Circulating levels of the miRNAs,miR-194, and miR-29b,as clinically useful biomarkers for colorectal cancer

Tumor Biology - The microRNAs (miRNAs), miR-194 and miR-29b, have been shown to downregulate in colorectal cancer (CRC) and may identify and classify CRC patients as compared with those in control...     

miRNA-binding site polymorphism in IL-15RA gene in rheumatoid arthritis and systemic lupus erythematosus: correlation with disease risk and clinical characteristics

Clinical Rheumatology - MiRSNPs may interfere with mRNA stability through effects on microRNAs (miRNAs)-mRNA interactions via direct changes in miRNA binding site or effect on the secondary...     

High Prevalence of AmpC β-Lactamases in Clinical Isolates of Escherichia coli in Ilam,Iran

Objectives

Widespread use of β-lactam antibiotics could cause resistance to this group of antibiotics in pathogenic bacteria through the production of the enzyme β-lactamases. The aim of this study is to determine the molecular detection of AmpC β-lactamases among clinical Escherichia coli isolated from Ilam hospitals in Ilam, Iran.

Methods

One hundred and twelve clinical isolates of E. coli were collected from hospitalized patients and were identified by biochemical tests. They were evaluated for extended spectrum beta-lactamases (ESBLs) production, and the positive strains were subjected to AmpC enzymes; for detection of AmpC cluster genes, multiplex polymerase chain reaction was applied.

Results

The analysis showed 62.5% of isolates were ESBLs positive and that five strains revealed the AmpC cluster genes. This is the first report of FOXM cluster genes in E. coli in Iran.

Conclusion

Based on our results, the prevalence of AmpC β-lactamases is increasing in Iran, which caused failure in antibiotic therapy. So, the current study recommended the revision of antibiotic policy in Iranian hospitals.     

Worldwide prevalence of microbial agents’ coinfection among COVID‐19 patients: A comprehensive updated systematic review and meta‐analysis

BackgroundTo provide information about pathogens’ coinfection prevalence with SARS‐CoV‐2 could be a real help to save patients’ lives. This study aims to evaluate the pathogens’ coinfection prevalence among COVID‐19 patients.MethodIn order to find all of the relevant articles, we used systematic search approach. Research‐based databases including PubMed, Web of Science, Embase, and Scopus, without language restrictions, were searched to identify the relevant bacterial, fungal, and viral coinfections among COVID‐19 cases from December 1, 2019, to August 23, 2021. In order to dig deeper, other scientific repositories such as Medrxiv were probed.ResultsA total of 13,023 studies were found through systematic search. After thorough analysis, only 64 studies with 61,547 patients were included in the study. The most common causative agents of coinfection among COVID‐19 patients were bacteria (pooled prevalence: 20.97%; 95% CI: 15.95–26.46; I ²: 99.9%) and less frequent were virus coinfections (pooled prevalence: 12.58%; 95% CI: 7.31–18.96; I ²: 98.7%). The pooled prevalence of fungal coinfections was also 12.60% (95% CI: 7.84–17.36; I ²: 98.3%). Meta‐regression analysis showed that the age sample size and WHO geographic region did not influenced heterogeneity.ConclusionWe identified a high prevalence of pathogenic microorganism coinfection among COVID‐19 patients. Because of this rate of coinfection empirical use of antibacterial, antifungal, and antiviral treatment are advisable specifically at the early stage of COVID‐19 infection. We also suggest running simultaneously diagnostic tests to identify other microbiological agents’ coinfection with SARS‐CoV‐2.     

