Analysis of Cellular Responses to Heavy Metal-induced Stress in Saccharomyces cerevisiae

Chronic exposure of heavy metals is highly correlated with the epidemic of degenerative disease, nephrotoxicity, cancers and aging, while the acute response of cells to the same heavy metals provides some nuanced insights into how cells are able to handle environmental insults, and perhaps characterize specific triggers of the process, itself. Some heavy metals, such as copper, trigger an immediate accumulation of reactive oxygen species (ROS), which impair vital cellular functions by oxidative stresses; which can lead to the onset of programmed cell death, or apoptosis, which becomes an inevitable fate once the damage is too disseminative to be recovered. Other heavy metals, such as cadmium, appear to trigger similar apoptotic responses in the cell –even before ROS increases to unmanageable levels. In either instance, however, before undergoing apoptosis, there are two cellular defensive mechanisms that are able to eliminate the metal-induced oxidative stresses: 1) the neutralization of anti-oxidants, and 2) the removal of the harmful substances through a series of self-cleaning mechanisms. We have used Saccharomyces cerevisiae, or baker’s yeast, as a model organism to demonstrate the response of cells to the presence of heavy metals. In so doing, we highlight pertinent aspects of the metabolic transcriptome response of these unicellular organisms to the presence of these metals, such as changes in expression of genes involved in the pentose phosphate pathway (PPP), which facilitates the reduction of oxidative glutathione, or induction of the genes most commonly associated with autophagy. These findings serve to indicate the protective mechanisms that are triggered upon metal exposures in yeast. Curiously, we also discovered that the autophagic response may be duplicitous, in that while the autophagic process can be cyto-protective it can also enhance the self-destructive mechanisms of the apoptotic response, indeed it is appears to be a requisite part of that response. Whether or not the cells respond to the cellular stress by autophagy or apoptosis appears to be “decided” by whether or not a full-blown autophagic response to cellular stressors (which can be independently induced by the drug, rapamycin) is initiated before the same autophagic process is able to trigger activation of a caspase-induced apoptosis. In addition, in order to monitor the autophagic process more carefully, we have developed a cytometric methodology to assess the autophagy flow, that is less labor-intensive and more dynamic than the traditional Western blot-based method. In so doing we have been able to decipher the factors of cell fate decision with heavy metal-induced oxidative stress in S. cerevisiae

Insights into Chinese perspectives on do-not-resuscitate (DNR) orders from an examination of DNR order form completeness for cancer patients

PURPOSE: Discussing end-of-life care with patients is often considered taboo, and signing a do-not-resuscitate (DNR) order is difficult for most patients, especially in Chinese culture. This study investigated distributions and details related to the signing of DNR orders, as well as the completeness of various DNR order forms. METHODS: Retrospective chart reviews were performed. We screened all charts from a teaching hospital in Taiwan for patients who died of cancer during the period from January 2010 to December 2011. A total of 829 patient records were included in the analysis. The details of the DNR order forms were recorded. RESULTS: The DNR order signing rate was 99.8 %. The percentage of DNR orders signed by patients themselves (DNR-P) was 22.6 %, while the percentage of orders signed by surrogates (DNR-S) was 77.2 %. The percentage of signed DNR forms that were completely filled out was 78.4 %. The percentage of DNR-S forms that were completed was 81.7 %, while the percentage of DNR-P forms that were completely filled out was only 67.6 %. CONCLUSION: Almost all the cancer patients had a signed DNR order, but for the majority of them, the order was signed by a surrogate. Negative attitudes of discussing death from medical professionals and/or the family members of patients may account for the higher number of signed DNR-S orders than DNR-P orders. Moreover, early obtainment of signed DNR orders should be sought, as getting the orders earlier could promote the quality of end-of-life care, especially in non-oncology wards

Plasma fatty acids and the risk of metabolic syndrome in ethnic Chinese adults in Taiwan

<p>Abstract</p> <p>Background</p> <p>Evidence of predictive power of various fatty acids on the risk of metabolic syndrome was scanty. We evaluated the role of various fatty acids, including saturated fat, monounsaturated fat, transfat, n-6 fatty acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for the risk of the metabolic syndrome in Taiwan.</p> <p>Results</p> <p>A nested case-control study based on 1000 cases of metabolic syndrome and 1:1 matched control subjects. For saturated fat, monounsaturated fat and transfat, the higher the concentration the higher the risk for metabolic syndrome: participants in the highest quintile had a 2.22-fold (95% confidence interval [CI], 1.66 to 2.97) higher risk of metabolic syndrome. In addition, the participants in higher EPA quintiles were less likely to have the risk of metabolic syndrome (adjusted risk, 0.46 [0.34 to 0.61] for the fifth quintile). Participants in the highest risk group (low EPA and high transfat) had a 2.36-fold higher risk of metabolic syndrome (95% CI, 1.38 to 4.03), compared with those in the lowest risk group (high EPA and low transfat). For prediction power, the area under ROC curves increased from 0.926 in the baseline model to 0.928 after adding fatty acids. The net reclassification improvement for metabolic syndrome risk was substantial for saturated fat (2.1%, <it>P </it>= 0.05).</p> <p>Conclusions</p> <p>Plasma fatty acid components improved the prediction of the metabolic syndrome risk in Taiwan.</p

Predicting the Severity and Prognosis of Trismus after Intensity-Modulated Radiation Therapy for Oral Cancer Patients by Magnetic Resonance Imaging

