Betaine postpones hyperglycemia-related senescence in ovarian and testicular cells: Involvement of RAGE and ß-galactosidase.

The structural and functional disorders of the testis and ovary are one of the main complications of hyperglycemia. Betaine is a trimethyl glycine with antioxidant, antidiabetic, and anti-inflammatory potential. The aim of this study is to investigate the potential of betaine on the expression of aging and oxidative stress markers in ovarian and testicular cells under hyperglycemic conditions. Testicular and ovarian cells were subjected to four different conditions, including normal glucose and hyperglycemia, with or without betaine (5 mM). The cells with hyperglycemia saw an increase in malondialdehyde (MDA), methylglyoxal (MGO), expression of a receptor for AGE, and aging-related genes (ß-GAL), and a decrease in the activity of antioxidant enzymes including catalase, glutathione peroxidase, and superoxide dismutase. The treatment with betaine, in contrast, decreased the amount of MGO and MDA, and also downregulated aging-related signaling. Although hyperglycemia induces senescence in testicular and ovarian cells, the use of betaine may have a protective effect against the cell senescence, which may be useful in the management of infertility.

Quantitative analysis of Merkel cell polyomavirus (MCPyV) genome in non-melanoma skin cancer and normal tumor margins.

Merkel cell polyomavirus (MCPyV) is the cause of approximately 80% of Merkel cell carcinomas (MCC). The common types of non-melanoma skin cancer (NMSC) including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are histologically similar to MCC. In the present study, 58 NMSC formalin-fixed paraffin-embedded tissue (FFPE) samples including 12 SCC, 46 BCC, and 58 FFPE samples of adjacent non-tumoral margins as the control were included. Determination of large tumor antigens (LTAg) copy number was performed by qReal-Time PCR as a viral copy number per cell to elucidate MCPyV carcinogenic role in non-melanoma skin cancer. Out of 58 samples, 36 (62%) cancerous and 22 (37.9%) normal tumor margins were positive for MCPyV LTAg. Median copy numbers of MCPyV LTAg among all NMSC samples and non-tumoral margins were 0.308×10-2 and 0.269×10-3 copies per cell respectively (P=0.001). In addition, although the viral load in the majority of samples was detected to be lower than one copy per cell, in 4 BCC samples, a viral load higher than one LTAg copy per cell was detected. The present study revealed that the detection of higher levels of MCPyV LTAg viral load in some BCC and SCC samples may be correlated with the role of MCPyV in some cases of BCC and SCC skin cancer.

Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors.

Deubiquitinating enzymes are key regulators of the ubiquitin-proteasome system and cell cycle, and their dysfunction leads to tumorigenesis. Our in vivo drop-out screens in patient-derived xenograft models identify USP7 as a regulator of melanoma. We show that USP7 downregulation induces cellular senescence, arresting melanoma growth in vivo and proliferation in vitro in BRAF- and NRAS-mutant melanoma. We provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a global transcriptomic and proteomics analysis. We show that RRM2 is a USP7 target and is regulated by USP7 during S phase of the cell cycle. Ectopic expression of RRM2 in USP7-depleted cells rescues the senescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.

The marginal causal effect of opium consumption on the upper gastrointestinal cancer death using parametric g-formula: An analysis of 49,946 cases in the Golestan Cohort Study, Iran.

Upper gastrointestinal (UGI) cancer, including esophageal and gastric, is one of the most common cancers in the world. Hence, the determination of risk factors of UGI helps to reduce the economic and social burden of this cancer in communities. In Iran, the consumption of opium because of its neighborhood with Afghanistan are considerable. In this study, we examine the causal effect of opium use on the time to UGI cancer death. Based on the Golestan Cohort Study (GCS) in northeastern of Iran, about 50000 adults were enrolled to the study for four years (2004-2008) and followed annually until July 2018. We used "parametric g-formula" to study the causal effect of opium use on the time to death due to UGI. In this study, the information of 49946 individuals due to missingness were analyzed. So the median of follow-up time was 144 months and the prevalence of opium use was 17% (about 8489 persons). During the follow-up period, 593 (1.2%) death from upper gastrointestinal cancer were reported. The study showed that the effect of opium use on the time to UGI death was statistically significant (adjusted risk-ratio based on parametric g-formula = 1.31, 95% CI: [1.04, 1.65]). Additionally, the Population Attributable Fraction (PAF) in UGI cancer deaths of opium use was estimated 5.3% (95% CI: [0.6%, 11.3%]). Our results showed a causal effect of opium use on the intensity of upper gastrointestinal cancer death.

