Autoimmune-associated HLA-B8-DR3 haplotypes in Asian Indians are unique in C4 complement gene copy numbers and HSP-2 1267A/G

The classical AH8.1 (HLA-A1-B8-DR3-DQ2) is the most common Caucasian haplotype, associated with several autoimmune diseases, immunologic hyperreactivity and rapid progression to the acquired immunodeficiency syndrome. However, in Asian Indians, there are multiple unique B8-DR3 haplotypes that are associated with autoimmunity and differ significantly from the common Caucasian AH8.1. The Indian HLA-A1-B8-DR3 is therefore referred to as an AH8.1 variant. The aims of this study were to compare C4A and C4B copy numbers and to identify alleles in HSP70-2 and LTA in these haplotypes. The Indian B8-DR3 haplotypes differ from the Caucasian AH8.1 at C4A and HSP70-2 loci. The Indian B8-DR3 haplotypes have 1 copy each at C4A and C4B, while the Caucasian AH8.1 has 1 copy at C4B but no C4A gene. Moreover, the Indian and Caucasian B8-DR3 haplotypes had HSP70-2 1267 (*)A, and *G alleles, respectively. By contrast, the LTA 252 *G allele occurred both in the Indian and Caucasian haplotypes. The Indian haplotypes also contained Bf*F and TNF-308*G that were different from the Caucasian equivalents Bf*S and TNF-308*A. These differences and previous studies support the hypothesis that B8-DR3-DQ2 haplotypes in Asian Indian population might have originated independently of Caucasian AH8.1 selectively through recombination and mutations. Because autoimmune disease associations are shared among these otherwise diverse haplotypes, these data strongly suggest that some shared component(s) of all these associated haplotypes may be playing a key role in such associations.     

Comparison of two long-term chemotherapy regimens, with or without agents to modify skeletal repair, in multiple myeloma

A randomized controlled trial was initiated in 1972 to compare two chemotherapeutic regimens [1-3-bis (2-chloroethyl) 1-nitrosourea (BCNU), cyclophosphamide, and prednisone versus melphalan and prednisone], to determine whether the two regimens are cross-resistant, and to evaluate the effectiveness of sodium fluoride, vitamin D, calcium gluconate, and fluoxymesterone in the promotion of bone healing. Initial responses (50%) and survival (36 mo median) for patients treated with the two chemotherapeutic regimens were the same. Patients on either regimen who failed to respond after 6 mo had a very low response rate to the alternative regimen (approximately 10%). Initially responding patients were randomly assigned to either an active drug regimen (sodium fluoride, vitamin D, calcium gluconate, fluoxymesterone) or placebo tablets. There was no significant difference in the low percentage of patients demonstrating bone improvement. Thus, the BCNU, cyclophosphamide, prednisone regimen is as effective as melphalan and prednisone. Fluoride, calcium, vitamin D, and androgenic steroids should not be routinely recommended in myeloma, as they seem to add little to effective chemotherapy and may contribute to morbidity.     

Hyperinsulinemia,insulin-like growth factor-I,insulin-like growth factor-binding protein-1, and sex-hormone binding-globulin in prepubertal and pubertal girls with premature adrenarche

Precocious adrenarche is defined as the development of pubic hair before the age of 8 years in girls and 9 years in boys. Pubarche caused premature adrenarche in girls has been considered as a normal variant of pubertal development for years. Recently, it is cleared that premature pubarche can be considered as a marker of increased risk for endocrine and metabolic abnormalities. Precocious adrenarche in affected girls is associated with hyperinsulinaemia and functional ovarian hyperandrogenism during puberty. Authors investigated serum levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1), insulin-like growth factor-binding protein-3 (IGFBP-3), sex hormone binding-globulin (SHBG) and levels of insulin during oral glucose tolerance test in 34 girls with premature adrenarche in 38 age- and BMI-matched healthy controls. Affected girls were assigned into prepubertal and pubertal subgroups. It has been shown that hyperinsulinaemia, decrease in IGFBP-1 and increase IGF-I levels may be present in some affected prepubertal patients. In the pubertal group, in addition to hyprinsulinaemia, decreased IGFBP-1 and increased IGF-I levels an attenuated SHBG level was observed. According to the authors, these laboratory parameters may predict endocrine and metabolic abnormalities in later life. The observed correlations support the hypothesis that insulin/IGF system plays role in the pathogenesis of hyperandrogenism in premature adrenarche and in later hormonal and metabolic changes.     

Oral high-dose methotrexate with citrovorum factor rescue in metastastic squamous cell carcinoma of the lung.

Thirteen patients with metastatic squamous cell cancer of the lung were treated, in a nonrandomized study, with an oral high-dose methotrexate and citrovorum factor rescue regimen. There was some response and/or stabilization of disease for at least three months in six (46%) of 13 cases. The median survival time of the study group was double (365 vs. 180 days) that of a retrospectively matched control group. This suggests a possible therapeutic effect of this treatment program in metastatic squamous cell cancer of the lung.     

Exosomes in Extracellular Matrix Bone Biology

Purpose of Review

Exosomes are membrane vesicles that are released by most cell types into the extracellular environment. The purpose of this article is to discuss the main morphological features and contents of bone-derived exosomes, as well as their major isolation and physical characterization techniques. Furthermore, we present various scenarios and discuss potential clinical applications of bone-derived exosomes in bone repair and regeneration.

Recent Findings

Exosomes were believed to be nanosized vesicles derived from the multivesicular body. Reports now suggest that nanovesicles could bud directly from the plasma membrane. However, the exosome cargo is cell-type specific and is derived from the parent cell. In the bone matrix, several intracellular proteins lacking a signal peptide are transported to the ECM by exosomes. Besides proteins, several mRNA, miRNA, and lipids are exported to the ECM by bone cells and bone marrow stromal cells. Recent evidence suggests that several of the functional components in the cargo could regulate processes of bone formation, inhibit osteoclast activity, and promote fracture repair.

Summary

Exosomes are powerful cellular molecular machines produced without human intervention and packaged with physiological cargo that could be utilized for molecular therapy in several skeletal disorders such as osteoporosis, osteogenesis imperfecta, and fracture healing. Although much work has been done, there is a lot of information that is still unknown, as exosomes contain a multitude of molecules whose identity and function have yet to be identified.

     

Possible therapeutic applications of single-chain antibodies in systemic autoimmune diseases

B cells participate in the induction and maintenance of systemic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, via production of pathogenic autoantibodies, contributing to the formation of immune complexes. Immune complex deposition in the kidney and joints causes inflammation and organ destruction, and chemokine production enhances T cell activation and tissue damage. The development of the disorder depends on several factors, for example, genetic susceptibility, environmental factors or immune dysregulation. Traditional therapies, which aimed at the alleviation of symptoms, are giving way to biological therapies with the potential of disrupting disease progression. This article focuses on antibody therapies, especially on the applications of single-chain antibodies, as new biological agents for the treatment of systemic autoimmune disorders.     

Performance of a new HPV and biomarker assay in the management of hrHPV positive women: Subanalysis of the ongoing multicenter TRACE clinical trial (n > 6,000) to evaluate POU4F3 methylation as a potential biomarker of cervical precancer and cancer

The ongoing Triage and Risk Assessment of Cervical Precancer by Epigenetic Biomarker (TRACE) prospective, multicenter study aimed to provide a clinical evaluation of the CONFIDENCE? assay, which comprises a human papillomavirus (HPV) DNA and a human epigenetic biomarker test. Between 2013 and 2015 over 6,000 women aged 18 or older were recruited in Hungary. Liquid‐based cytology (LBC), high‐risk HPV (hrHPV) DNA detection and single target host gene methylation test of the promoter sequence of the POU4F3 gene by quantitative methylation‐specific polymerase chain reaction (PCR) were performed from the same liquid‐based cytology sample. The current analysis is focused on the baseline cross‐sectional clinical results of 5,384 LBC samples collected from subjects aged 25 years or older. The performance of the CONFIDENCE HPV? test was found to be comparable to the cobas® HPV test with good agreement. When applying the CONFIDENCE Marker? test alone in hrHPV positives, it showed significantly higher sensitivity with matching specificity compared to LBC‐based triage. For CIN3+ histological endpoint in the age group of 25–65 and 30–65, the methylation test of POU4F3 achieved relative sensitivities of 1.74 (95% CI: 1.25–2.33) and 1.64 (95% CI: 1.08–2.27), respectively, after verification bias adjustment. On the basis of our findings, POU4F3 methylation as a triage test of hrHPV positives appears to be a noteworthy method. We can reasonably assume that its quantitative nature offers the potential for a more objective and discriminative risk assessment tool in the prevention and diagnostics of high‐grade cervical intraepithelial neoplasia (CIN) lesions and cervical cancer.     

A simple clinical method for predicting the benefit of prone vs. supine positioning in reducing heart exposure during left breast radiotherapy

Background and purpose

The benefit of reduced radiation heart exposure in the prone vs. supine position individually differs. In this prospective cohort study, the goal was to develop a simple method for the operation of a validated model for the prediction of preferable treatment position during left breast radiotherapy.