Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9.

ADP-ribosylation of proteins is emerging as an important regulatory mechanism. Depending on the family member, ADP-ribosyltransferases either conjugate a single ADP-ribose to a target or generate ADP-ribose chains. Here we characterize Parp9, a mono-ADP-ribosyltransferase reported to be enzymatically inactive. Parp9 undergoes heterodimerization with Dtx3L, a histone E3 ligase involved in DNA damage repair. We show that the Dtx3L/Parp9 heterodimer mediates NAD+-dependent mono-ADP-ribosylation of ubiquitin, exclusively in the context of ubiquitin processing by E1 and E2 enzymes. Dtx3L/Parp9 ADP-ribosylates the carboxyl group of Ub Gly76. Because Gly76 is normally used for Ub conjugation to substrates, ADP-ribosylation of the Ub carboxyl terminus precludes ubiquitylation. Parp9 ADP-ribosylation activity therefore restrains the E3 function of Dtx3L. Mutation of the NAD+ binding site in Parp9 increases the DNA repair activity of the heterodimer. Moreover, poly(ADP-ribose) binding to the Parp9 macrodomains increases E3 activity. Dtx3L heterodimerization with Parp9 enables NAD+ and poly(ADP-ribose) regulation of E3 activity.

PARP7 mono-ADP-ribosylates the agonist conformation of the androgen receptor in the nucleus.

We recently described a signal transduction pathway that contributes to androgen receptor (AR) regulation based on site-specific ADP-ribosylation by PARP7, a mono-ADP-ribosyltransferase implicated in several human cancers. ADP-ribosylated AR is recognized by PARP9/DTX3L, a heterodimeric complex that contains an ADP-ribose reader (PARP9) and a ubiquitin E3 ligase (DTX3L). Here, we have characterized the cellular and biochemical requirements for AR ADP-ribosylation by PARP7. We found that the reaction requires nuclear localization of PARP7 and an agonist-induced conformation of AR. PARP7 contains a Cys3His1-type zinc finger (ZF), which also is critical for AR ADP-ribosylation. The Parp7 ZF is required for efficient nuclear import by a nuclear localization signal encoded in PARP7, but rescue experiments indicate the ZF makes a contribution to AR ADP-ribosylation that is separable from the effect on nuclear transport. ZF mutations do not detectably reduce PARP7 catalytic activity and binding to AR, but they do result in the loss of PARP7 enhancement of AR-dependent transcription of the MYBPC1 gene. Our data reveals critical roles for AR conformation and the PARP7 ZF in AR ADP-ribosylation and AR-dependent transcription.

De novo mutations in SIK1 cause a spectrum of developmental epilepsies.

Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy.

Genomic analysis of DNA repair genes and androgen signaling in prostate cancer.

BACKGROUND: The cellular effects of androgen are transduced through the androgen receptor, which controls the expression of genes that regulate biosynthetic processes, cell growth, and metabolism. Androgen signaling also impacts DNA damage signaling through mechanisms involving gene expression and transcription-associated DNA damaging events. Defining the contributions of androgen signaling to DNA repair is important for understanding androgen receptor function, and it also has translational implications. METHODS: We generated RNA-seq data from multiple prostate cancer lines and used bioinformatic analyses to characterize androgen-regulated gene expression. We compared the results from cell lines with gene expression data from prostate cancer xenografts, and patient samples, to query how androgen signaling and prostate cancer progression influences the expression of DNA repair genes. We performed whole genome sequencing to help characterize the status of the DNA repair machinery in widely used prostate cancer lines. Finally, we tested a DNA repair enzyme inhibitor for effects on androgen-dependent transcription. RESULTS: Our data indicates that androgen signaling regulates a subset of DNA repair genes that are largely specific to the respective model system and disease state. We identified deleterious mutations in the DNA repair genes RAD50 and CHEK2. We found that inhibition of the DNA repair enzyme MRE11 with the small molecule mirin inhibits androgen-dependent transcription and growth of prostate cancer cells. CONCLUSIONS: Our data supports the view that crosstalk between androgen signaling and DNA repair occurs at multiple levels, and that DNA repair enzymes in addition to PARPs, could be actionable targets in prostate cancer.

