Granzyme G is expressed in the two-cell stage mouse embryo and is required for the maternal-zygotic transition

<p>Abstract</p> <p>Background</p> <p>Detailed knowledge of the molecular and cellular mechanisms that direct spatial and temporal gene expression in pre-implantation embryos is critical for understanding the control of the maternal-zygotic transition and cell differentiation in early embryonic development. In this study, twenty-three clones, expressed at different stages of early mouse development, were identified using differential display reverse transcription polymerase chain reaction (DDRT-PCR). One of these clones, which is expressed in 2-cell stage embryos at 48 hr post-hCG injection, shows a perfect sequence homology to the gene encoding the granzyme G protein. The granzyme family members are serine proteases that are present in the secretory granules of cytolytic T lymphocytes. However, the pattern of granzyme G expression and its function in early mouse embryos are entirely unknown.</p> <p>Results</p> <p>Upon the introduction of an antisense morpholino (2 mM) against granzyme G to knock-down endogenous gene function, all embryos were arrested at the 2- to 4-cell stages of egg cleavage, and the <it>de novo </it>synthesis of zygotic RNAs was decreased. The embryonic survival rate was dramatically decreased at the late 2-cell stage when serine protease-specific inhibitors, 0.1 mM 3,4-dichloroisocoumarin (3,4-DCI), and 2 mM phenyl methanesulphonyl fluoride (PMSF), were added to the <it>in vitro </it>embryonic culture medium. Survival was not affected by the addition of 0.5 mM EDTA, a metalloproteinase inhibitor.</p> <p>Conclusion</p> <p>We characterized for the first time the expression and function of <it>granzyme G </it>during early stage embryogenesis. Our data suggest that granzyme G is an important factor in early mouse embryonic development and may play a novel role in the elimination of maternal proteins and the triggering of zygotic gene expression during the maternal-zygotic transition.</p

Double primary bronchogenic carcinoma of the lung and papillary thyroid carcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Double primary bronchogenic carcinoma and papillary carcinoma of the thyroid are extremely rare. We describe the case of a patient who underwent surgical resection for these two cancers.</p> <p>Case presentation</p> <p>A 56-year-old man presented to our hospital complaining of a cough with blood-tinged sputum. A slowly growing mass in the left lobe of the lung had been noted for about 1 year. He underwent video-assisted thoracic surgery of the left lower lobe and mediastinal lymph node dissection through an 8 cm utility incision. Pathology revealed a well-differentiated adenocarcinoma and the dissected lymph nodes were negative for malignancy. He also complained of a mass in his neck, which had grown slowly for over 5 years. A computed tomography scan of the neck revealed a left thyroid mass compressing the trachea towards the right side. There was no cervical lymphadenopathy. A left thyroid lobectomy was performed and pathology revealed a papillary carcinoma. Thus, he underwent a second operation to remove the right lobe of the thyroid. He underwent subsequent adjuvant chemotherapy.</p> <p>Conclusion</p> <p>In a review of the literature, it appears that there has only been one previously reported case of these two cancers, which was in Japan. The relationship between these two cancers is still unclear, and more case reports are required to determine this relationship.</p

Dynamics of HBV cccDNA expression and transcription in different cell growth phase

