Tumor-derived exosomes encapsulating miR-34a promote apoptosis and inhibit migration and tumor progression of colorectal cancer cells under in vitro condition

BackgroundMicroRNA (miR)-34a, as a master tumor suppressor in colorectal cancer (CRC), could regulate multiple genes participating in tumor proliferation, invasion, immune evasion, and inflammation-induced progression. Exosomes, as novel nano-carriers, were found to be capable of shuttling crucial mediators to various cells. Since the conventional CRC therapeutics currently are a matter of debate, implication of microRNAs in malignancy remedies have been addressed illustrating promising outlooks.ObjectivesIn this study, we aimed to investigate the delivery of miR-34a to CRC cell line CT-26 by encapsulating into tumor-derived exosomes (TEXs), in order to evaluate the anti-proliferative and progressive effects of the novel nano-carrier complex under in vitro condition.MethodsExosomes were purified from the starved CT-26 cells and then enriched by miR-34a using the calcium chloride (Cacl₂) modified solution. Following the detection of miR-34a expression in the enriched TEXs, the viability of CT-26 cells treated by multiplicity concentrations of either TEXs or TEX-miR-34a was examined. Moreover, the apoptosis rate of the cells was evaluated, and the migration of CT-26 cells subjected to both TEX-miR-34a and TEX was also measured. Thereafter, the expressions of miR-34a target genes, as IL-6R, STAT3, PD-L1, and VEGF-A, which play roles in tumor progression, were determined in the treated CT-26 cells.ResultsThe viability of CT-26 cells was harnessed following the treatment with TEX-miR-34a and the apoptosis levels of the cells were also observed to be enhanced dose-dependently. TEX-miR-34a was able to diminish the migration rate of the TEX-miR-34a treated cells and the expressions of IL-6R, STAT3, PD-L1, and VEGF-A were significantly restricted. Moreover, TEXs alone increased the apoptosis rate of tumor cells and repressed the proliferation and migration of these cells which were boosted by enrichment of TEXs with miR-34a.ConclusionExosomes isolated from the starved CT-26 cells were found to have a potential to deliver miR-34a into tumor cells properly with high functionality maintenance for miR-34a in case of regulating genes related to tumor progression and TEXs which showed no positive effect favoring cancer cells, presumably act as a favorable adjuvant in the CRC therapy.Graphical abstract      

Cobalt metal–organic framework-based ZIF-67 for the trace determination of herbicide molinate by ion mobility spectrometry: investigation of different morphologies

Co-MOF-based zeolitic imidazolate frameworks (ZIF-67) with various morphologies were prepared via an innovative way under distinct reaction conditions. By changing the reaction conditions, including the cobalt source, solvent, time, temperature, and linking agent to the cobalt ions, the morphological evolution of Co-MOF-based ZIF-67 was investigated. The Co-MOF-based ZIF-67 was applied as an adsorbent fiber in the solid-phase microextraction (SPME) technique for extracting a herbicide, namely molinate (as a test compound), in aqueous samples. For recognizing the molinate molecules, drift tube ion mobility spectrometry (IMS) was employed as a sensitive, rapid, and simple detection technique. Two essential parameters, namely extraction temperature and extraction time, influenced the extraction efficiency, and these parameters were also analyzed and optimized. The linear dynamic range (LDR) and the determination coefficient were found to be 0.5–20.0 μg L⁻¹ and 0.9990, respectively. In this regard, the limit of quantification (LOQ) and the detection limit (LOD) were calculated and found to be 0.5 μg L⁻¹ and 0.15 μg L⁻¹, respectively. Finally, the effect of the adsorbent with different morphologies on the extraction efficiency was compared.

Co-MOF-based zeolitic imidazolate frameworks (ZIF-67) with various morphologies were prepared via an innovative way under distinct reaction conditions.     

Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach

Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. Although early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death, the latter approaching 70% or more at 5 years.     

Endothelin-1 activates ET(A) receptors to increase intracellular calcium in model sensory neurons.

Endothelin-1 (ET-1) induces endothelin-A (ETA) receptor-mediated pain and selective excitation of nociceptors. Here we studied ET-1-induced changes in intracellular calcium (Ca2+in) in Fura-2 loaded mouse neuroblastoma-rat dorsal root ganglion hybrid cells (ND7/104). ET-1 (1-400 nM) induced concentration-dependent, transient increases in Ca2+in, probably of intracellular source. Responses to repeated application declined with increasing ET-1 concentration, implying receptor desensitization. Treatment of cells with the selective ETA receptor antagonist, BQ-123, produced a dose-dependent inhibition of the response that was 20% of ET-1 alone (IC50 = 20 nM, KI = 7 nM). No inhibition of the calcium response was observed with the selective ETB antagonist, BQ-788 (10-1000 nM). These results demonstrate that ET-1 induces dose- and ETA receptor-dependent release of Ca2+in in nociceptor-like neurons, and permit further examination of the pathways that underlie ET-1-induced pain signaling.     

Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival

OBJECTIVE: To assess the rate of progression of pulmonary hypertension (PHT) in systemic sclerosis (SSc) and its bearing on mortality. METHODS: A retrospective record review of 930 patients with SSc attending a specialist centre was carried out. Those at risk for both idiopathic and secondary PHT were assessed by serial Doppler echocardiography. Mortality data were reviewed. RESULTS: The cumulative prevalence of PHT was 13%. Pressures remained static in most cases. The mortality among those with a single pressure reading of 30 mmHg or higher was 20% at 20 months. An increased mortality risk was associated with high initial pressures and rising pressures. Rapid pressure rises occurred more frequently in limited than in diffuse SSC. CONCLUSIONS: The prevalence of PHT in SSc is high and the detection of PHT at any time in the disease course is associated with substantial mortality. These results demonstrate the value of echocardiographic screening for PHT in all patients with SSC.     

Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach

OBJECTIVE: To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort. METHODS: A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (TLCO) <50% predicted, or a precipitous fall in TLCO >20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice. RESULTS: The prevalence of PAH was 12% (89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure--raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3). CONCLUSIONS: The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.     

Serum bactericidal antibody response to serogroup C polysaccharide meningococcal vaccination in children with primary antibody deficiencies

Primary antibody deficiencies are characterized by decreased serum levels of immunoglobulin isotypes and increased susceptibility to infection by various microorganisms including encapsulated bacteria. This study was performed in order to evaluate bactericidal antibody response of these patients to polysaccharide meningococcal vaccine. Twenty-four antibody deficient children of mean age 11.2+/-3.5 years, and 15 sex and age-matched healthy volunteers were enrolled. All subjects received meningococcal polysaccharide vaccine A+C; blood samples were collected before vaccination and 3 weeks after vaccination. Following vaccination, the serum bactericidal antibody (SBA) geometric mean titre was significantly increased compared to the prevaccination level in the patient group (8.98 versus 1.63, P<0.001) and the control group (12.13 versus 1.26, P<0.001). All controls had a protective SBA response (SBA titre of >or=8 post-vaccination or rise of >or=4-fold from pre- to post-vaccination), whereas only 16 of 24 patients (66.6%) had a protective response (P=0.014). The non-responder patients included 5 cases with common variable immunodeficiency, two cases with hyper IgM syndrome, and one case with IgG subclass deficiency. This study indicates that some patients with primary antibody deficiencies can produce protective post-vaccination titres similar to the normal population, despite the common perception that patients with primary antibody deficiencies respond poorly to vaccination. This supports the use of polysaccharide-containing vaccines in these patients.     

Arylhydrazines: novel and versatile electrophilic partners in cross-coupling reactions

Arylhydrazines are extremely valuable compounds in organic chemistry that are widely used for the synthesis of a variety of biologically active molecules such as indoles, indazoles, pyrazoles, aryltriazoles, β-lactams and quinazolines. These compounds have also been widely utilized as arylation agents in oxidative cross-coupling reactions. In this review, we will highlight the most important explorations and developments in the carbon–carbon and carbon–heteroatom (nitrogen, phosphorus, sulfur, and selenium) cross-coupling of arylhydrazines. The literature has been surveyed from 2001 to June 2018.

Arylhydrazines are extremely valuable compounds in organic chemistry that are widely used for the synthesis of a variety of biologically active molecules such as indoles, indazoles, pyrazoles, aryltriazoles, β-lactams and quinazolines.     

Genotyping of human parechoviruses in Iranian young children with aseptic meningitis and sepsis-like illness

Human parechoviruses (HPeV) are classified into 14 genotypes. HPeV1 and HPeV2 are the most prevalent genotypes in young children, which have been associated with mild to severe diseases. This study was conducted to investigate the involvement of HPeVs in aseptic meningitis and sepsis-like illness in Iran. Viral RNA was extracted from 148 cerebrospinal fluid samples from children <8 years old with primary diagnosis of aseptic meningitis and/or sepsis-like illness. Specific HPeV, HEV real-time PCR and HPeV typing were done to identify the infection rate of these viruses. HPeV and HEV were detected in 64 (43.24 %), 31 (20.94 %) of 148 patients with 10 (6.75 %) coinfection. VP1/VP3 junction region was successfully sequenced from 12 of the HPeV-positive specimens, and all of them were identified as HPeV1. HPeV was more prevalent than HEV in both aseptic meningitis and sepsis-like illness, so further studies are needed to understand the disease burden of HPeV infections, and clinical manifestations especially in specific illnesses of possible viral etiology. Direct detection of these viruses leads to reduce hospitalization and use of antibiotic, which are often followed by other complications in neonates and young children.