Human Cysticercosis in Asia: A Systematic Review and Meta-Analysis.

BACKGROUND: Cysticercosis in among the neglected tropical disease caused by eating the egg of parasite Taenia solium. In this review, we aimed to verify the prevalence of human cysticercosis in different countries of Asia using systematic review and meta-analysis approach. METHODS: Based of the protocol, reliable databases including PubMed, SCOPUS, Science Direct, Embase, and Cochrane Library from 1990-2018 were searched using a panel of keywords. Overall, 48 countries of Asia were searched in turn and data were analyzed using a category of statistical tests. RESULTS: Out of 28 included studies, 586175 samples were collected and included in the data analysis. Based on the meta-analysis results, the overall pooled percent of cysticercosis was estimated 3.8% (95% CI: [2.0, 7.0]). According to the result of heterogeneity statistics including I-squared, chi-square, and tau-squared, it was statistically significant (Tau2 = 2.94, chi2 = 12733.31, P<0.001, I2 = 100%) therefore a random effect model was used to handle the heterogeneity of studies. To evaluate the trend of cysticercosis over the time, Cumulative meta-analysis was performed and the result showed that there was a minor upward tendency in the prevalence of cysticercosis over the time. CONCLUSION: Although, considering the religious culture and food habits in Asia, we might have expected to witness a low prevalence of human cysticercosis, but we noticed more or less significant infection in some countries of the region. Regarding the new feature of immigration and travel between countries, all authorities are advised to take measures on controlling and monitoring the disease.

Breast cancer risk factors in Iran: a systematic review & meta-analysis.

OBJECTIVES: Breast cancer is known as one of the deadliest forms of cancer, and it is increasing globally. There are a variety of proven and controversial risk factors for this malignancy. Herein, we aimed to undertake a systematic review and meta-analysis focus on the epidemiology of breast cancer risk factors in Iran. METHODS: We performed a systematic search via PubMed, Scopus, Web of Science, and Persian databases for identifying studies published on breast cancer risk factors up to March 2019. Meta-analyses were done for risk factors reported in more than one study. We calculated odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using a fixed/random-effects models. RESULTS: Thirty-nine studies entered into the meta-analysis. Pooling of ORs showed a significant harmful effect for risk factors including family history (OR: 1.80, 95%CI 1.47-2.12), hormonal replacement therapy (HRT) (OR: 5.48, 95%CI 0.84-1.74), passive smokers (OR: 1.68, 95%CI 1.34-2.03), full-term pregnancy at age 30 (OR: 3.41, 95%CI 1.19-5.63), abortion (OR: 1.84, 95%CI 1.35-2.33), sweets consumption (OR: 1.71, 95%CI 1.32-2.11) and genotype Arg/Arg (crude OR: 1.59, 95%CI 1.07-2.10), whereas a significant protective effect for late menarche (OR: 0.58, 95%CI 0.32-0.83), nulliparity (OR: 0.68, 95%CI 0.39-0.96), 13-24 months of breastfeeding (OR: 0.68, 95%CI 0.46-0.90), daily exercise (OR: 0.59, 95%CI 0.44-0.73) and vegetable consumption (crude OR: 0.28, 95%CI 0.10-0.46). CONCLUSIONS: This study suggests that factors such as family history, HRT, passive smokers, late full-term pregnancy, abortion, sweets consumption and genotype Arg/Arg might increase risk of breast cancer development, whereas late menarche, nulliparity, 13-24 months breastfeeding, daily exercise and vegetable consumption had an inverse association with breast cancer development.

Age-Dependent Maturation of iPSC-CMs Leads to the Enhanced Compartmentation of ß2AR-cAMP Signalling.

