TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma

Background

Disseminated soft tissue sarcoma still represents a therapeutic dilemma because effective cytostatics are missing. Therefore we tested TRAIL and Tarolidine (TRD), two substances with apoptogenic properties on human fibrosarcoma (HT1080).

Methods

Viability, apoptosis and necrosis were visualized by TUNEL-Assay and quantitated by FACS analysis (Propidiumiodide/AnnexinV staining). Gene expression was analysed by RNA-Microarray and the results validated for selected genes by rtPCR. Protein level changes were documented by Western Blot analysis. NFKB activity was analysed by ELISA and proliferation assays (BrdU) were performed.

Results and discussion

The single substances TRAIL and TRD induced apoptotic cell death and decreased proliferation in HT1080 cells significantly. Gene expression of several genes related to apoptotic pathways (TRAIL: ARHGDIA, NFKBIA, TNFAIP3; TRD: HSPA1A/B, NFKBIA, GADD45A, SGK, JUN, MAP3K14) was changed. The combination of TRD and TRAIL significantly increased apoptotic cell death compared to the single substances and lead to expression changes in a variety of genes (HSPA1A/B, NFKBIA, PPP1R15A, GADD45A, AXL, SGK, DUSP1, JUN, IRF1, MYC, BAG5, BIRC3). NFKB activity assay revealed an antipodal regulation of the several subunits of NFKB by TRD and TRD+TRAIL compared to TRAIL alone.

Conclusion

TRD and TRAIL are effective to induce apoptosis and decrease proliferation in human fibrosarcoma. A variety of genes seems to be involved, pointing to the NFKB pathway as key regulator in TRD/TRAIL-mediated apoptosis.     

(Dis-)Connected Dots in Dementia with Lewy Bodies—A Systematic Review of Connectivity Studies

Studies on dementia with Lewy bodies (DLB) have mainly focused on the degeneration of distinct cortical and subcortical regions related to the deposition of Lewy bodies. In view of the proposed trans-synaptic spread of the α-synuclein pathology, investigating the disease only in this segregated fashion would be detrimental to our understanding of its progression. In this systematic review, we summarize findings on structural and functional brain connectivity in DLB, as connectivity measures may offer better insights on how the brain is affected by the spread of the pathology. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched Web of Science, PubMed, and SCOPUS for relevant articles published up to November 1, 2021. Of 1215 identified records, we selected and systematically reviewed 53 articles that compared connectivity features between patients with DLB and healthy controls. Structural and functional magnetic resonance imaging, positron emission tomography, single-positron emission computer tomography, and electroencephalography assessments of patients revealed widespread abnormalities within and across brain networks in DLB. Frontoparietal, default mode, and visual networks and their connections to other brain regions featured the most consistent disruptions, which were also associated with core clinical features and cognitive impairments. Furthermore, graph theoretical measures revealed disease-related decreases in local and global network efficiency. This systematic review shows that structural and functional connectivity characteristics in DLB may be particularly valuable at early stages, before overt brain atrophy can be observed. This knowledge may help improve the diagnosis and prognosis in DLB as well as pinpoint targets for future disease-modifying treatments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Strong acceleration of murine lupus by injection of the SmD183–119 peptide

Objective

The mechanisms of IgG anti–double‐stranded DNA (anti‐dsDNA) antibody induction are incompletely understood. We recently demonstrated a high prevalence of autoantibodies to the C‐terminus of SmD1 in patients with systemic lupus erythematosus (SLE) that was closely associated with anti‐dsDNA reactivity. The aim of the present study was to analyze the influence of the SmD1 C‐terminus on the generation of pathogenic anti‐dsDNA antibodies in a murine model of SLE.

Methods

Female lupus‐prone prenephritic (NZB × NZW)F₁ mice (NZB/NZW mice) as well as female control BALB/c, NZW, and (BALB/c × NZW)F₁ mice (CWF₁ mice) were subcutaneously injected with keyhole limpet hemocyanin (KLH)–coupled SmD1^83–119. Controls received injections of recombinant SmD1 (rSmD1), KLH‐rSmD1, KLH‐coupled randomized peptide of SmD1^83–119, ovalbumin, or saline. Animals were monitored for survival and proteinuria and for levels of plasma creatinine, urea, and autoantibodies. In addition, histologic examinations were performed and T cell responses against SmD1^83–119 peptide and rSmD1 protein were determined in SmD1^83–119‐treated and ‐untreated NZB/NZW mice.

Results

Immunization with KLH‐SmD1^83–119, but not with control peptide, significantly accelerated the natural course of lupus in NZB/NZW mice, with premature renal failure and increased development of anti‐dsDNA antibodies. Control strains of mice remained healthy, with no relevant anti‐SmD1^83–119 antibodies detectable even after immunization. In contrast to findings in control mice, a T cell response against SmD1^83–119 was already present in unmanipulated NZB/NZW mice, and this response was further amplified after immunization.

Conclusion

The SmD1^83–119 peptide can influence the pathogenic anti‐dsDNA response in the NZB/NZW murine lupus model. The data suggest that an SmD1^83–119‐specific T cell response is critical. Therefore, modulation of these autoantigen‐specific T cells by tolerance induction may provide a therapeutic approach to specific immunosuppression in lupus.

     

Development,psychometric assessment,and predictive validity of a breastfeeding subjective norms scale among an Australian prospective cohort of first-time parents

Objectives

Breastfeeding has a number of benefits for both mothers and their infants. Research has examined the psychosocial influences on breastfeeding, yielding important findings in relation to particular constructs that play a significant role in this vital health behaviour. One such construct is subjective norms. However, there are mixed findings in relation to the role of subjective norms in breastfeeding behaviours. This may be due to the lack of consistent measure of subjective norms across studies. Further, the influence of fathers' subjective norms on breastfeeding continuation remains unclear due to a lack of measurement. Thus, the aim of the current study was to develop and assess a reliable and valid subjective norms scale specific to breastfeeding for use among both mothers and fathers.

Design/Methods

Subjective norms items were developed by researchers in the domain and were tested among 949 couples.

Results

Findings indicated that both subjective norms scales had excellent reliability, construct validity, and predictive validity. It was also found that both the mothers' and fathers' subjective norms scales tapped into two key structures: breastfeeding in general, and breastfeeding in public. Further, maternal subjective norms were predictive of breastfeeding behaviours but not paternal subjective norms.

Conclusions

These findings indicate that the developed subjective norms scales are reliable and valid and capture key elements of breastfeeding subjective norms among both mothers and fathers. Use of this measure in future research can help better understand the role of both mothers' and fathers' subjective norms in influencing breastfeeding behaviours.