 versus best supportive care or maintenance chemotherapy or studies comparing IL-2 plus maintenance chemotherapy versus maintenance chemotherapy alone. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data with a predefined extraction form, and assessed risk of bias of included studies. We extracted data on the following outcomes: disease-free survival, overall survival, event-free survival, treatment-related mortality, adverse events, and quality of life. We measured the treatment effect on time-to-event outcomes and dichotomous outcomes with hazard ratio (HR) and risk ratio, respectively. We used inverse-variance method to combine HRs with fixed-effect model unless there was significant between-study heterogeneity. MAIN RESULTS: We included nine RCTs with a total of 1665 participants, comparing IL-2 with no treatment. Six studies included adult participants, and three studies included both adults and children. However, the latter three studies did not report data for children, thus we were unable to conduct subgroup analysis of children. One Chinese study did not report any outcomes of interest for this review. We included six trials involving 1426 participants in the meta-analysis on disease-free survival, and included five trials involving 1355 participants in the meta-analysis on overall survival. There is no evidence for difference between IL-2 group and no-treatment group regarding disease-free survival (HR 0.95; 95% CI 0.86 to 1.06, P = 0.37; quality of evidence: low) or overall survival (HR 1.05; 95% CI 0.95 to 1.16, P = 0.35; quality of evidence: moderate). Based on one trial of 161 participants, IL-2 exerted no effect on event-free survival (HR 1.02; 95% CI 0.79 to 1.32, P = 0.88; quality of evidence: low). Adverse events (including thrombocytopenia, neutropenia, malaise/fatigue, and infection/fever) were more frequent in participants receiving IL-2, according to one trial of 308 participants. No mortality due to adverse events was reported. None of the included studies reported treatment-related mortality or quality of life. AUTHORS' CONCLUSIONS: There is no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to disease-free survival or overall survival of people with AML in first CR; however, the quality of the evidence is moderate or low, and further research is likely or very likely to have an important impact on the estimate or our confidence in the estimate. Adverse events seem to be more frequent in participants treated with IL-2, but the quality of the evidence is very low and our confidence in the estimates is very uncertain. Thus, further prospective randomised trials are needed before definitive conclusions can be drawn on these issues.

Synergistic effect of lung tumor-associated dendritic cell-derived HB-EGF and CXCL5 on cancer progression.

The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and its effect on cancer development. The combination of HB-EGF (heparin-binding EGF-like growth factor) and CXCL5 (CXCL5/epithelial neutrophil-activating peptide-78) produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB-EGF plus CXCL5-mediated tumor spheroid formation in a three-dimensional culture system, suggesting that AKT/HSP27 was required for HB-EGF/CXCL5-mediated cancer progression. Inhibiting RSK also reduces the modulation of c-Fos phosphorylation, Snail upregulation and cell migration by HB-EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB-EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross-points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemotherapy or immunotherapy.

Ly6G ligation blocks recruitment of neutrophils via a ß2-integrin-dependent mechanism.

Ly6G is a glycosylphosphatidylinositol (GPI)-anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice. In the present study, we found that doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB(4) and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and ß2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of ß2-integrins in LTB(4)-stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of ß2-integrin-deficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a ß2-integrin-dependent mechanism.

Chemotherapy with cetuximab versus chemotherapy alone for chemotherapy-naive advanced non-small cell lung cancer.

