Targeted drug delivery of Methotrexate in situ gels for the treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is considered a debilitating disease that increases the risk of significant morbidity and premature mortality. To circumvent drug-related toxicity and ineffectiveness of anti-inflammatory drugs, there is a significant need for an advanced delivery system that increases bioavailability. The feasibility of in situ gel of methotrexate sodium (MTS) as an effective management for Rheumatoid arthritis was investigated. It was formulated with pluronic F-127 (PLF-127) as primary polymer, hydroxypropyl methylcellulose K4M (HK4M), and polycarbophil (PCL) as a copolymer and characterized by various parameters. The efficacy evaluation by Freund's complete adjuvant (FCA) model, biocompatibility assessment by histopathological studies conducted. The optimized in situ gel (M4) was thermoresponsive, released 93.26 ± 2.39% MTS at 96 hours. In addition, distribution of MTS was even in the optimized sterile and syringeable in situ gel. In vivo studies on wistar rats demonstrated a substantial reduction in paw oedema during the 28-day study period and were biocompatible with the tissues at the injection site. The study was successful in formulating, optimizing MTS in situ gel for effective management of RA.     

幽门螺杆菌及胃蛋白酶原、胃泌素17水平在胃癌前病变诊断中的应用价值

目的 探讨幽门螺杆菌(H.pylori)与胃蛋白酶原(PG)、胃泌素17(G17)与胃癌前病变的相关性。方法 选取在我院行胃镜检查的患者856例,其中471例病理检出癌前病变的患者为病例组,385例未检出癌前病变的患者为对照组。病例组按病理诊断结果分为慢性萎缩性胃炎(CAG)组157例,肠化(IM)组153例,低级别上皮内瘤变(LGIN)组82例,高级别上皮内瘤变(HGIN)组79例。检测各组H.pylori感染分型及PG、G17水平。结果 CAG组Ⅰ型感染率高于对照组(P<0.05);CAG组PGⅠ 低于对照组(P<0.05);IM组、LGIN组、HGIN组PGⅡ高于对照组(P<0.05);CAG组、IM组、LGIN组、HGIN组PGⅠ/PGⅡ(PGR)均低于对照组(P<0.05);LGIN组、HGIN组G17均高于对照组(P<0.05);PGⅠ、PGⅡ、G17与H.pylori感染阳性存在正相关,PGR与H.pylori感染阳性存在负相关(P<0.05)。结论 H.pylori感染分型、PG、G17水平与胃癌前病变密切相关,检测H.pylori感染分型、PG、G17对于早期筛查胃癌前病变具有重要价值。     

Targeting autophagy reverses de novo resistance in homologous recombination repair proficient breast cancers to PARP inhibition

Background Poly(ADP-ribose) polymerase inhibitors (PARPi) target tumours defective in homologous recombination (HR). Most BRCA-wild-type (WT) HR-proficient breast cancers are intrinsically resistant to PARP inhibitors, e.g., talazoparib. We evaluated the role of autophagy in this de novo resistance and determined the underlying mechanism to overcome this.Methods Autophagosome formation and autophagic flux were assessed by evaluating endogenous LC3-II levels and ectopic expression of EGFP-LC3 and mRFP-EGFP-LC3 in breast cancer cells. Autophagy-defective cells were generated by genetic depletion of BECN1, ATG5, p62/SQSTM1 and LAMP1 by using CRISPR-Cas9 double nickase system. The response of PARPi was evaluated in autophagy-proficient and -defective breast cancer cells and in xenograft SCID-mice model.Results Pro-survival autophagy was significantly enhanced upon talazoparib treatment in BRCA-WT breast cancer cell lines. Autophagy-deficient cells were hypersensitive to talazoparib. Targeting autophagy synergistically enhanced the therapeutic efficacy of talazoparib in BRCA1-WT breast cancer cells in vitro and in vivo xenograft tumour mouse model. Mechanistically, autophagy inhibition by chloroquine promoted deleterious NHEJ mediated DSB-repair, leading to extensive genomic instability and mitotic catastrophe.Conclusions Autophagy confers de novo resistance to PARP inhibitor, talazoparib. Autophagy inhibition improves the therapeutic outcome of PARPi treatment in preclinical mice model, bearing HR-proficient breast tumours, warranting its usage in the clinical settings.Subject terms: Breast cancer, Cancer therapy     

Neighborhood Disadvantage and Self-Esteem—Do Socioeconomic and Relational Resources Matter?

Extensive research suggests that living in a socioeconomically disadvantaged neighborhood is associated with poor mental health. Few studies, however, have examined (1) whether neighborhood disadvantage is associated with residents’ self-esteem; and (2) the extent to which individual-level socioeconomic resources such as income and education, and relational resources such as marriage and social support moderate the association between neighborhood disadvantage and self-esteem. This study employs data from the Americans’ Changing Lives panel survey (hereafter ACL), a 15-year panel study of the U.S. adult population ages 25 and older in original sample. Because hierarchical linear model was employed to analyze data, findings provide fixed effect coefficients for independent variables at both the individual and census tract levels while controlling for random intercepts between census tracts. Findings based on data from the 4th wave of ACL reveal that neighborhood disadvantage is not associated with self-esteem. We do, however, find that living in a disadvantaged neighborhood worsens self-esteem for those who have lower levels of informal social support and are currently unmarried. These findings imply that while neighborhood disadvantage does not necessarily impact self-esteem, neighborhood disadvantage is detrimental to the self-esteem of those who report lower level of relational resources.     

Agreement and repeatability of Icare ic100 tonometer

Purpose:To find the agreement and repeatability of Icare ic100 tonometer.Methods:We included 150 subjects above the age of 18 years for this cross-sectional, multicenter study with intraocular pressure (IOP) ≥7 mmHg. After the initial ophthalmic examination, two masked examiners took five IOP measurements using three different instruments; Icare ic100, Icare TA01i, and Goldmann applanation tonometer (GAT) in only one eye of the participants. Comparison of agreement of IOP using different instruments was quantified with intraclass correlation coefficient (ICC) using the two-way random effects models of absolute agreement and Cronbach''s alpha. The test-retest variability of the instruments was assessed by deriving repeatability coefficient (RC) and coefficient of variation (CV).Results:Agreement between the tonometers across the different IOP groups had no statistically significant difference in their mean IOP. Icare ic100 was found to have good reliability across all IOP groups (ICC value >0.78) when compared with Icare TA01i. In comparison with GAT, Icare ic100 showed good reliability across all IOP groups (ICC >0.87) except >16 to <23 mmHg group where it showed moderate reliability (ICC = 0.52). Icare ic100 showed good repeatability with RC and CV of 2.67 and 4.89, respectively.Conclusion:Icare ic100 rebound tonometer can measure IOP with relatively small measurement error and can provide a reliable and repeatable reading in comparison with GAT across a wide pressure range without hampering corneal health.