Amyopathic dermatomyositis: retrospective review of 37 cases

Criteria for diagnosis of amyopathic dermatomyositis vary, and the prognosis is not clear. Our purpose was to investigate prognosis regarding progression to myositis and associated malignancy. We reviewed the medical records of patients with dermatomyositis evaluated at our institution from 1976 to 1994. Of 746 patients with dermatomyositis, 37 (5%) with the amyopathic subtype were divided into 3 groups: group 1 (73%), no subjective or objective evidence of myopathy; group 2 (13%), no subjective muscle weakness but abnormalities detected by objective tests; group 3 (13%), subjective muscle weakness but no objective evidence of myopathy. Follow-up was conducted by means of a mailed questionnaire. For 25 patients, follow-up of 1 to 17 years after diagnosis showed muscle weakness in 2 patients in group 1 within 5 years after diagnosis. Five patients (13%) had associated malignancies. Of 7 (19%) patients with disease onset before the age of 18 years, none had progression to myopathy. Although it presents with cutaneous lesions indistinguishable from those of classic dermatomyositis, amyopathic dermatomyositis is a distinct entity. In most patients, amyopathic dermatomyositis does not progress to myopathy. Prognosis appears favorable, but malignancy may develop.     

How often do patients undergo repeat PET or PET/CT examinations? Experience from a UK institution

BACKGROUND AND AIM: According to the report of the Intercollegiate Standing Committee on Nuclear Medicine, the UK requires 40-60 positron emission tomography (PET) machines in the next decade (Intercollegiate Standing Committee on Nuclear Medicine). Positron Emission Tomography: a Strategy for Provision in the UK. London: Royal College of Physicians of London; 2003, pp. 1-9). This figure is based mainly on patients receiving only one examination and restricting the clinical indication to three primary diagnoses. The aim of this study was to assess the appropriateness of this figure and the assumptions made in the Intercollegiate report on UK PET provision. METHODS: We examined retrospectively our institution's entire PET and PET/computed tomography (CT) database, which spans 4 years and 9 months. We recorded the number of patients who received repeat examinations. RESULTS: Reports were available for 3354 PET/CT or PET-only studies; 418 of 2268 patients (18.4%) received at least one repeat PET/CT examination. The three main indications for PET examination in the Intercollegiate report only accounted for approximately 60% of the examinations undertaken. CONCLUSION: Our records suggest that basing the UK's future PET provision on a single examination and on three clinical indications only is no longer realistic.     

The evaluation of hepatitis C virus core antigen in immunized BALB/c mice

Background

Hepatitis infection represents one of the important causes of morbidity and mortality in developing countries, however there is not any effective vaccine against hepatitis C which is one of the significant problems in vaccine project.

Objectives

The aim of the present study is to evaluate the role of HCV core protein in inducing IFN-Gamma secretion and TCL activities as a vaccine in Balb/C mice.

Material and Methods

Our previous cloned plasmid (HCV Core gene into pETDuet-1) applied for protein expression in bacteria. The expressed and purified recombinant protein together with Freund’s adjuvant was injected to 15 Balb/c mice. The total IgG and IgG2a of immunized mice sera were evaluated after a week. Two weeks after booster injection, we studied the proliferation and IFNγ secretion of spleens, inguinal and popliteal lymph nodes lymphocytes by ELISA and ELISPOT.

Results

The FSFC (Frequency of spot forming cells) of secreting cells of immunized mice with HCV/Core protein and sera IgG2a were considerably higher than the control groups.

Conclusions

The core protein together with proper adjuvant can be a candidate vaccine against of HCV infection.     

Bevacizumab treatment for human glioblastoma. Can it induce cognitive impairment?

