An overview of the current status of engineered therapeutic monoclonal antibodies

Since the commercialization of the first therapeutic monoclonal antibody (mAb) product in 1986, this class of biopharmaceutical products have grown significantly. Due to the enhanced antigen binding and reduced cellular toxicity, they result in more efficacy in treatment of variety of diseases. The global sales of mAbs which was 95.1 b$in 2017 have grown annually due to the dramatic increase in cancer and severe diseases rates and are estimated to reach 131.33 b$ by 2023, this represents a clear accelerating trend with more than 5.53% growth. In this review, we discuss some of these mAbs which have been approved by the FDA as well as others that are experiencing or being evaluated in clinical phases. Global sales of some monoclonal antibodies in 2016 are also considered, suggesting a significant increase in sales of mAbs over the years ahead. &nbsp

Cefazolin-Loaded Double-Shelled Hollow Mesoporous Silica Nanoparticles/Polycaprolactone Nanofiber Composites: A Delivery Vehicle for Regenerative Purposes

Purpose: As important challenges in burn injuries, infections often lead to delayed and incomplete healing. Wound infections with antimicrobial-resistant bacteria are other challenges in the management of wounds. Hence, it can be critical to synthesize scaffolds that are highly potential for loading and delivering antibiotics over long periods. Methods: Double-shelled hollow mesoporous silica nanoparticles (DSH-MSNs) were synthesized and loaded with cefazolin. Cefazolin-loaded DSH-MSNs (Cef*DSH-MSNs) were incorporated into polycaprolactone (PCL) to prepare a nanofiber-mediated drug release system. Their biological properties were assessed through antibacterial activity, cell viability, and qRT-PCR. The morphology and physicochemical properties of the nanoparticles and nanofibers were also characterized. Results: The double-shelled hollow structure of DSH-MSNs demonstrated a high loading capacity of cefazolin (51%). According to in vitro findings, the Cef*DSH-MSNs embedded in polycaprolactone nanofibers (Cef*DSH-MSNs/PCL) provided a slow release for cefazolin. The release of cefazolin from Cef*DSH-MSNs/PCL nanofibers inhibited the growth of Staphylococcus aureus. The high viability rate of human adipose-derived stem cells (hADSCs) in contact with PCL and DSH-MSNs/PCL was indicative of the biocompatibility of nanofibers. Moreover, gene expression results confirmed changes in keratinocyte-related differentiation genes in hADSCs cultured on the DSH-MSNs/PCL nanofibers with the up-regulation of involucrin. Conclusion: The high drug-loading capacity of DSH-MSNs presents these nanoparticles as suitable vehicles for drug delivery. In addition, the use of Cef*DSH-MSNs/PCL can be an effective strategy for regenerative purposes

DNA Methylation and Histone Acetylation Patterns in Cultured Bovine Adipose Tissue-Derived Stem Cells (BADSCs)

Objective: Many studies have focused on the epigenetic characteristics of donor cells to improve somatic cell nuclear transfer (SCNT). We hypothesized that the epigenetic status and chromatin structure of undifferentiated bovine adipose tissue-derived stem cells (BADSCs) would not remain constant during different passages. The objective of this study was to determine the mRNA expression patterns of DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and histone deacetyltransferses (HDAC1, HDAC2, HDAC3) in BADSCs. In addition, we compared the measured levels of octamer binding protein-4 expression (OCT4) and acetylation of H3K9 (H3K9ac) in BADSCs cultures and different passages in vitro. Materials and Methods: In this experimental study, subcutaneous fat was obtained from adult cows immediately post-mortem. Relative level of DNMTs and HDACs was examined using quantitative real time polymerase chain reaction (q-PCR), and the level of OCT4 and H3K9ac was analyzed by flow cytometry at passages 3 (P3), 5 (P5) and 7 (P7). Results: The OCT4 protein level was similar at P3 and P5 but a significant decrease in its level was seen at P7. The highest and lowest levels of H3K9ac were observed at P5 and P7, respectively. At P5, the expression of HDACs and DNMTs was significantly decreased. In contrast, a remarkable increase in the expression of DNMTs was observed at P7. Conclusion: Our data demonstrated that the epigenetic status of BADSCs was variable during culture. The P5 cells showed the highest level of stemness and multipotency and the lowest level of chromatin compaction. Therefore, we suggest that P5 cells may be more efficient for SCNT compared with other passages

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Characterization and Release Behavior of a Thiosemicarbazone from Electrospun Polyvinyl Alcohol Core-Shell Nanofibers

Mats of polyvinyl alcohol (PVA) core-shell nanofibers were produced using coaxial electrospinning in the presence of a thiosemicarbazone (TSC)N4-(S)-1-phenylethyl)-2-(pyridin-2-yl-ethylidene)hydrazine-1-carbothioamide (HapyTSCmB). Monolithic fibers with 0% or 5% TSC and core-shell fibers with 10% TSC in the spinning solution were studied to compare stability and release rates. SEM showed the formation of uniform, bead-free, cylindrical, and smooth fibers. NMR spectroscopy and thermal analysis (TG/DTA) gave proof for the chemical integrity of the TSC in the fiber mats after the electrospinning process. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy showed no TSC on the surface of the PVA/TSC-PVA fibers confirming the core-shell character. The TSC release profiles of the fibers as studied using UV-vis absorption spectroscopy showed a slower release from the PVA/TSC-PVA core-shell structure compared with the monolithic PVA/TSC fibers as well as lower cumulative release percentage (17%). Out of several release models, the Korsmeyer-Peppas model gave the best fit to the experimental data. The main release phase can be described with a Fick-type diffusion mechanism. Antibacterial properties were tested against the Gram-positiveStaphylococcus aureusbacterium and gave a minimal inhibitory concentration of 12.5 mu g/mL. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide (MTT)-based cytotoxicity experiments showed that the cell viability of fibroblast at different contents of TSC was slightly decreased from 1.5% up to 3.5% when compared to control cells