BACKGROUND: In advanced non-small cell lung cancer (NSCLC), the effectiveness of standard cytotoxic chemotherapy seems to have reached a 'plateau', and there is a continuous need for new treatments to further improve the prognosis. Cetuximab is a monoclonal antibody targeted at the epidermal growth factor receptor (EGFR) signalling pathway. Basically, it is designed to inhibit the growth and metastasis among other biological processes of cancer. In combination with chemotherapy, it has been evaluated as a first-line treatment for advanced NSCLC in some randomised controlled trials (RCTs), with inconsistent results. OBJECTIVES: To evaluate the efficacy and toxicity of chemotherapy plus cetuximab, compared with chemotherapy alone, for advanced non-small cell lung cancer (NSCLC) previously untreated with chemotherapy or epidermal growth factor receptor (EGFR)-targeted drugs. SEARCH METHODS: We systematically searched the Cochrane Lung Cancer Review Group's Specialized Register (from inception to 17 December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 12), MEDLINE (accessed through PubMed, 1966 to 17 December 2013), EMBASE (1980 to 17 December 2013), ClinicalTrials.gov (from inception to 17 December 2013), and the World Health Organization (WHO) International Clinical Trials Registry Platform (from inception to 17 December 2013). We also handsearched the proceedings related to lung cancer from the American Society of Clinical Oncology and European Society of Medical Oncology (2000 to 17 December 2013). We checked the reference lists of all eligible primary studies and review articles for additional potentially eligible studies. SELECTION CRITERIA: Eligible studies were RCTs that compared chemotherapy plus cetuximab with the same chemotherapy alone, in advanced NSCLC, previously untreated with chemotherapy or EGFR-targeted drugs, and measured at least one of the following: overall survival, progression-free survival, one-year survival rate, objective response rate, quality of life, or serious adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We extracted the following data from each study: publication details, participant characteristics, regimens for intervention and control arms, outcome measures and effect size, and information related to the methodological quality of the study. We measured the treatment effects on dichotomous and time-to-event outcomes by risk ratio (RR) and hazard ratio (HR), with 95% confidence intervals (CIs), respectively. We conducted meta-analyses with Review Manager 5 using the random-effects model. We employed the Mantel-Haenszel method to combine RRs and the inverse-variance method to combine HRs. MAIN RESULTS: We included four trials, containing 2018 patients. The subjects were mostly white people (female: 26% to 56%), with a median age of 58 to 66 years. About half of them had histologically proven adenocarcinoma. Of the 2018 patients, 83% to 99% had their status measured using the Eastern Cooperative Oncology Group performance status, and had a score of 0 to 1 (which is usually considered as physically "fit").All four studies provided data on overall survival, progression-free survival, one-year survival rate, objective response rate, and serious adverse events, with two studies (1901 patients) investigating the effect of cetuximab on quality of life as well. The risk of bias was low for the data on overall survival and one-year survival rate, and high for the data on all other outcomes, mainly due to lack of blinding. Compared with chemotherapy alone, chemotherapy plus cetuximab improved overall survival (10.5 months versus 8.9 months; HR 0.87, 95% CI 0.79 to 0.96), one-year survival rate (45% versus 40%; RR 1.13, 95% CI 1.02 to 1.25), and objective response rate (30% versus 23%; RR 1.31, 95% CI 1.14 to 1.51). The difference in progression-free survival was at the limit of the statistical significance (4.9 months versus 4.4 months; HR 0.91, 95% CI 0.83 to 1.00). No significant difference in quality of life between the two treatment arms was reported by the two relevant studies. Patients in the cetuximab group experienced more acneiform rash (11.2% versus 0.3%; RR 37.36, 95% CI 10.66 to 130.95), hypomagnesemia (5.3% versus 0.8%; RR 6.57, 95% CI 1.13 to 38.12), infusion reaction (3.9% versus 1.1%; RR 3.50, 95% CI 1.76 to 6.94), diarrhoea (4.8% versus 2.3%; RR 2.10, 95% CI 1.26 to 3.48), hypokalaemia (6.3% versus 3.6%; RR 1.74, 95% CI 1.02 to 2.99), febrile neutropenia (10.6% versus 7.6%; RR 1.40, 95% CI 1.10 to 1.77), and leukopenia (58.1% versus 42.7%; RR 1.36, 95% CI 1.17 to 1.58) than did those in the control group. The difference in other adverse events did not reach statistical significance. According to the reports of original studies, the adverse events were generally manageable. There were no cetuximab-related deaths.The quality of the evidence is high for overall survival and one-year survival rate, but low for most secondary outcomes. AUTHORS' CONCLUSIONS: The combination of chemotherapy plus cetuximab is better than chemotherapy alone as the first-line treatment of advanced NSCLC in improving overall survival, while inducing higher rates of some reportedly manageable adverse events.

Lung tumor-associated dendritic cell-derived resistin promoted cancer progression by increasing Wolf-Hirschhorn syndrome candidate 1/Twist pathway.