Recent results from 2 double-blind, placebo-controlled phase III trials (RTOG 0825) and (AVAglio) for first-line treatment of glioblastoma patients with the VEGF antibody bevacizumab, showed similar results, related to overall and progression-free survival. The RTOG 0825 trial indicated, opposed to the AVAglio trial, that patients treated with bevacizumab showed a decline in global neurocognitive function compared to untreated patients, -a decline that was most obvious after prolonged treatment. At present, there is a considerably controversy related to these observations. In the present work we point at the possibility that bevacizumab treatment of the normal brain can reduce synaptic plasticity in the hippocampus. We believe that such a phenomenon may partly explain the reduced cognitive function observed in patients in the RTOG 0825 trial. Since the same effects were not clearly defined in the AVAglio trial, further studies on putative neurocognitive effects after bevacizumab treatment are warranted.Dear Editor,The vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin) has since 2009 been extensively used in the clinic for the treatment of recurrent glioblastoma (GBM). Recently, results from two double-blind, placebo-controlled phase III trials, one publicly supported by the National Cancer Institute (NCI), conducted by the Radiation Therapy Oncology Group¹ (RTOG 0825), and one industry sponsored trial² (AVAglio) were released (The 2013 ASCO Annual meeting). The results from both trials show that bevacizumab treatment does not increase overall survival (OS) in the patient treatment group, whereas progression-free survival was improved in the bevacizumab arm, yet with some differences between the two trials. As a part of the results from the RTOG 0825 trial it was reported that patients in the bevacizumab arm showed less quality of life (QOL) and a worse symptom burden related to neurocognitive function^1,2 an observation that was less recognized in the AVAglio trial. In the RTOG 0825 trial, 507 patients were evaluated at diagnosis and at intervals throughout bevacizumab treatment. Objective tests of cognitive function and subjective assessments of symptoms and quality of life were performed during periods were the tumors were not obviously progressing. Longitudinal analyses indicated that patients treated with bevacizumab showed a more pronounced decline in global neurocognitive function compared to untreated patients, a decline that was most obvious after prolonged treatment.Based on these observations, there is an obvious need for further studies adding to the questions whether bevacizumab induces a putative cognitive impairment in the normal brain or whether such an impairment is a result of treatment effects on the tumor tissue.It is well known that VEGF-A signaling modulates both vascular and neuronal behavior in the central nervous system (CNS). For instance it has been shown that VEGF-A can increase neurite number, length and size in the absence of glia cells, indicating an essential role in neuronal function.^3–5 VEGF-A is also a potent survival factor for many neuronal populations^5,6 and may provide neuroprotection from hypoxia^7,8 and mechanical trauma⁹ which represent important environmental factors induced by progressive tumor growth. In the normal adult brain VEGF is expressed in a region specific manner that is incompatible with angiogenic growth¹⁰ indicating angiogenesis and perfusion independent functions of VEGF in the CNS. In particular, VEGF is expressed in the choroid plexus, in the olfactory bulb, in the cortex (pyramidal neurons), in the cerebellum (Purkinje cells) and in the hippocampus (by CA1 pyramidal neurons).¹⁰ The hippocampal regions known as CA1, CA3 and Dentate gyrus (DG) play an important role in spatial learning and short term memory function. At present there is considerable consensus that VEGF is not essential for maintaining basal neurogenesis but may be important in maintaining homeostatic functions in the CNS.¹⁰ In the hippocampus, it has been shown that VEGF overexpression can augment learning and memory whereas loss of function impairs this effect.^11,12Synaptic plasticity (SP) describes changes in synaptic strength that among others are important in learning and memory. SP is orchestrated by the amount of neurotransmitters available, the synaptic density and how effectively the cells respond to neurotransmitters. It is well known that a complex web of intracellular signaling pathways mediates SP. An informative study linking VEGF to synaptic plasticity was performed using long-term potentiation (LTP), which represents a method to determine dynamic plasticity changes in the hippocampus. This method measures the increase in synaptic response following potentiating pulses of electrical stimuli that are sustained at a level above the baseline response for hours or longer.