<p>Abstract</p> <p>Background</p> <p>The covalently closed-circular DNA (cccDNA) of hepatitis B virus (HBV) is associated with viral persistence in HBV-infected hepatocytes. However, the regulation of cccDNA and its transcription in the host cells at different growth stages is not well understood.</p> <p>Methods</p> <p>We took advantages of a stably HBV-producing cell line, 1.3ES2, and examine the dynamic changes of HBV cccDNA, viral transcripts, and viral replication intermediates in different cellular growth stages.</p> <p>Results</p> <p>In this study, we showed that cccDNA increased suddenly in the initial proliferation phase of cell growth, probably attributable to its nuclear replenishment by intracellular nucleocapsids. The amount of cccDNA then decreased dramatically in the cells during their exponential proliferation similar to the loss of extrachromosomal plasmid DNA during cell division, after which it accumulated gradually while the host cells grew to confluency. We found that cccDNA was reduced in dividing cells and could be removed when proliferating cells were subjected to long term of lamivudine (3TC) treatment. The amounts of viral replicative intermediates were rapidly reduced in these proliferating cells and were significantly increased after cells reaching confluency. The expression levels of viral transcripts were increased in parallel with the elevated expression of hepatic transcription factors (HNF4α, CEBPα, PPARα, etc.) during cell growth confluency. The HBV transcripts were transcribed from both integrated viral genome and cccDNA, however the transcriptional abilities of cccDNA was less efficient then that from integrated viral genome in all cell growth stages. We also noted increases in the accumulation of intracellular viral particles and the secretion of mature virions as the cells reached confluency and ceased to grow.</p> <p>Conclusions</p> <p>Based on the dynamics of HBV replication, we propose that HBV replication is modulated differently in the different stages of cell growth, and can be divided into three phases (initial proliferation phase, exponential proliferation phase and growth confluency phase) according to the cell growth curve. The regulation of cccDNA in different cell growth phase and its importance regarding HBV replication are discussed.</p

Tabernacles of the Spirit

In the classic tradition of the exploratory essay, George Gammack examines the theme of community in this paper. He details varied aspects of the creation of community among those who are retired, taking as its focus the Men’s Sheds movement. The paper explores the relationship between persons and community in later years, looking in particular at how those with a lifetime’s worth of skills and knowledge can continue to contribute to the life of a community. Along the way we are introduced to the work of authors such as Charles Taylor, Richard Niebuhr, Primo Levi, Seamus Heaney and Richard Sennett on the subject of work and what comes after it.Publisher PD

Intraoperative hyperthermic intraperitoneal chemotherapy as adjuvant chemotherapy for advanced gastric cancer patients with serosal invasion

AbstractBackgroundTo evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) as an adjuvant chemotherapy in advanced gastric cancer (AGC) patients with serosal invasion.MethodsPatients who received radical surgery and palliative surgery between January 2002 and December 2010 were retrospectively examined. Patients were divided into two groups, namely, one group that underwent surgery and another group that underwent surgery with HIPEC. All patients who received HIPEC had suspected serosal invasion on an abdominal computed tomography or by the surgeon's assessment during the operation.ResultsThe prophylactic groups included 83 patients who underwent gastrectomy alone. A total of 29 patients underwent gastrectomy with HIPEC. The 5-year survival rates were 10.7% and 43.9%, respectively. The 5-year mean survival times were 22.66 (17.55–25.78) and 34.81 (24.97–44.66) months (p = 0.029), respectively. There were 52 patients who had a recurrence of carcinomatosis among 133 patients who had resections (52/133, 39.1%). The 3-year disease-free survival rate for carcinomatosis was 28.87% in the group that received surgery alone, whereas it was 66.03% in the group that received HIPEC. There was no significant difference in the rate of complication between the two groups in the prophylactic group (p = 0.542). Thus, curative surgery with HIPEC had a better prognosis for AGC with serosal invasion. The carcinomatosis recurrence time was longer in patients who underwent gastrectomy with HIPEC and received R0 resection.ConclusionThe survival benefit of HIPEC as an adjuvant therapy for gastric cancer patients with serosal invasion should be validated in a large cohort

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist

Comparison of single-incision mini-slings (Ajust) and standard transobturator midurethral slings (Align) in the management of female stress urinary incontinence: A 1-year follow-up