To develop magnetic resonance imaging (MRI) indicators to predict trismus outcome for post-operative oral cavity cancer patients who received adjuvant intensity-modulated radiation therapy (IMRT), 22 patients with oral cancer treated with IMRT were studied over a two-year period. Signal abnormality scores (SA scores) were computed from Likert-type ratings of the abnormalities of nine masticator structures and compared with the Mann-Whitney U-test and Kruskal–Wallis one-way ANOVA test between groups. Seventeen patients (77.3%) experienced different degrees of trismus during the two-year follow-up period. The SA score correlated with the trismus grade (r = 0.52, p<0.005). Patients having progressive trismus had higher mean doses of radiation to multiple structures, including the masticator and lateral pterygoid muscles, and the parotid gland (p<0.05). In addition, this group also had higher SA-masticator muscle dose product at 6 months and SA scores at 12 months (p<0.05). At the optimum cut-off points of 0.38 for the propensity score, the sensitivity was 100% and the specificity was 93% for predicting the prognosis of the trismus patients. The SA score, as determined using MRI, can reflect the radiation injury and correlate to trismus severity. Together with the radiation dose, it could serve as a useful biomarker to predict the outcome and guide the management of trismus following radiation therapy

Extremely High Methane Concentration in Bottom Water and Cored Sediments from Offshore Southwestern Taiwan

It has been found that Bottom Simulating Reflections (BSRs), which infer the existence of potential gas hydrates underneath seafloor sediments, are widely distributed in offshore southwestern Taiwan. Fluids and gases derived from dissociation of gas hydrates, which are typically methane enriched, affect the composition of seawater and sediments near venting areas. Hence, methane concentration of seawater and sediments become useful proxies for exploration of potential gas hydrates in a given area. We systematically collected bottom waters and sedimentary core samples for dissolved and pore-space gas analyses through five cruises: ORI-697, ORI-718, ORII-1207, ORII-1230, and ORI-732 from 2003 to 2005 in this study. Some sites with extremely high methane concentrations have been found in offshore southwestern Taiwan, e.g., sites G23 of ORI-697, N8 of ORI-718, and G96 of ORI-732. The methane concentrations of cored sediments display an increasing trend with depth. Furthermore, the down-core profiles of methane and sulfate reveal very shallow depths of sulfate methane interface (SMI) at some sites in this study. It implies sulfate reduction being mainly driven by the process of anaerobic methane oxidation (AMO) in sediments; thus indicating that there is a methane-enriched venting source, which may be the product of dissociation of gas hydrates in this area

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

© 2021 Edwards, Mitchell, Abdul-Sater, Chan, Sun, Sheth, He, Jiang, Yuan, Sharma, Czader, Chin, Liu, de Cárcer, Nalepa, Broxmeyer, Clapp and Sierra Potchanant.Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.This work was supported by the NIH R01-HL132921-01A1 award (DWC), St. Baldrick’s Foundation Scholar award (GN), Heroes Foundation (GN), the Bone Marrow Failure Research Fund at Riley Children’s Foundation (GN), NIH T32 HL007910 “Basic Science Studies on Gene Therapy of Blood Diseases” grant (ES), NIH Diversity Supplement 3R01HL132921-03S1 (ES), and NCI 1F30CA200227-01A1 fellowship (DE)

Prevalence of PIK3CA mutations in Taiwanese patients with breast cancer: a retrospective next-generation sequencing database analysis

BackgroundBreast cancer is the most common cancer type that affects women. In hormone receptor–positive (HR+), human epidermal growth factor receptor 2−negative (HER2–) advanced breast cancer (ABC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of PIK3CA mutations in the Taiwanese breast cancer population.MethodologyThis is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of PIK3CA mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment.ResultsPIK3CA mutations were identified in 278 of 728 patients (38%). PIK3CA mutations were reported in 43% of patients with HR−/HER2+ subtype and 42% of patients with HR+/HER2– postmenopausal status. A lower prevalence of PIK3CA mutations was observed in triple-negative (27%) and HR+/HER2– premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the PIK3CA mutation cohort and 16 months (95% CI: 11-23 months) in the PIK3CA wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the PIK3CA mutation cohort and 6 months (95% CI: 2-9 months) in the PIK3CA wild-type cohort.ConclusionA high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes

Use and effectiveness of dapagliflozin in patients with type 2 diabetes mellitus: a multicenter retrospective study in Taiwan

Aims/Introduction To investigate the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) who initiated dapagliflozin in real-world practice in Taiwan. Materials and Methods In this multicenter retrospective study, adult patients with T2DM who initiated dapagliflozin after May 1st 2016 either as add-on or switch therapy were included. Changes in clinical and laboratory parameters were evaluated at 3 and 6 months. Baseline factors associated with dapagliflozin response in glycated hemoglobin (HbA1c) were analyzed by univariate and multivariate logistic regression. Results A total of 1,960 patients were eligible. At 6 months, significant changes were observed: HbA1c by −0.73% (95% confidence interval [CI] −0.80, −0.67), body weight was -1.61 kg (95% CI −1.79, −1.42), and systolic/diastolic blood pressure by −3.6/−1.4 mmHg. Add-on dapagliflozin showed significantly greater HbA1c reduction (−0.82%) than switched therapy (−0.66%) (p = 0.002). The proportion of patients achieving HbA1c <7% target increased from 6% at baseline to 19% at Month 6. Almost 80% of patients experienced at least 1% reduction in HbA1c, and 65% of patients showed both weight loss and reduction in HbA1c. Around 37% of patients had at least 3% weight loss. Multivariate logistic regression analysis indicated patients with higher baseline HbA1c and those who initiated dapagliflozin as add-on therapy were associated with a greater reduction in HbA1c. Conclusions In this real-world study with the highest patient number of Chinese population to date, the use of dapagliflozin was associated with significant improvement in glycemic control, body weight, and blood pressure in patients with T2DM. Initiating dapagliflozin as add-on therapy showed better glycemic control than as switch therapy

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