¹³ In the context of VEGF, hippocampal slice cultures, as well as in vivo experiments have shown VEGF to increase LTP in CA1 pyramidal cells and that the absence of VEGF abrogates this effect.^11,14 It is therefore highly likely that reduced VEGF levels in the CNS may affect neuronal populations. A key question in this context is the source of VEGF in the normal brain. In the brain parenchyma, co-expression studies have shown that both astrocytes and neurons can secrete VEGF, that is up-regulated by hypoxia inducible factor (HIF1) target genes.^15–17We have recently shown that vascular remodeling induced by bevacizumab treatment leads to a more hypoxic tumor microenvironment which favors metabolic changes in GBMs toward glycolysis.¹⁸ This study indicates that induced hypoxia, mediated by bevacizumab treatment, may also lead to an induction of VEGF production in neural cell populations to maintain homeostasis. It is therefore likely that the presence of the neutralizing antibody bevacizumab, during treatment abrogates the neuroprotective effects of VEGF.As a part of our bevacizumab treatment study¹⁸ we performed a number of control experiments where we treated normal non-tumor bearing rats with bevacizumab (10 mg/kg once a week during a 3-week period). We then performed gene expression analyses and observed significant changes in gene expression in the treatment group compared to the control group (3074 differentially expressed genes at a FDR of 5%) (Fig. 1A). Based on GO terms, not surprisingly, genes important for endothelial function and development were observed in the treatment group, but also a deregulation of genes involved in CNS function and development (Fig. 1A). More interesting, we then performed a highly standardized LTP experiment, comparing the bevacizumab treatment group with the control group. As seen in Fig. 1B, treatment caused a strong reduction in LTP compared to the controls animals, strongly implying a reduced neurocognitive function after bevacizumab treatment. Open in a separate windowFig. 1.(A) Gene expression data from four rats in each of treated (bevacizumab) and control (vehicle) groups. Whole genome gene expression data was obtained using RNA extracted from rat brains of animals in the 2 groups. The Agilent 4 × 44k v3 rat Gene Expression Arrays were used. Principal Component Analysis (PCA) was carried out using Partek^® and differentially expressed genes were obtained using Limma (Linear Models for Microarray Data in R) PCA shows that 2 main clusters are obtained (Ctrl and Treat). A functional analysis based on the list of differentially expressed genes was performed using Ingenuity Pathway analysis (IPA). The table shows a selection of gene ontology (GO) terms that are highly enriched in Avastin treated animals (right panel). (B) Hippocampal LTP recordings obtained from 6 rats (treatment group receiving 10 mg/kg bevacizumab twice a week during a 3-week period) and from 6 control rats (receiving sodium chloride) showing a significant LTP reduction in the bevacizumab treated group. Briefly, a bipolar concentric stimulating electrode was placed in the perforant path and a recording electrode was inserted into the dentate gyrus of the dorsal hippocampus according to stereotactic coordinates as described in.¹⁹ Evoked responses were amplified, filtered at 1 Hz to 1 kHz, and stored for later analysis. Input–output relations was examined by using three stimulus intensities (1.5, 3, and 4.5V). Paired-pulse responses were measured at three interstimulus intervals (15, 30, and 60 ms). LTP was induced by applying high frequency stimulation (HFS) of 5 trains of 8 0.4-ms, 400-Hz pulses of 1.5V. Ten measurements were taken every 5 min and LTP was computed as the change in the evoked responses measured during 60 min. after HFS in comparison with pre-HFS responses. 2-way Anova analysis using Matlab 8.2 (MathWorks Inc, Natick, MA, USA), using the treatment and time as factors of variation. The treatment significantly affected the LTP response (P value <10⁻⁵) throughout the whole duration of the LTP experiment. (ANOVA P < .02).In conclusion, in light recent clinical trials and supporting the observations made in the RTOG 0825 trial,¹ the relatively simple experiments performed here, strongly support the notion that bevacizumab can cause cognitive impairment. The fact that bevacizumab will reduce circulating as well as local VEGF levels in the brain may lead to a reduced accessibility of this growth factor to neurons that can lead to cognitive impairment. A central question, that warrants further studies, is if this impairment is reversible or not. In our mind this question should be addressed by in depth neuro-cognitive studies of cancer patients treated with bevacizumab for other malignancies (eg colorectal cancer).