The ability to differentiate induced-pluripotent stem cells into cardiomyocytes (iPSC-CMs) has opened up novel avenues for potential cardiac therapies. However, iPSC-CMs exhibit a range of somewhat immature functional properties. This study explored the development of the beta-adrenergic receptor (ßAR) pathway, which is crucial in regulating contraction and signifying the health and maturity of myocytes. We explored the compartmentation of ß2AR-signalling and phosphodiesterases (PDEs) in caveolae, as functional nanodomains supporting the mature phenotype. Förster Resonance Energy Transfer (FRET) microscopy was used to study the cyclic adenosine monophosphate (cAMP) levels in iPSC-CMs at day 30, 60, and 90 following ßAR subtype-specific stimulation. Subsequently, the PDE2, PDE3, and PDE4 activity was investigated using specific inhibitors. Cells were treated with methyl-ß-cyclodextrin (MßCD) to remove cholesterol as a method of decompartmentalising ß2AR. As iPSC-CMs mature with a prolonged culture time, the caveolae density is increased, leading to a reduction in the overall cytoplasmic cAMP signal stimulated through ß2AR (but not ß1AR). Pan-phosphodiesterase inhibition or caveolae depletion leads to an increase in the ß2AR-stimulated cytoplasmic cAMP. Moreover, with time in culture, the increase in the ßAR-dependent cytoplasmic cAMP becomes more sensitive to cholesterol removal. The regulation of the ß2AR response by PDE2 and 4 is similarly increased with the time in culture. We conclude that both the ß2AR and PDEs are restricted to the caveolae nanodomains, and thereby exhibit a tighter spatial restriction over the cAMP signal in late-stage compared to early iPSC-CMs.

Use of low-vault posterior chamber collagen copolymer phakic intraocular lenses for the correction of myopia: a 3-year follow-up.

BACKGROUND: Phakic intraocular lens (pIOL) models have indicated an association between cataract formation and inadequate vaulting. In this study, the efficacy and safety of low-vault posterior chamber pIOLs in the correction of myopia were examined over 3 years. METHODS: From 316 patients undergoing surgery, 14 eyes with a low vault (≤ 150 µm) were examined from 14 patients. After implanting the Visian Implantable Collamer pIOL for the correction of myopia (moderate and high), the pIOL vault, endothelial cell loss, uncorrected distance visual acuity (UDVA), corrected DVA (CDVA), and detrimental events were examined over 3 years. RESULTS: Based on the findings, the mean spherical equivalent reduced from - 8.15 ± 3.29 before surgery to - 1.02 ± 0.75 diopters 3 years after the surgery. In terms of visual outcomes, the mean UDVA (Log MAR) significantly increased from 0.95 ± 037 to 0.27 ± 0.28, and the mean CDVA also increased from 0.99 ± 0.11 to 0.06 ± 0.08 (P < 0.05). The mean indices of safety and efficacy were respectively 1.075 and 0.748. The eyes lost not more than two visual acuity lines. Based on the findings, 82% achieved 0.80 or better CDVA, while the total endothelial cell loss was 7.96% during 3 years. Overall, vision-threatening conditions were not reported. CONCLUSION: The introduced pIOL can be considered a safe and efficient method for myopia at moderate to high levels.

Nicotine-Induced Oxidative Stress in Human Primary Endometrial Cells.

Nicotine is a major component of tobacco plants and is responsible for the development of reproductive problems in smokers. Nicotine has been recognized to result in oxidative stress by inducing the generation of reactive oxygen species (ROS) in some parts of female reproductive system, but the effect of nicotine on endometrium that plays an important role in reproductive biology stays unexplored. The aim of this work was to clarify the direct effects of nicotine administration on the antioxidant defense system and lipid peroxidation in human endometrial cells. Human endometrial stromal primary cells were treated with nicotine (0, 10-11, 10-8, and 10-6 M) for 24 hours. On nicotine administration, the endometrial cells were associated with a decrease in antioxidant defense markers such as Glutathione (GSH) level, glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) enzymes activity and higher levels of malondialdehyde (MDA) in a dose-dependent manner when compared to the control. We concluded that nicotine as a pro-oxidant affects the oxidative state of the endometrial cells.

Juvenile ischemic stroke secondary to cardiogenic embolism: a rare case report.