Antioxidant properties of Ziziphus Jujuba Mill. aqueous extract of and its preventive role on RBC hemolysis induced by AAPH

Background and Aim: Jujube (Ziziphus Jujuba Mill.) is one of the medicinal herbs with grows in dry and semi-dry areas in Iran; mainly in the South Khorasan province. The present study aimed at evaluating anti-oxidant and free radical scavenging capacity in different types of Jujuba. Materials and Methods: Four ecotypes of Jujubes were collected from different parts of the South Khorasan providence (Sarayan, Quaen, Arish, and Boshad). The collected samples were air dried and then their aqueous extract was prepared in different dilutions. Anti-oxidant and free radical scavenging capacity of the samples were assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) methods. Their AAPH-induced hemolysis prevention was also analyzed. The total phenolic content of the samples was assessed using Folin–Ciocalteau method. Results: Maximum phenolic content was obtained from Quaen Jujube (1317±4.3 equal to μmol Gallic acid). The highest antioxidant capacity by FRAP (1390.1 ± 65.5μmol/L) also belonged to Quaen jujube. The ability of Arish Jujube extracts in scavenging and neutralizing free radical, tested by DPPH, was always higher compared to the other extracts. Results obtained from the effects of different dilutions of Jujube extracts (0-25 – 5 mg/ml) on hemolysis showed a dose dependent relationship. All the extracts showed dose dependent reducing hemolysis in a specific range of concentrations, induced by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH). There was no significant statistical difference between jujube ecotypes in preventing hemolysis. Conclusion: According to total phenolic content of the Jujobe extracts, its significant antioxidant properties and radical scavenging activities, which was tested through different methods, it can be a potential booster for anti-oxidant capacities

Effect of a High Dairy Diet on Serum Antibody Titers to Heat Shock Protein 27 in Overweight and Obese Children

Objective: An immune response to heat shock proteins appears to be involved in atherogenesis. To date, there has been no report on the impact of dairy or calcium consumption on serum antibody titers to heat shock protein 27 (anti-HSP27). We have investigated whether an increase in dairy food consumption is capable of affecting serum antibody titers to heat shock protein 27 (anti-HSP27) level in children. Methods: Overweight and obese children (n=99, age: 12-18 y, body mass index: 27-40 kg/m2) were randomized to receive a calorie restricted diet providing a 500 kcal/d deficit from total energy expenditure and two (n=38), three (n=26) or four (n=35) servings of dairy products/day. Serum anti-HSP27 level in addition to the serum hs-CRP and lipid profile were measured at baseline and after 12 weeks. Findings: Serum anti-HSP27 concentrations did not change significantly in any of the mentioned groups. Serum hs-CRP and lipid profile did not change significantly either, apart from a significant increase in HDL-cholesterol in the low-dairy group. Conclusion: An increased intake of dairy products does not lead to a significant change in serum anti-HSP27 level in overweight and obese children

Adverse effects of BCG vaccine 1173 P2 in Iran: A meta-analysis

Although in the last two decades the World Health Organization (WHO) has introduced tuberculosis as “a threat to global”, the vaccination with the Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the only way for the prevention of this fatal infectious disease. Despite of the efficacy of BCG vaccine especially against infants' meningitis, it has still some limitations due to a variety of adverse effects. Many studies have evaluated the side effects of different strains of BCG vaccines in different countries. In Iran, some studies have been done so far to evaluate the adverse effects of 1173 P2 strain which is used for BCG vaccination. Each of these studies have used different standardization and sampling methods. This review will survey all studies that have been published about adverse effects of 1173 P2 strain of BCG vaccine in Iran using data mining methods

Association between indices of body mass and antibody titers to heat-shock protein-27 in healthy subjects

OBJECTIVES We have assessed the relationship between indices of adiposity and antibody titers to Hsp-27 in healthy subjects. DESIGN Two-hundred and fifty subjects were studied, including 50 normal-weight subjects (body-mass-index (BMI) 25 kg/m(2)), 100 overweight subjects (BMI 25 to 30 kg/m(2)) (n=100) and 100 obese subjects (BMI ≥ 30 kg/m(2)). RESULTS Anti-Hsp27-antibody levels in obese subjects were [0.34 (0.20-0.39) absorbency unit], being significantly higher than overweight and normal-weight groups (P<0.05). Anti-Hsp27-antibody levels in overweight subjects [0.29 (0.15-0.34) absorbency unit] were statistically higher than controls [0.18 (0.10-0.23) absorbency unit] (P<0.05). CONCLUSION High anti-Hsp-27-antibody levels in obese-subjects without established coronary disease may be related to a heightened state of immunoactivation associated with obesity