The protein kinase C super-family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression.

BACKGROUND: Phosphoinositide-3 (PI-3) kinase signaling has a pervasive role in cancer. One of the key effectors of PI-3 kinase signaling is AKT, a kinase that promotes growth and survival in a variety of cancers. Genetically engineered mouse models of prostate cancer have shown that AKT signaling is sufficient to induce prostatic epithelial neoplasia (PIN), but insufficient for progression to adenocarcinoma. This contrasts with the phenotype of mice with prostate-specific deletion of Pten, where excessive PI-3 kinase signaling induces both PIN and locally invasive carcinoma. We reasoned that additional PI-3 kinase effector kinases promote prostate cancer progression via activities that provide biological complementarity to AKT. We focused on the PKN kinase family members, which undergo activation in response to PI-3 kinase signaling, show expression changes in prostate cancer, and contribute to cell motility pathways in cancer cells. METHODS: PKN kinase activity was measured by incorporation of 32 P into protein substrates. Phosphorylation of the turn-motif (TM) in PKN proteins by mTOR was analyzed using the TORC2-specific inhibitor torin and a PKN1 phospho-TM-specific antibody. Amino acid substitutions in the TM of PKN were engineered and assayed for effects on kinase activity. Cell motility-related functions and PKN localization was analyzed by depletion approaches and immunofluorescence microscopy, respectively. The contribution of PKN proteins to prostate tumorigenesis was characterized in several mouse models that express PKN transgenes. The requirement for PKN activity in prostate cancer initiated by loss of phosphatase and tensin homolog deleted on chromosome 10 (Pten), and the potential redundancy between PKN isoforms, was analyzed by prostate-specific deletion of Pkn1, Pkn2, and Pten. RESULTS AND CONCLUSIONS: PKN1 and PKN2 contribute to motility pathways in human prostate cancer cells. PKN1 and PKN2 kinase activity is regulated by TORC2-dependent phosphorylation of the TM, which together with published data indicates that PKN proteins receive multiple PI-3 kinase-dependent inputs. Transgenic expression of active AKT and PKN1 is not sufficient for progression beyond PIN. Moreover, Pkn1 is not required for tumorigenesis initiated by loss of Pten. Triple knockout of Pten, Pkn1, and Pkn2 in mouse prostate results in squamous cell carcinoma, an uncommon but therapy-resistant form of prostate cancer.

Aripiprazole for the treatment of tic disorders in children: a systematic review and meta-analysis.

BACKGROUND: Tic disorders (TDs) are common neuropsychiatric disorders in children. Typical antipsychotics, such as haloperidol and pimozide have been prescribed to control tic symptoms as first-line agents. However, adverse effects have led to the use of newer atypical antipsychotics. Aripiprazole is one of alternatives. The aim of this study was to evaluate the efficacy and safety of aripiprazole for children with TDs. METHODS: Randomized controlled trials (RCTs), quasi-RCTs and control studies evaluating aripiprazole for children with tic disorders were identified from PubMed, Embase, Cochrane library, Cochrane Central, four Chinese database and relevant reference lists. Quality assessment referred to the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Twelve studies involving 935 participants were included. The general quality of included studies was poor. Only one study used placebo as a control and others used positive drug controls. Participants were aged between 4 and 18 years. The period of treatment ranged from 8 to 12 weeks. Seven studies (N = 600 patients) used the YGTSS scale as the outcome measurement, and there was no significant difference in reduction of the total YGTSS score between the aripiprazole and positive control groups (MD = -0.48, 95 % CI [-6.22, 5.26], P = 0.87, I(2) = 87 %). Meta-analysis of four of the studies (N = 285 patients) that compared aripiprazole with haloperidol showed that there was no significant difference in reduction of the total YGTSS score (MD = 2.50, 95 % CI [-6.93, 11.92], P = 0.60, I(2) = 88 %). Meta-analysis of two studies (N = 255 patients) that compared aripiprazole with tiapride showed that there was no significant difference in reduction of the total YGTSS score (MD = -3.15, 95 % CI [-11.38, 5.09], P = 0.45, I(2) = 86 %). Adverse events (AEs) were reported in 11 studies. Drowsiness (5.1 %-58.1 %), increased appetite (3.2 %-25.8 %), nausea (2 %-18.8 %) and headache (2 %-16.1 %) were common AEs. CONCLUSION: In conclusion, aripiprazole appears to be a promising therapy for children with TDs. Further well-conducted RCTs are required to confirm this issue.

Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method.

We present in this paper the efficient synthesis of three macrocyclic lactone units which are core structures of natural resin glycosides by the use of a Keck macrolactonization approach.

10-year trend in quantity and quality of pediatric randomized controlled trials published in mainland China: 2002-2011.

BACKGROUND: Quality assessment of pediatric randomized controlled trials (RCTs) in China is limited. The aim of this study was to evaluate the quantitative trends and quality indicators of RCTs published in mainland China over a recent 10-year period. METHODS: We individually searched all 17 available pediatric journals published in China from January 1, 2002 to December 30, 2011 to identify RCTs of drug treatment in participants under the age of 18 years. The quality was evaluated according to the Cochrane quality assessment protocol. RESULTS: Of 1287 journal issues containing 44398 articles, a total of 2.4% (1077/44398) articles were included in the analysis. The proportion of RCTs increased from 0.28% in 2002 to 0.32% in 2011. Individual sample sizes ranged from 10 to 905 participants (median 81 participants); 2.3% of the RCTs were multiple center trials; 63.9% evaluated Western medicine, 32.5% evaluated traditional Chinese medicine; 15% used an adequate method of random sequence generation; and 10.4% used a quasi-random method for randomization. Only 1% of the RCTs reported adequate allocation concealment and 0.6% reported the method of blinding. The follow-up period was from 7 days to 96 months, with a median of 7.5 months. There was incomplete outcome data reported in 8.3%, of which 4.5% (4/89) used intention-to-treat analysis. Only 0.4% of the included trials used adequate random sequence allocation, concealment and blinding. The articles published from 2007 to 2011 revealed an improvement in the randomization method compared with articles published from 2002 to 2006 (from 2.7% to 23.6%, p = 0.000). CONCLUSIONS: In mainland China, the quantity of RCTs did not increase in the pediatric population, and the general quality was relatively poor. Quality improvements were suboptimal in the later 5 years.

Drug-Related Problems of Children With Chronic Diseases in a Chinese Primary Health Care Institution: A Cross-Sectional Study.

Introduction: Drug-related problems (DRPs) refer to events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes. DRPs might be severe for children with chronic diseases managed at primary health care institutions, but the relevant research is scarce. Objective: In this cross-sectional study, we aimed to explore the prevalence, types, causes, and influencing factors of DRPs in children with chronic diseases in a Chinese primary health care institution. Methods: We recruited children with chronic diseases who visited the pediatric outpatient department in a primary health care institution from July 1 to 12 October 2021. Clinical pharmacists identified DRPs through medication therapy reviews, classified the types and causes of DRPs, and distinguished the manifested DRPs that affected the outcome and potential DRPs that were going to affect the outcome. Results: A total of 188 children with chronic diseases was included, and 584 DRPs were identified in 89.89% of participants. The most common type of DRPs was "treatment effectiveness" (a manifested problem or potential problem with the effect of the pharmacotherapy; 83.56%), of which 67.29% were potential DRPs. The second common type was "treatment safety" (patient suffers or could suffer from an adverse drug event; 14.21%), of which 89.16% were potential DRPs. The most common cause of DRPs was related to the process of use (42.24%), such as "patient uses/takes less drug than prescribed or does not take the drug at all," "patient stores drug inappropriately," and "patient administers/uses the drug in a wrong way." The second common cause was related to the process of dispensing (29.83%), such as "necessary information not provided or incorrect advice provided" and "prescribed drug is not available." The third common cause was related to the process of prescribing (26.21%), such as "drug dose is too low" and "no or incomplete drug treatment despite an existing indication." The number of combined medications was an influencing factor for the frequency of DRPs (p < 0.05). Conclusion: This cross-sectional study showed that the current situation regarding DRPs among children with chronic diseases managed in the primary health care institution was serious. The types of DRPs were mainly related to treatment effectiveness, and improper usage of medications was one of the main causes of DRPs. The number of combined drugs was the influencing factor for the frequency of DRPs. In the future, pharmacists should consider formulating pharmaceutical intervention strategies for this specific group according to the characteristics of DRPs.

Multi-center investigation on personnel training and scientific research status of pharmacy intravenous admixture services (PIVAS) in mainland China based on the perspectives of PIVAS leaders.

ABSTRACT: We sought to analyze the current situation of personnel training and scientific research regarding pharmacy intravenous admixture services (PIVAS), to provide evidence-based medical knowledge to inform personnel training for PIVAS in mainland China.A cross-sectional survey was used to examine the current status of PIVAS personnel training, research capabilities, needs, and research output of PIVAS personnel based from the perspective of leaders in PIVAS in China. The survey period was from March to April 2019.A total of 137 hospitals in China participated in this survey. The main training content areas of PIVAS staff in each hospital were professional theoretical knowledge (100.00%, 137/137) and practical operation ability (98.54%, 135/137). The frequency of training was typically 1 to 2 times/month (56.9%, 78/137). The average duration of a single training session was typically 1 h or less (68.6%, 94/137). The most common forms of PIVAS training were lectures (94.89%, 130/137) and practical operations (79.56%, 109/137). A total of 51.8% (71/137) of PIVAS leaders believed that PIVAS personnel had a high degree of scientific research needs, but 61.3% (84/137) believed that few personnel had mastered scientific research methodology, and 41.6% (57/137) believed that the scientific research ability of personnel was relatively poor. Among PIVAS personnel, only 38.7% (53/137) had specialized scientific training. The annual total SCI output was 0 to 18 articles (median 0 articles) and the total number of national-level funding grants was 0 to 2 (median 0). There were no significant differences in the training of PIVAS personnel and scientific research between different provinces and hospital levels.The training content of PIVAS personnel in China was found to be relatively rich, but management tools, career development, and training in scientific research were found to be relatively weak, and the scientific research output was very low. It is necessary to build a comprehensive training system for career development among PIVAS personnel.

Drug-Related Problems of Patients in Primary Health Care Institutions: A Systematic Review.

Introduction: Drug-related problems (DRPs) are not only detrimental to patients' physical health and quality of life but also lead to a serious waste of health care resources. The condition of DRPs might be more severe for patients in primary health care institutions. Objective: This systematic review aims to comprehensively review the characteristics of DRPs for patients in primary health care institutions, which might help find effective strategies to identify, prevent, and intervene with DRPs in the future. Methods: We searched three English databases (Embase, The Cochrane Library, and PubMed) and four Chinese databases (CNKI, CBM, VIP, and Wanfang). Two of the researchers independently conducted literature screening, quality evaluation, and data extraction. Qualitative and quantitative methods were combined to analyze the data. Results: From the 3,368 articles screened, 27 met the inclusion criteria and were included in this review. The median (inter-quartile range, IQR) of the incidences of DRPs was 70.04% (59%), and the median (IQR) of the average number of DRPs per patient was 3.4 (2.8). The most common type of DRPs was "treatment safety." The causes of DRPs were mainly in the prescribing section, including "drug selection" and "dose selection", while patients' poor adherence in the use section was also an important cause of DRPs. Risk factors such as the number of medicines, age, and disease condition were positively associated with the occurrence of DRPs. In addition, the medians (IQR) of the rate of accepted interventions, implemented interventions, and solved DRPs were 78.8% (22.3%), 64.15% (16.85%), and 76.99% (26.09%), respectively. Conclusion: This systematic review showed that the condition of DRPs in primary health care institutions was serious. In pharmaceutical practice, the patients with risk factors of DRPs should be monitored more closely. Pharmacists could play important roles in the identification and intervention of DRPs, and more effective intervention strategies need to be established in the future.

Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling.

Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze ADP-ribosylation and play critical roles in normal and disease settings. The PARP family member, PARP7, is a mono-ADP-ribosyltransferase that has been suggested to play a tumor suppressive role in breast, ovarian, and colorectal cancer. Here, we have investigated how androgen signaling regulates PARP7 homeostasis in prostate cancer cells, where PARP7 is a direct target gene of AR. We found that the PARP7 protein is extremely short-lived, with a half-life of 4.5 min. We show that in addition to its transcriptional regulation by AR, PARP7 is subject to androgen-dependent post-transcriptional regulation that increases its half-life to 25.6 min. This contrasts with PARP1, PARP2, PARP9, and PARP14, which do not display rapid turnover and are not regulated by androgen signaling. Androgen- and AR-dependent stabilization of PARP7 leads to accumulation in the nucleus, which we suggest is a major site of action. Mutations in the catalytic domain, the Cys3His1 zinc finger, and WWE (tryptophan-tryptophan-glutamate) domains in PARP7 each reduce the degradation rate of PARP7, suggesting the overall structure of the protein is tuned for its rapid turnover. Our finding that PARP7 is regulated by AR signaling both transcriptionally and post-transcriptionally in prostate cancer cells suggests the dosage of PARP7 protein is subject to tight regulation.

Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly.

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.

Petty syndrome and Fontaine-Farriaux syndrome: Delineation of a single syndrome.

In 1990, Petty et al. described two patients representing a novel syndrome with "congenital progeriod" features and neither had classical progeria nor Wiedemann-Rautenstrauch syndrome, though many findings were overlapping. One of the cases had previously been described by Dr. Wiedemann in 1948. The key features of Petty syndrome include pre and postnatal growth restriction, decreased subcutaneous fat with loose skin, enlarged fontanelle with underdeveloped calvarium, coronal synostosis, unruly hair pattern with non-uniform distribution, prominent eyebrows, umbilical hernia, distal digital hypoplasia, and normal or near normal development. Significant overlap to other syndromes, particularly the Fontaine-Farriaux syndrome, is apparent. In 2004, Ardinger postulated that Petty syndrome, like classical progeria, might be secondary to a defect in the lamin A/C (LMNA) gene. The purpose of this paper is to describe two new unrelated cases of this unique syndrome that further delineate the phenotype, compare to phenotypically similar syndromes, and postulate that Petty syndrome could represent a new laminopathy. In addition, evidence suggesting that the Petty syndrome and Fontaine-Farriaux syndromes are variable expressions of the same condition is discussed.

Ligand binding to the androgen receptor induces conformational changes that regulate phosphatase interactions.

We describe a mechanism for protein phosphatase 2A (PP2A) targeting to the androgen receptor (AR) and provide insight into the more general issue of kinase and phosphatase interactions with AR. Simian virus 40 (SV40) small t antigen (ST) binding to N-terminal HEAT repeats in the PP2A A subunit induces structural changes transduced to C-terminal HEAT repeats. This enables the C-terminal HEAT repeats in the PP2A A subunit, including HEAT repeat 13, to discriminate between androgen- and androgen antagonist-induced AR conformations. The PP2A-AR interaction was used to show that an AR mutant in prostate cancer cells (T877A) is activated by multiple ligands without acquiring the same conformation as that induced by androgen. The correlation between androgen binding to AR and increased phosphorylation of the activation function 1 (AF-1) region implies that changes in AR conformation or chaperone composition are causal to kinase access to phosphorylation sites. However, AF-1 phosphorylation sites are kinase accessible prior to androgen binding. This suggests that androgens can enhance the phosphorylation state of AR either by negatively regulating the ability of the ligand-binding domain to bind phosphatases or by inducing an AR conformation that is resistant to phosphatase action. SV40 ST subverts this mechanism by promoting the direct transfer of PP2A onto androgen-bound AR, resulting in multisite dephosphorylation.

Usefulness of serum glucose and potassium ratio as a predictor for 30-day death among patients with severe traumatic brain injury.

BACKGROUND: Serum glucose and potassium ratio (GPR) was recently found to be related to outcome of aneurysmal subarachnoid hemorrhage. This retrospectively study was to investigate the association of serum GPR with mortality in severe traumatic brain injury (sTBI). METHODS: Clinical data were retrospectively reviewed of isolated sTBI patients admitted within 12 h after trauma between January 2014 and January 2019. We analyzed relationships between admission serum GPR and post-traumatic 30-day mortality in addition to admission Glasgow coma scale (GCS) scores. Discriminative ability was evaluated using area under receiver operating characteristic curve (AUC). RESULTS: A total of 146 patients, of whom 37 (25.3%) died within 30 days following trauma, were included. Admission serum GPR emerged as an independent predictor for 30-day mortality (odds ratio, 5.256; 95% confidence interval (CI), 1.111-14.856) and overall survival (hazard ratio, 4.822; 95% CI, 1.157-12.870), with an AUC of 0.777 (95% CI, 0.693-0.835), which was equivalent to that of GCS scores (AUC, 0.831; 95% CI, 0.760-0.888; P = 0.179). There was a significant correlation between admission serum GPR and GCS scores (r2 = 0.293). CONCLUSIONS: Serum GPR in cases of sTBI is substantially associated with trauma severity and 30-day mortality. Therefore, the potential value of serum GPR for predicting short-term mortality of sTBI patients is favorable.

Serum CXC chemokine ligand-12 as a potential predictor for in-hospital major adverse events after severe traumatic brain injury.

BACKGROUND: CXC chemokine ligand-12 (CXCL12) is associated with brain inflammation. We attempted to discern whether serum CXCL12 is a promising predictor for in-hospital major adverse events (IMAEs) after traumatic brain injury (TBI), including death, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. METHODS: In this prospective, observational study, serum CXCL12 levels were quantified among 117 severe TBI patients. We investigated the relation of CXCL12 levels to IMAEs using a multivariate analysis. RESULTS: Median value of serum CXCL12 concentrations was substantially higher in patients with IMAEs than in other remainders (21.1 vs. 11.6 ng/ml). With an increasing number of IMAEs, serum CXCL12 concentrations were significantly increased (r = 0.702). Serum CXCL12 independently predicted IMAEs (odds ratio, 1.253; 95% CI, 1.100-1.428). Serum CXCL12 concentrations discriminated risk of IMAEs with area under receiver operating characteristic curve of 0.759 (95% CI, 0.672-0.834), its concentrations >16.0 ng/ml distinguished IMAEs with 83.9% sensitivity and 67.2% specificity and its combination with Glasgow coma scale scores produced the best predictive ability compared with each one alone (p = 0.0116 or 0.0004). CONCLUSION: Serum CXCL12 concentrations are independently associated with IMAEs following TBI, substantializing serum CXCL12 as a useful prognostic biomarker for head trauma patients.

Ovary and uterus related adverse events associated with statin use: an analysis of the FDA Adverse Event Reporting System.