Myxomas, the most common primary cardiac tumors, are known as a source of cardiogenic emboli. The possibility of their early detection has made them of great importance for emergency medicines. Detection of the disease is probable at early stages using echocardiography and associate complications such as syncope, cerebral embolic ischemic strokes, and sudden death. We report experience of a rare case of juvenile acute stroke in a patient with cardiac myxoma affecting all cardiac chambers presenting to the emergency department. In young stroke patients with signs and symptoms compatible with cardiovascular involvement, cardiogenic emboli should be taken into consideration; early echocardiographic studies are highly recommended. Prompt myxoma resection is required in both asymptomatic and stroke patients in whom intravenous thrombolysis course has not been implemented due to any limitations.

Wing pattern diversity in Brassolini butterflies (Nymphalidae, Satyrinae) / Diversidade de padrao das asas em Brassolini (Nymphalidae, Satyrinae)

This study describes and compares the diverse dorsal and ventral wing color patterns of Brassolini butterflies. Thirty-three species are illustrated, where pattern elements of the nymphalid ground plan are labeled in color. In general, a larger number of pattern elements can be identified on the ventral than on the dorsal surface of both wings, and the forewing has a larger number of discernible pattern elements than the hind wing. The dorsal elements are broad, diffuse, and more difficult to identify against the typically brown brassoline wing background color. Species with a light colored dorsal background served as a guide for our proposal that fewer pattern elements are present dorsally, particularly on the hind wing. Colorful bands or markings generally present on the dorsal surface seem to be associated with specific pattern elements and have correspondence to the ventral pattern. We refer to these as trailing bands, and they constitute a predominant feature of the brassoline dorsal coloration. We propose a subordinate groundplan for brassolines and interpret some of the ventral pattern variation in light of their phylogeny. Dorsal color pattern variation that leads to sexual dimorphism and mimetic resemblance are also discussed.

Este estudo descreve e compara os diversos padrões de coloração dorsal e ventral das borboletas da tribo Brassolini. Com o objetivo de demarcar os elementos do padrão de base dos ninfalídeos (‘pattern elements of the nymphalid ground plan’), 33 espécies são ilustradas. De maneira geral, o número de elementos-padrão identificados na face ventral é maior do que o da face dorsal em ambas as asas, e a asa anterior contém um número maior de elementos visíveis do que a posterior. Os elementos da face dorsal são mais largos e difusos, e também mais difíceis de identificar devido à usual coloração de fundo marrom escuro dos brassolíneos. Espécies que apresentam coloração de fundo clara serviram como guia para a nossa interpretação de que a superfície dorsal das asas apresenta um número reduzido de elementos-padrão, especialmente a da asa posterior. Faixas ou manchas coloridas que geralmente aparecem na superfície dorsal estão aparentemente associadas com elementos-padrão específicos, e apresentam correspondência com faixas que aparecem na face ventral. Estas faixas (‘trailing bands’) se alastram a partir da borda de certos elementos e constituem uma característica predominante da coloração dorsal dos brassolíneos. Nós propomos um padrão de base para os brassolíneos que é subordinado ao dos ninfalídeos, e utilizamos a filogenia do grupo para interpretar alguns aspectos da variação de elementos-padrão da superfície ventral. As variações de padrão e cor que resultam em dimorfismo sexual e mimetismo são discutidas.

Atypical presentation of vitamin B12 deficiency.

Vitamin B12 deficiency (B12D) has wide variety of neurological and non-neurological signs and symptoms. We describe a 61-year-old man who was admitted to Emergency Department (ED) with trouble to walk independently, suffering from weakness and a long history of dyspepsia that had worsened in the last four weeks. He had mild impairment of cognitive functions; motor strength was normal and his patellar and achilles reflexes were absent, also the plantar reflexes were abolished. All blood tests were normal except hemoglobin concentration which showed mild anemia. At further studies regarding trouble walking of this patient, he was candidated for lumbar disk surgery based on mild disk bulging seen at L3-L4 level in the lumbar spine MRI. Further examinations before the surgery due to approach to anemia showed severely decreased serum vitamin B12 level. The patient's symptoms improved after treating with intramuscular cobalamin. Being a very commonly seen disorder in the general population, B12 deficiency should be born in mind as a probable diagnosis in patients with peripheral neuropathy and no clear underlying cause presenting to the ED. Therefore, simple screening with a CBC might decrease the neurologic complications, morbidity and inappropriate workups through early diagnosis and treatment.