Tissue-specific shRNA delivery: a novel approach for gene therapy in cancer

A novel tissue-specific shRNA delivery system has been developed using cre-lox technology. Conditionally silenced pSico vector containing oligonucleotides of CD44shRNA and tissue-specific promoter-driven Cre-recombinase expression vector are packaged into transferrin-coated nanoparticles that can deliver shRNA into specific tumors. This system has strong potential in cancer therapy.     

Protective effects of Fumaria parviflora L. on lead‐induced testicular toxicity in male rats

In recent years, the clinical importance of herbal drugs has received considerable attention in reducing free radical‐induced tissue injury. Oxidative stress has been proposed as a possible mechanism involved in lead toxicity that causes reproductive system failure in both human and animals. Fumaria parviflora L., a traditional herb, has been used to cure various ailments in Persian folk medicine. This study was carried out to investigate whether ethanolic extract of F. parviflora leaves could protect the male rats against lead‐induced testicular oxidative stress. Adult Wistar rats were treated with 0.1% lead acetate in drinking water with or without 200 mg kg day^?1 F. parviflora extract via gavage for 70 days. Lead acetate treatment resulted in significant reduction in testis weight, seminiferous tubules diameter, epididymal sperm count, serum testosterone level, testicular content of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Moreover, significant elevation was observed in content of malondialdehyde (MDA) in lead‐treated rats. However, co‐administration of F. parviflora extract showed a significant increase in selected reproductive parameters in lead‐treated rats. The results indicated that ethanolic extract of F. parviflora leaves has a potential to restore the suppressed reproduction associated with lead exposure and prevented lead‐induced testicular toxicity in male Wistar rats.     

Diagnostic outcome of muscle biopsy

Introduction: We reviewed the diagnostic yield of muscle biopsy according to the presence or absence of muscle weakness, hyperCKemia, and electromyogaphic (EMG) abnormalities. Methods: In a retrospective study, 698 muscle biopsy reports were analyzed. Logistic regression models for myopathy and specific myopathy were fit, and receiver‐operating characteristic (ROC) curves were generated to assess prediction accuracy. The probability of finding specific myopathy was considered the main indication of a positive muscle biopsy. Results: Isolated hyperCKemia was poorly predictive of either myopathy or specific myopathy. Combined myopathic EMG, proximal weakness, and hyperCKemia were predictive. The predictability increased proportionally to the creatine kinase (CK) level in patients with proximal weakness and myopathic EMG. Cross validation showed accuracy around 70% for a probability threshold of 50%. Conclusions: The presence of hyperCKemia, proximal weakness, and myopathic EMG together were associated with highly positive diagnostic outcome of muscle biopsy. Isolated hyperCKemia had a poor diagnostic yield. Muscle Nerve 51 :662–668, 2015     

Structural Conservation and Functional Diversity of the Poxvirus Immune Evasion (PIE) Domain Superfamily

Poxviruses encode a broad array of proteins that serve to undermine host immune defenses. Structural analysis of four of these seemingly unrelated proteins revealed the recurrent use of a conserved beta-sandwich fold that has not been observed in any eukaryotic or prokaryotic protein. Herein we propose to call this unique structural scaffolding the PIE (Poxvirus Immune Evasion) domain. PIE domain containing proteins are abundant in chordopoxvirinae, with our analysis identifying 20 likely PIE subfamilies among 33 representative genomes spanning 7 genera. For example, cowpox strain Brighton Red appears to encode 10 different PIEs: vCCI, A41, C8, M2, T4 (CPVX203), and the SECRET proteins CrmB, CrmD, SCP-1, SCP-2, and SCP-3. Characterized PIE proteins all appear to be nonessential for virus replication, and all contain signal peptides for targeting to the secretory pathway. The PIE subfamilies differ primarily in the number, size, and location of structural embellishments to the beta-sandwich core that confer unique functional specificities. Reported ligands include chemokines, GM-CSF, IL-2, MHC class I, and glycosaminoglycans. We expect that the list of ligands and receptors engaged by the PIE domain will grow as we come to better understand how this versatile structural architecture can be tailored to manipulate host responses to infection.     

Thymoquinone accelerates osteoblast differentiation and activates bone morphogenetic protein-2 and ERK pathway

Thymoquinone (TQ), the active component of Nigella sativa L. is well known for its various beneficial effects against several diseases. However, its detailed effect on bone metabolism has not been studied before. Therefore, the aim of the present study is to evaluate the effect of TQ on the proliferation, differentiation, and mineralization of MC3T3-E1 osteoblast cells. Our data shows that TQ induced the proliferation of MC3T3-E1 cells and proved to be non-toxic for up to 72 h of incubation. TQ induced the mineralization of MC3T3-E1 cells as evidenced by an increase in bone nodule formation 14 days post TQ treatment. qRT-PCR analysis shows that TQ induced the expression levels of differentiation related genes including alkaline phosphatase, osteocalcin, and osteopontin, while no effect was seen on collagen 1a1. TQ also induced the expression levels of bone morphogenetic protein-2 (BMP-2) and upregulated the phosphorylation of ERK signaling pathway. In summary, the present study shows for the first time that TQ has anabolic effects on MC3T3-E1 cells and that this effect is mediated by an increase in the expression of BMP-2 along with the involvement of the ERK signaling pathway. This study also reveals that TQ may be beneficial in inducing osteogenesis.     

A new hereditary colorectal cancer network in the Middle East and eastern mediterranean countries to improve care for high-risk families

Colorectal cancer (CRC) has a very high incidence in the western world. Data from registries in the Middle East showed that the incidence of CRC is relatively low in these countries. However, these data also showed that CRC incidence has increased substantially over the past three decades and that a high proportion of cases are diagnosed at an early age (<50 years). In view of these findings, more attention should be paid to prevention. Because of the often limited financial resources, focused screening of individuals with hereditary CRC, in particular those with Lynch syndrome, appears to be the most cost-effective strategy. During recent meetings of the Palestinian Society of Gastroenterology and the Mediterranean Task force for Cancer Control (MTCC) in Jericho, and the Patient’s Friends Society of Jerusalem in Hebron the issue of hereditary CRC in the Middle East was discussed and the idea was conceived to establish a network on hereditary colorectal cancer (HCCN-ME) with the goal of improving care for high-risk groups in the Middle East and (Eastern) Mediterranean Countries.     

Preponderance of inhibitory versus excitatory intramuscular nerve fibres in human chagasic megacolon

Introduction

Megacolon, chronic dilation of a colonic segment, is a frequent sign of Chagas disease. It is accompanied by an extensive neuron loss which, as shown recently, results in a partial, selective survival of nitrergic myenteric neurons. Here, we focused on the balance of intramuscular excitatory (choline acetyltransferase [ChAT]-immunoreactive) and inhibitory (neuronal nitric oxide synthase [NOS]- as well as vasoactive intestinal peptide [VIP]-immunoreactive) nerve fibres.

Materials and methods

From surgically removed megacolonic segments of seven patients, three sets of cryosections (from non-dilated oral, megacolonic and non-dilated anal parts) were immunhistochemically triple-stained for ChAT, NOS and VIP. Separate area measurements of nerve profiles within the circular and longitudinal muscle layers, respectively, were compared with those of seven non-chagasic control patients. Additionally, wholemounts from the same regions were stained for NOS, VIP and neurofilaments (NF).

Results

The intramuscular nerve fibre density was significantly reduced in all three chagasic segments. The proportions of inhibitory (NOS only, VIP only, or NOS/VIP-coimmunoreactive) intramuscular nerves were 68?%/58?% (circular/longitudinal muscle, respectively) in the controls and increased to 75?%/69?% (oral parts), 84?%/76?% (megacolonic) and 87?%/94?% (anal) in chagasic specimens. In the myenteric plexus, NF-positive neurons co-staining for NOS and VIP also increased proportionally. The almost complete lack of dendritic structures in ganglia of chagasic specimens hampered morphological identification.

Discussion and conclusion

We suggest that preponderance of inhibitory, intramuscular nerve fibres may be one factor explaining the chronic dilation. Since the nerve fibre imbalance is most pronounced in the anal, non-dilated segment, other components of the motor apparatus (musculature, interstitial cells, submucosal neurons) have to be considered.     

Alternaria in patients with allergic rhinitis

Inhalation of fungal spores is shown to participate in the development of allergic rhinitis symptoms. In this study, relation between presence of Alternaria in the human nasal cavity and allergic rhinitis is assessed. In a case-control study, 58 allergic rhinitis patients were compared with a well-matched control group of fifty healthy volunteers for sensitization to Alternaria (by skin prick test) and detection of Alternaria in their nasal mucous by conventional methods (microscopy with Methylene Blue stain and culture in Sabourad dextrose agar). Severity of the disease was determined according to the ARIA classification. Pearson chi-square test was applied to compare the proportional difference between the study groups for detection of Alternaria in the nasal cavity, and sensitization to Alternaria. Relation between detection of Alternaria and allergic rhinitis was significant [OR = 18.18 (4.02-82.50)] In addition, sensitization to Alternaria showed a significant relation with the disease [OR = 2.8 (2.1-3.8)]. There was a significant relation between the presence of Alternaria in the nasal cavity and sensitization to Alternaria [OR = 10.4 (3.8-28.3)]. Both sensitization to Alternaria and presence of Alternaria in the nasal cavity did not have a significant relation with the severity of allergic rhinitis. This study suggests Alternaria as a major allergen that its presence in the nasal cavity and subsequent development of sensitization have significant role in the induction of allergic rhinitis.