ST 2825

ST 2825 is a specific inhibitor of MyD88 dimerization [1].

ST 2825 is a synthetic compound which mimics the structure of the heptapeptide in the BB-loop of the MyD88-TIR domain and interferes the homodimerization of MyD88. ST 2825 was proved to specifically inhibit the homodimerization of MyD88 TIR domains without affecting the homodimerization of death domains. In HEK293T cells transfected with Flag-MyD88 and Myc-MyD88, ST 2825 inhibited the interaction of the two MyD88 by 80% at the concentration of 10 μM. This inhibition resulted in the subsequent interference of the IRAK1 and IRAK4 recruitment. Besides that, administration of ST 2825 significantly inhibited the IL-6 production stimulated by IL-1β at doses of 100 and 200 mg/kg in mice. Furthermore, 8 μM ST 2825 completely blocked the TLR9-induced B cell proliferation. ST2825 also suppressed the generation of plasma cells induced by CpG dose-dependently [1].

References:
[1] Loiarro M, Capolunghi F, Fantò N, et al. Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. Journal of leukocyte biology, 2007, 82(4): 801-810.

NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology.[Pubmed:28798345]

Sci Rep. 2017 Aug 10;7(1):7733.

Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-beta signaling in the kidney and biliary tract, respectively. The pathogenic mechanisms underlying these abnormalities have not been determined. In the current report, we find that disrupting PKHD1 results in altered sub-cellular localization and function of the C2-WWW-HECT domain E3 family of ligases regulating these processes. We also demonstrate altered activity of RhoA and increased TGF-beta signaling and ENaC activity. Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd1 gene product, FPC, also contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Our results provide a mechanistic explanation for both the cellular effects and in vivo phenotypic abnormalities in mice and humans that result from Pkhd1/PKHD1 mutation.

Do small changes in rotation affect measurements of lower extremity limb alignment?[Pubmed:28532505]

J Orthop Surg Res. 2017 May 22;12(1):77.

BACKGROUND: The alignment of the lower extremity has important implications in the development of knee arthritis. The effect of incremental rotations of the limb on common parameters of alignment has not been studied. The purpose of the study was to (1) determine the standardized neutral position measurements of alignment and (2) determine the effect of rotation on commonly used measurements of alignment. METHODS: Eighty-seven full length CT angiography studies (49 males and 38 females, average age 66 years old) were included. Three-dimensional models were created using a rendering software program and placed on a virtual plane. An image of the extremity was obtained. Thirty scans were randomly selected, and those models were rotated in 3 degrees intervals around the longitudinal axis and additional images were obtained. RESULTS: In the neutral position, the mechanical lateral distal femoral articular angle (mLDFA) was 85.6 +/- 2.3 degrees , medial proximal tibial angle (MPTA) was 86.1 +/- 2.8 degrees , and mechanical tibiofemoral angle (mTFA) was -0.7 +/- 3.1 degrees . Females had a more valgus alignment with a mTFA of 0.5 +/- 2.9 degrees while males had a more varus alignment with a mTFA of -1.7 +/- 2.9 degrees . The anatomic tibiofemoral angle (aTFA) was 4.8 +/- 2.6 degrees , the anatomic lateral distal femoral angle (aLDFA) measured 80.2 +/- 2.2 degrees , and the anatomical-mechanical angle (AMA) was 5.4 +/- 0.7 degrees . The prevalence of constitutional varus was 18%. The effect of rotation on the rotated scans led to statistically significant differences relative to the 0 degrees measurement for all measurements. These effects may be small, and their clinical importance is unknown. CONCLUSIONS: This study provides new information on standardized measures of lower extremity alignment and the relationship between discreet axial rotations of the entire lower extremity and these parameters.

Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis.[Pubmed:28418520]

Ann Intern Med. 2017 May 16;166(10):715-724.

Background: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI). Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 microg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain. Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016). Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization. Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 microg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies. Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died. Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies. Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome. Primary Funding Source: Emergency Care Foundation.

The Stability of Self-Reported Anxiety in Youth with Autism Versus ADHD or Typical Development.[Pubmed:28593597]

J Autism Dev Disord. 2017 Dec;47(12):3756-3764.

Children with autism spectrum disorder (ASD) are at risk for anxiety symptoms. Few anxiety measures are validated for individuals with ASD, and the nature of ASD raises questions about reliability of self-reported anxiety. This study examined longitudinal stability and change of self-reported anxiety in higher functioning youth with ASD (HFASD) compared to youth with symptoms of attention deficit hyperactivity disorder and typical development (TD) using the Multidimensional Anxiety Scale for Children (March, 2012; March et al. J Am Acad Child Adolesc Psychiatry 36(4):554-565, 1997). Diagnostic groups demonstrated comparable evidence of stability for most dimensions of anxiety. The HFASD group displayed higher anxiety than both comparison groups, especially physical symptoms. These findings have implications for identification and measurement of anxiety in ASD.

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2.[Pubmed:28882436]

Gynecol Oncol. 2017 Nov;147(2):267-275.

OBJECTIVE: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). METHODS: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600mg BID, irrespective of BRCA1/2 mutation status and prior treatments. RESULTS: In the efficacy population (n=106), ORR was 53.8% (95% confidence interval [CI], 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2months (95% CI, 6.6-11.6). In the safety population (n=377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade >/=3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile.

ST 2825 is a specific MyD88 dimerization inhibitor. ST2825 interferes with recruitment of IRAK1 and IRAK4 by MyD88, causing inhibition of IL-1β-mediated activation of NF-κB transcriptional activity.

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