Experimental studies have demonstrated statin-induced toxicity for ovary and uterus. However, the safety of statins on the functions of ovary and uterus in real-world clinical settings remains unknown. The aim of this study was to identify ovary and uterus related adverse events (AEs) associated with statin use by analyzing data from FDA Adverse Event Reporting System (FAERS). We used OpenVigil 2.1 to query FAERS database. Ovary and uterus related AEs were defined by 383 Preferred Terms, which could be classified into ten aspects. Disproportionality analysis was performed to assess the association between AEs and statin use. Our results suggest that statin use may be associated with a series of ovary and uterus related AEs. These AEs are involved in ovarian cysts and neoplasms, uterine neoplasms, cervix neoplasms, uterine disorders (excl neoplasms), cervix disorders (excl neoplasms), endocrine disorders of gonadal function, menstrual cycle and uterine bleeding disorders, menopause related conditions, and sexual function disorders. Moreover, there are variabilities in the types and signal strengths of ovary and uterus related AEs across individual statins. According to our findings, the potential ovary and uterus related AEs of statins should attract enough attention and be closely monitored in future clinical practice.

Detection of ADP-Ribosylation of the Androgen Receptor Using the Recombinant Macrodomain AF1521 from Archaeoglobus fulgidus.

ADP-ribosylation is a posttranslational modification generated by members of the superfamily of ADP-ribosyltransferases, known as the Parp enzymes. Depending on the superfamily member, Parp enzymes can mono- or poly-ADP-ribosylate a protein substrate. Parp superfamily members confer regulation to a variety of biological processes that include cell signaling, DNA repair, transcription, and stress responses. Here, we describe biochemical methods for detection of ADP-ribose conjugated to the androgen receptor (AR) using the archaeal macrodomain, AF1521, from Archaeoglobus fulgidus. The utility of AF1521 is based on its highly selective recognition of ADP-ribose conjugated to protein. AF1521 immobilized on beads can be used to enrich for ADP-ribosylated proteins, which in our application results in recovery of ADP-ribosylated AR from prostate cancer cell extracts. We engineered tandem AF1521 macrodomains and found this improves the recovery of ADP-ribosylated AR under native conditions, and it enabled development of an assay for detection of ADP-ribosylation on blots. Thus, AF1521 can be used to query ADP-ribosylation of protein under both native and denaturing conditions. Our assays should prove useful for understanding how ADP-ribosylation regulates AR function.

Methodological quality of clinical practice guidelines for genetic testing in children: A systematic assessment using the appraisal of guidelines for research and evaluation II instrument.

Genetic testing of children is faced with numerous problems. High-quality clinical practice guidelines (CPGs) are needed to ensure its safe, and appropriate use. This study aimed to systematically identify the current CPGs for genetic testing in children, and to assess the methodological quality of these CPGs.We searched 6 databases, 3 guideline clearinghouses, and 9 web sites of relevant academic agencies from inception to February 2019. CPGs focused on genetic testing in children were included. Four reviewers independently appraised the quality of the eligible CPGs using the appraisal of guidelines for research, and evaluation (AGREE) II instrument.Seventeen CPGs meeting our inclusion criteria were included. Among them, 16 CPGs were focused on the genetic diagnosis/evaluation of diseases, while only 1 CPG was focused on pharmacogenetics. The median domain scores from highest to lowest were: scope and purpose 80.56% (range: 56.95%-87.50%), clarity of presentation 72.22% (range: 45.83%-88.89%), stakeholder involvement 45.83% (range: 27.78%-55.56%), applicability 31.25% (range: 19.79%-54.17%), rigor of development 21.88%, (range: 13.02%-71.88%), and editorial independence 18.75% (range: 0%-83.33%). According to the overall quality, 6 (35%) CPGs were "not recommended," 8 (47%) CPGs were "recommended with modifications," and only 3 (18%) CPGs were "recommended." The clinical topics of the "recommended" CPGs were warfarin, familial Mediterranean fever, and pediatric pulmonary arterial hypertension.The quality of CPGs for genetic testing in children was generally low, and variable across different CPGs and different AGREE II domains. In future guideline development, more attention should be paid to the aspects of stakeholder involvement, rigor of development, applicability, and editorial independence. Not only will guideline users benefit from our results when determining whether to adopt related CPGs to guide genetic testing in children, but guideline developers could also take into account our results to improve the quality of future CPGs.