The interaction between tumors and their microenvironments leads to a vicious cycle, which strengthens both immune suppression and cancer progression. The present study demonstrates for the first time that tumor-associated dendritic cells (TADCs) are a source of resistin, which is responsible for increasing lung cancer epithelial-to-mesenchymal transition. In addition, large amounts of resistin in the condition medium (CM) of TADCs increase cell migration and invasion, as well as the osteolytic bone metastatic properties of lung cancer cells. Neutralization of resistin from TADC-CM prevents the advanced malignancy-inducing features of TADC-CM. Significantly elevated levels of resistin have been observed in mice transplanted with lung cancer cells, tumor-infiltrating CD11c(+) DCs in human lung cancer samples and lung cancer patients' sera. Induction of lung cancer progression by TADC-derived resistin is associated with increased expression of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), a histone methyltransferase. Resistin-induced WHSC1 increases the dimethylation of histone 3 at lysine 36 and decreases the trimethylation of histone 3 at lysine 27 on the promoter of Twist, resulting in an enhancement of the expression of Twist. Knockdown of WHSC1 by small interfering RNA transfection significantly decreases resistin-mediated cancer progression by decreasing the upregulation of Twist, suggesting that WHSC1 plays a critical role in the regulation of Twist by epigenetic modification. Furthermore, mice that received antiresistin antibodies showed a decreased incidence of cancer development and metastasis. These findings suggest that TADC-derived resistin may be a novel candidate in promoting the development of lung cancer.

Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a systematic review with meta-analysis.

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs). However, many patients with KRAS wild-type tumors still do not respond to the treatment. We conducted a systematic review with meta-analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild-type mCRC treated with anti-EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression-free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random-effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67-4.03; HR = 2.52, 95% CI 1.33-4.78 and HR = 1.75, 95% CI 1.19-2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79-4.19; HR = 3.29, 95% CI 1.60-6.75 and HR = 1.85, 95% CI 1.30-2.64, respectively) and lower ORR (RD = -36%, 95% CI -44 to -28%; RD = -38%, 95% CI -51 to -24% and RD = -41%, 95% CI -68 to -14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of worseoutcomes in KRAS wild-type mCRC treated with anti-EGFR MoAbs [corrected]. However, the quality of included studies varied, and some of the meta-analyses were limited by significant between-study heterogeneity. In the future, well-designed large randomized controlled trials conducted in KRAS wild-type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: The authors conducted a systematic review and meta-analysis to examine whether patients who had metastatic colorectal cancer (mCRC) with the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and received cetuximab treatment had better clinical outcomes than patients who had mCRC tumors with KRAS codon 12 mutations. METHODS: Relevant studies were identified by a search of MEDLINE, EMBASE, the Chinese Biomedical Database, and Wan Fang Digital Journals from inception to October 2011. The primary clinical outcomes included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effects or random-effects models according to heterogeneity between studies. RESULTS: Ten studies were considered eligible that included 1487 patients with mCRC. Patients who had tumors with the KRAS p.G13D mutation had a significantly higher ORR (10 studies; RR, 1.642; 95% confidence interval [CI], 1.131-2.384), longer PFS (1 study; HR, 0.54; 95% CI, 0.36-0.81), and longer OS (1 study; HR, 0.52; 95% CI, 0.33-0.80) than patients who had tumors with KRAS codon 12 mutations. Compared with patients who had KRAS wild-type tumors, patients with the p.G13D mutation had a significantly lower ORR (9 studies; RR, 0.540; 95% CI, 0.381-0.765) and nonsignificantly shorter PFS (1 study; HR, 0.99; 95% CI, 0.68-1.45) and OS (1 study; HR, 1.01; 95% CI, 0.66-1.54). CONCLUSIONS: Patients who had mCRC with the KRAS p.G13D mutation appeared to benefit more from cetuximab than patients who had tumors with KRAS codon 12 mutations. However, because of the limited sample sizes in the current meta-analysis, these results should be interpreted with caution.

Concentration of plasma neutrophil gelatinase-associated lipocalin in patients with chronic kidney disease.

BACKGROUND: The inclining incidence of chronic kidney disease which has led to high mortality and immense medical burden over the past decades has become a distressing concern in epidemiology. Unfortunately, the number of biomarkers that allow the monitoring of chronic kidney disease (CKD) is limited. Neutrophil gelatinase-associated lipocalin (NGAL) is an emerging biomarker which has been shown to be able to diagnose kidney injuries. METHODS: Eighty-one nondiabetic patients with chronic kidney disease, stage 2 to 5, were recruited for this study, and 17 healthy volunteers with eGFR greater than 90 mL/minute/1.73m(2) were selected as the control group. RESULTS: Our study demonstrated that the pNGAL level is elevated during CKD, and the pNGL level has a strong correlation with the concentration of sCr and eGFR. CONCLUSIONS: Plasma neutrophil gelatinase-associated lipocalin is a potent tool in the diagnosis of chronic kidney diseases and is shown to have high correlation with serum creatinine and estimated glomerular filtration rate.