AbstractObjectiveTo investigate the effectiveness and safety of a new single-incision mini-sling (SIMS)—Ajust—compared with the standard transobturator midurethral sling (SMUS)—Align—for the treatment of female stress urinary incontinence (SUI).Materials and MethodsA retrospective cohort study was conducted between January 1, 2010 and August 31, 2012. Women with SUI who underwent either SMUS-Align or SIMS-Ajust were recruited. The primary outcomes included operation time, estimated operative blood loss, postoperative pain, and complications. The secondary outcomes included subjective and objective success, defined as an International Consultation on Incontinence Questionnaire (ICIQ) score of 0 or improvement as felt by the patient and a long-term complication, such as dyspareunia and mesh erosion after 6 months and 12 months of follow-up.ResultsA total of 136 patients were enrolled, including 76 receiving SMUS-Align and 60 receiving SIMS-Ajust. Baseline characteristics of the patients in both groups were similar, without a statistically significant difference. Primary outcomes between both groups were similar, except that women treated with SIMS-Ajust had statistically significantly shorter operation time (p = 0.003), less intent to treat (p < 0.05), and earlier postoperative discharge (p = 0.001) than women treated with SMUS-Align. Secondary outcomes were similar without a significant difference between the two groups (93% vs. 88% success rate in each group).ConclusionOur results showed that SIMS-Ajust was not inferior to SMUS-Align with respect to success rate, and might have a slight advantage in early discharge. A long-term follow-up or prospective study is needed to confirm the above findings

Genome-Wide Gene Expression Analysis Suggests an Important Role of Hypoxia in the Pathogenesis of Endemic Osteochondropathy Kashin-Beck Disease

Kashin-Beck Disease (KBD) is an endemic osteochondropathy, the pathogenesis of which remains unclear now. In this study, we compared gene expression profiles of articular cartilage derived respectively from KBD patients and normal controls. Total RNA were isolated, amplified, labeled and hybridized to Agilent human 1A 22 k whole genome microarray chip. qRT-PCR was conducted to validate our microarray data. We detected 57 up-regulated genes (ratios ≥2.0) and 24 down-regulated genes (ratios ≤0.5) in KBD cartilage. To further identify the key genes involved in the pathogenesis of KBD, Bayesian analysis of variance for microarrays(BAM) software was applied and identified 12 potential key genes with an average ratio 6.64, involved in apoptosis, metabolism, cytokine & growth factor and cytoskeleton & cell movement. Gene Set Enrichment Analysis (GSEA) software was used to identify differently expressed gene ontology categories and pathways. GSEA found that a set of apoptosis, hypoxia and mitochondrial function related gene ontology categories and pathways were significantly up-regulated in KBD compared to normal controls. Based on the results of this study, we suggest that chronic hypoxia-induced mitochondrial damage and apoptosis might play an important role in the pathogenesis of KBD. Our efforts may help to understand the pathogenesis of KBD as well as other osteoarthrosis with similar articular cartilage lesions

Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals

<p>Abstract</p> <p>Background</p> <p>Metformin protection against cancer risk in Orientals is uncertain. We examined the possible metformin effect on total, esophageal, gastric, colorectal (CRC), hepatocellular (HCC) and pancreatic cancers in a Taiwanese cohort.</p> <p>Methods</p> <p>A representative sample of 800,000 was drawn from the Taiwanese National Health Insurance data of 2000. A cohort of 480,984 participants 20 years or older, diabetes-cancer-free on 1st January 2000 was formed and categorized as four groups by DM and metformin usage status. Eligible incident cancer events had to occur one year after the index date until the end of 2007. The Cox proportional-hazards model evaluated relative risk of cancer for treated DM patients with or without metformin. The covariates included age, gender, other oral anti-hyperglycemic medication, Charlson comorbidity index (CCI) score and metformin exposure dosage and duration.</p> <p>Results</p> <p>With diabetes but no anti-hyperglycemic medication, cancer incidence density increased at least 2-fold for total, CRC and HCC. On metformin, total, CRC and HCC incidences decreased to near non-diabetic levels but to varying degrees depending on gender and cancer type (CRC in women, liver in men). Adjustment for other oral anti-hyperglycemic agents usage and CCI made the benefit of metformin more evident [hazard ratios (95% confidence intervals): total 0.12 (0.08-0.19), CRC 0.36 (0.13-0.98), liver 0.06 (0.02-0.16), pancreas 0.15 (0.03-0.79)]. There was a significant gender interaction with metformin in CRC which favored women. Metformin dosage for a significant decrease in cancer incidence was ≤500 mg/day.</p> <p>Conclusions</p> <p>Metformin can reduce the incidences of several gastroenterological cancers in treated diabetes.</p

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan

AbstractEndometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities