MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients.

Cancer therapy failure is a fundamental challenge in cancer treatment. One of the most common reasons for therapy failure is the development of acquired resistance of cancer cells. DNA-damaging agents are frequently used in first-line chemotherapy regimens and DNA damage response, and DNA repair pathways are significantly involved in the mechanisms of chemoresistance. MRE11, a part of the MRN complex involved in double-strand break (DSB) repair, is connected to colorectal cancer (CRC) patients' prognosis. Our previous results showed that single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3'UTR) microRNA (miRNA) binding sites of MRE11 gene are associated with decreased cancer risk but with shorter survival of CRC patients, which implies the role of miRNA regulation in CRC. The therapy of colorectal cancer utilizes oxaliplatin (oxalato(trans-l-1,2-diaminocyclohexane)platinum), which is often compromised by chemoresistance development. There is, therefore, a crucial clinical need to understand the cellular processes associated with drug resistance and improve treatment responses by applying efficient combination therapies. The main aim of this study was to investigate the effect of miRNAs on the oxaliplatin therapy response of CRC patients. By the in silico analysis, miR-140 was predicted to target MRE11 and modulate CRC prognosis. The lower expression of miR-140 was associated with the metastatic phenotype (p < 0.05) and poor progression-free survival (odds ratio (OR) = 0.4, p < 0.05). In the in vitro analysis, we used miRNA mimics to increase the level of miR-140 in the CRC cell line. This resulted in decreased proliferation of CRC cells (p < 0.05). Increased levels of miR-140 also led to increased sensitivity of cancer cells to oxaliplatin (p < 0.05) and to the accumulation of DNA damage. Our results, both in vitro and in vivo, suggest that miR-140 may act as a tumor suppressor and plays an important role in DSB DNA repair and, consequently, CRC therapy response.

Axial posture disorders in Parkinson's disease: Clinical correlates and future treatment directions1.

BACKGROUND: Postural disorders are frequently observed in Parkinson's disease (PD). The underlying mechanisms that cause postural disorders are not fully understood and the majority of these disorders have no response to antiparkinsonian treatments. These disabling conditions require further investigation to better understand the underlying mechanisms in order to develop effective treatments. OBJECTIVE: The aim of this study was to investigate the frequency of axial postural disorders in PD and to determine the associated clinical risk factors. METHODS: In this single-center clinical trial, the data of PD patients were reviewed retrospectively. The frequencies of postural disorders were determined, and the demographic clinical characteristics of the patients were compared. RESULTS: The records of 127 patients with idiopathic PD were analyzed. Axial posture disorders were found in 42.6% of patients. Patients with axial posture disorders were older when the disease onset was detected, amongst these patients the condition was also longer lasting. The mean levodopa dose was higher in the patients with posture disorders. The initial symptom was bradykinesia and the Hoehn and Yahr's score was ⩾ 3 in the majority of the patients with posture disorder. Additionally, constipation, hallucinations, postural instability, and falls were significantly more common in patients with posture disorders. CONCLUSION: Posture disorders were observed in nearly half of PD patients and were more frequently observed in patients with an advanced condition. In addition, our investigation has found that it is crucial to follow up with patients who present with bradykinesia for the development of postural disorder.

Investigation of SOSTDC1 gene in non-syndromic patients with supernumerary teeth

BACKGROUND: The etiology of supernumerary teeth is still unclear however heredity is believed to be a major factor and this idea was supported by several case reports. Recently, a relationship between supernumerary tooth formation and deficiency of Uterine Sensitization Associated Gene-1 (Usag-1), a rat gene that is expressed in sensitized endometrium, was reported in mice. The human homolog gene for Usag-1, Sclerostin Domain Containing 1 (SOS-TDC1), shows 85% identity with mouse Usag-1. The present study aimed to investigate SOSTDC1 coding regions in non-syndromic patients with one or more supernumerary teeth. MATERIAL AND METHODS: Twenty-five non-syndromic patients (21 male and 4 female) aged 5-15 years, with one or more supernumerary teeth were included in the study. Saliva samples were collected from patients and DNA samples were isolated and analyzed using PCR. RESULTS: Eight phenotypes of supernumerary tooth formation were observed in the study. From the DNA analysis, 2 novel and 3 previously identified sequence alterations were identified however, in investigating the Usag-1 homolog SOSTDC1 gene, the present study could not find any phenotype-genotype relationship. CONCLUSIONS: There are many SOSTDC1 homolog genes in the human genome and future studies should investigate these candidate genes. Also studies in larger case groups including family members may reveal the hereditary pattern

SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.

BACKGROUND: Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children. METHODS: In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol. RESULTS: The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance. CONCLUSIONS: SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.

The effects of ventilation with high density oxygen on the strength of gastrointestinal anastomosis.

PURPOSE: The aim of our study is to evaluate the effects of administration of perioperative supplemental oxygen on anastomoses. METHODS: Forty male Wistar albino rats were used in the study and randomized into 4 groups. Ischemia-reperfusion models were built in groups 3 and 4. Jejunojejunostomy was performed in all rats and assigned to an oxygen/nitrous oxide mixture with a fraction of inspired oxygen of 30% in groups 1 and 3 and 80% in groups 2 and 4. The measurements of perianastomotic tissue oxygen pressure, bursting pressure, level of hydroxyproline were evaluated and compared in all groups. RESULTS: The perianastomotic tissue oxygen pressures, bursting pressures and levels of hydroxyproline were identified as significantly high in groups 2 and 4, administered a fraction of inspired oxygen of 80%, compared to groups 1 and 3, administered a fraction of inspired oxygen of 30%. CONCLUSION: Perioperative supplemental oxygen contributes positively to the anastomotic healing.