The Efficacy of Health Promotion Program Among Parents Who Had Children With Attention-Deficit/Hyperactivity-Disorder.

OBJECTIVES: To explore the effect of health promotion program (HPP) on stress, quality of life, health-promoting lifestyles, and children's attention-deficit/hyperactivity disorder (ADHD) symptoms in parents of children with ADHD. METHODS: Sixty parents of children with ADHD were equally randomized into the intervention (health promotion program) and control (usual care) groups. Outcomes included parents' stress, quality of life, health-promoting lifestyles, and children's ADHD symptoms before, immediately after, and 1, 3, and 6 months after the intervention. The GEE was used to evaluate the effectiveness. RESULTS: The intervention group reported significant improvement in the children's hyperactivity/impulse and opposition at the 6- and 3-month, respectively. Parental overall stress significantly improved at 3 and 6 months. Parents' quality of life had significant effects at the immediate, 3-month, and 6-month. Self-actualization behavior for health-promoting lifestyles had significant effects at the immediate follow-up. CONCLUSION: HPP can promote the mental well-being of parents of children with ADHD.

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities.

Immune-mediated arthritis is an important chronic inflammatory disease of joints causing debilitating morbidity in affected patients. The mechanisms underlying immune-mediated arthritis have been intensively investigated, however the cellular and molecular factors contributing to the joint inflammation in different redox conditions have not been clearly elucidated. Previous research showed that phagocyte-produced reactive oxygen species (ROS) plays an anti-inflammatory role in K/BxN serum-transfer arthritis and NOX2-deficient mice tend to have more severe arthritis. Although many leukocytes play critical roles in the development of immune-mediated arthritis, the role of neutrophils, which are the main producers of ROS in inflammation, is still controversial. We hence assessed the immunomodulatory function of neutrophils from arthritic joints of NOX2-deficient and wild type mice in this study. We found more neutrophils accumulation in NOX2-deficient inflamed joints. RNA-sequencing and quantitative PCR revealed significantly increased expression of acute inflammation genes including IL1b, Cxcl2, Cxcl3, Cxcl10 and Mmp3 in activated neutrophils from the inflamed joints of NOX2-deficient mice. Moreover, gene set enrichment analysis (GSEA) showed enriched gene signatures in type I and II IFN responses, IL-6-JAK-STAT3 signaling pathway and TNF-α signaling pathway via NF-κB in NOX2-deficient neutrophils. In addition, we found that NOX2-deficient neutrophils expressed lower levels of PD-L1 and were less suppressive than WT neutrophils. Moreover, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Both the strong pro-inflammatory and weakened anti-inflammatory functions of neutrophils due to abnormal redox regulation may be targets of treatment for immune-mediated arthritis.

Comparative Risks of High-Grade Adverse Events Among FDA-Approved Systemic Therapies in Advanced Melanoma: Systematic Review and Network Meta-Analysis.

Background: Head-to-head evidence is lacking in comparative risks of high-grade adverse events (AEs) among different systemic treatment options for advanced melanoma. Methods: An up-to-date systematic review and network meta-analysis (NMA) was performed. Randomized controlled trials (RCTs) of patients with advanced melanoma were eligible if at least one intervention was the Food and Drug Administration-approved targeted or immune checkpoint inhibitors. Risks of high-grade AEs were estimated by random-effects Bayesian NMAs, based on relative risks. Surface under the cumulative ranking probabilities was used to assess relative ranking of treatments. The summary incidences were calculated. Results: Twenty-five RCTs (12,925 patients) comparing 10 different systemic treatment options were included. BRAF/MEK had the highest risk of overall high-grade AEs (pooled incidence: 32.11%). BRAF had the highest risk of high-grade arthralgia (0.39%), whereas MEK had the highest risk of high-grade hypertension (2.28%) and nausea (0.37%). Cytotoxic T-lymphocyte antigen 4 (CTLA-4)/chemo had the highest risk of high-grade diarrhea (1.31%), alanine aminotransferase (0.60%), and aspartate aminotransferase elevation (0.59%). Programmed cell death 1 (PD-1)/CTLA-4 had the highest risks of high-grade pyrexia (1.14%) and rash (0.94%). Using PD-1 inhibitor alone had the lowest risks of overall high-grade AEs. Conclusions: Different systemic treatment options have varying high-grade AEs in advanced melanoma treatment. Current evidences highlight the important risks of BRAF/MEK, CTLA-4/chemo, and PD-1/CTLA-4.

Comparative Safety of PD-1/PD-L1 Inhibitors for Cancer Patients: Systematic Review and Network Meta-Analysis.

Background: Comprehensive evidence comparing treatment-related adverse events (trAEs) among PD-1/PD-L1 inhibitors is unavailable. Methods: A systematic review and network meta-analysis (NMA) was conducted. Randomized controlled trials in cancer patients treated with PD1/PD-L1 inhibitors or their combinations with chemotherapy/placebo and compared with PD1/PD-L1 inhibitors/chemotherapy/placebo were identified through comprehensive searches of multiple databases. Bayesian NMA was performed using random-effects model. Relative ranking of treatments was assessed with surface under the cumulative ranking (SUCRA) probabilities. Incidences and odds ratios of trAEs and immune-related adverse events (irAEs) of all-grade (Grade 1-5) and high-grade (Grade 3-5) were estimated. Results: Twenty-three RCTs (14,204 patients) comparing six different strategies were included. The incidence of trAEs was lowest for PD-L1 inhibitors (all-grade: pooled incidence = 60.4%, SUCRA = 77.2%; high-grade: 6.4, 73.8%). PD-L1 inhibitors plus chemotherapy had the highest incidence of all-grade trAEs (88.6, 10.1%), while PD-1 inhibitors plus chemotherapy had the highest incidence of high-grade trAEs (8.2, 9.3%). The use of PD-1/PD-L1 inhibitors alone was associated with significant reductions on high-grade trAEs, compared with PD-1/PD-L1 inhibitors plus chemotherapy. PD-1 inhibitors had the highest incidence of irAEs (all-grade: 15.1, 9.5%; high-grade: 3.5, 16.8%). Compared with PD-L1 inhibitors, PD-1 inhibitors neither increased trAEs nor irAEs significantly. Results from sensitivity analyses were consistent. Conclusions: Current data showed that PD-L1 inhibitors had the best safety on both trAEs and irAEs. Awareness of the comparative safety could promote further appropriate utilization of PD-1/PD-L1 inhibitors in clinical practice.

Molecular Mechanisms of Anticancer Effects of Phytoestrogens in Breast Cancer.

Phytoestrogens derived from plants exert estrogenic as well as antiestrogenic effects and multiple actions within breast cancer cells. Chemopreventive properties of phytoestrogens have emerged from epidemiological observations. In recent clinical research studies, phytoestrogens are safe and may even protect against breast cancer. In this brief review, the molecular mechanisms of phytoestrogens on regulation of cell cycle, apoptosis, estrogen receptors, cell signaling pathways, and epigenetic modulations in relation to breast cancer are discussed. Phytoestrogens have a preferential affinity for estrogen receptor (ER)-ß, which appears to be associated with antiproliferative and anticarcinogenic effects. Moreover, while phytoestrogens not only inhibit ER-positive but also ER-negative breast cancer cells, the possibility of epigenetic modulation playing an important role is also discussed. In conclusion, as there are multiple targets and actions of phytoestrogens, extensive research is still necessary. However, due to low toxicity, low cost, and easy availability, their potent chemoprevention effects deserve further study.

Brain metastasis from renal urothelial carcinoma successfully treated by metastasectomy.

Upper tract urothelial cancer (UTUC) arises from the urothelial lining of the urinary tract. UTUC spreads in several different ways including direct invasion, lymphatic spread, and hematogeneous metastases. Regional lymph nodes are commonly the initial site of metastasis, followed by the liver, lung, and bone. Brain metastasis is uncommon in patients with urothelial carcinoma. Here, we report an uncommon case of kidney urothelial carcinoma with brain metastasis in a 55-year-old woman presenting with dysarthria with right side limb weakness. The patient recovered well after resection of the brain lesion without any sequelae after 1 year of follow-up.