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Until recently, most genetic studies of headache have been conducted on participants with European ancestry. We therefore conducted a large-scale genome-wide association study of self-reported headache in individuals of East Asian ancestry (specifically those who were identified as Han Chinese). In this study, 108,855 participants were enrolled, including 12,026 headache cases from the Taiwan Biobank. For broadly-defined headache phenotype, we identified a locus on chromosome 17, with the lead single nucleotide polymorphism (SNP) rs8072917 (odds ratio 1.08, p = 4.49 × 10–8) mapped to two protein-coding genes RNF213 and ENDOV. For severe headache phenotype, we found a strong association on chromosome 8, with the lead SNP rs13272202 [odds ratio 1.30, p = 1.02 × 10–9], mapped to gene RP11-1101K5.1. We then conducted a conditional analysis and a statistical fine mapping of the broadly-defined headache-associated loci and identified a single credible set of loci with rs8072917 supporting that this lead variant was the true causal variant on RNF213 gene region. RNF213 replicated the result of previous studies and played important roles in the biological mechanism of broadly-defined headache. On the basis of the previous results found in the Taiwan biobank, we conducted phenome-wide association studies for the lead variants using data from the UK biobank, and found that the causal variant (SNP rs8072917) was associated with muscle symptoms, cellulitis and abscess of face and neck, and cardiogenic shock. Our findings foster the genetic architecture of headache in individuals of East Asian ancestry. Our study can be replicated using genomic data linked to electronic health records from a variety of countries, therefore affecting a wide range of ethnicities globally. Our genome-phenome association study may facilitate the development of new genetic tests and novel drug mechanisms.

STAT3 activation is important in the development of gastric cancer (GCA), but its role in DNA methylation is not fully understood. STAT3-mediated DNA methylation is controlled by K685 acetylation, we therefore hypothesized that distribution of acetyl-CoA could affect the role of STAT3 in DNA methylation. Here, by methylation microarray from GCA patients and cells depleted with STAT3, we identified a STAT3-related CpG island methylator phenotype (CIMP), located at neuronal genes (neuronal CIMP). Further TCGA RNA-Seq identified neuronal CIMP+ve to be positively associated with the expression and higher cyto/mito ratio of acetyl-CoA synthetase (ACSS2). Intriguingly, patients with neuronal-CIMP +ve or higher cyto/mito ratio of ACSS were associated with a better survival, suggesting a different role of acetyl-STAT3. As STAT3 pathway plays a key role in chemokine response, we also analyze whether neuronal-CIMP contributes to anti-tumor immune response. Surprisingly, CIMP +ve patients correlated with pro-inflammatory niche, including activated CD4 + T cells and M1 macrophages. In conclusion, neuronal-CIMP may be a biomarker to predict patient’s immune responses in GCA. Citation Format: Jie-Ting Low, Yu-Ming Chuang, Yu-Ting Lee, Michael Wing-Yan Chan. Acetyl-coA distribution devote STAT3 related neuronal methylation phenotype and pro-inflammatory niche in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1254.

Breast cancer is among the most frequently diagnosed cancer types and the leading cause of cancer-related death in women. The mortality rate of patients with breast cancer is currently increasing, perhaps due to a lack of early screening tools. In the present study, using The Cancer Genome Atlas (TCGA) breast cancer dataset (n=883), it was determined that methylation of the protocadherin β15 (

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients’ survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10–21.66), hemoglobin less than 8 g/dl (adjusted HR 3.34, 95% CI 1.32–8.42), serum albumin

The impact of coronavirus disease 2019 (COVID-19) on economic and medical systems is significant, especially in the emergency department (ED). The patterns of ED visits have also changed significantly and may play a crucial role in rearranging medical resources to the most needed departments during the pandemic. This was a retrospective study conducted in hospitals of the Cathay Health System. All patients presented to the EDs between January 21, 2020 to April 30, 2020 (pandemic stage) and January 21, 2019 to April 30, 2019 (before the pandemic stage). Basic demographics, including visit characteristics, disposition, and chief complaints, of the patients visiting the ED between these 2 periods of time will be compared and analyzed. A total of 71,739 patients were included in the study. A reduction in ED visits was noted in 15.1% (32,950 ED visits) during the pandemic stage. ED visiting patients with the chief complaints of upper respiratory infection and social problems increased by 14.23% and 1.86%, respectively, during the pandemic period. Critical chief complaints such as cardiac arrest, chest pain and altered mental status decreased to less than the ED visits difference (−15.1%) between the pandemic and prepandemic stages, for 0%, −7.67%, and −13.8% respectively. Rearrangement of the ED pediatric staff to the COVID-19 special units and recruiting more social workers to the ED should be performed to respond to the COVID-19 pandemic.

4-Mercapto-4-methyl-2-pentanone (4MMP), a high-impact aroma compound with the box tree and black currant flavors was first identified in wines and could be released by microbial cysteine-S-conjugate β-lyases from its precursors. In this study, various yeasts and bacteria encoding β-lyases were selected to examine their β-lyase activities. A thiol precursor of 4MMP, cysteine-conjugate of 4MMP (cys-4MMP), was synthesized with a purity of >95% in a relatively environmentally friendly approach, and its chemical structure was confirmed by nuclear magnetic resonance spectroscopy. The β-lyase activities of the crude cell extract from the bacteria and yeast strains for different substrates were examined using a colorimetric method. Shewanella putrefaciens cell extract exhibited the highest β-lyase activity for all tested substrates. Additionally, the optimum pH and temperature for their β-lyase activities were determined. To monitor the conversion efficiency of precursor cys-4MMP to 4MMP, liquid chromatography-mass spectrometry was used. Our data indicate that selected bacteria and yeasts could convert cys-4MMP into 4MMP, and S. putrefaciens exhibited the best conversion yield. This study demonstrated the potential use of microbial cell extracts to produce sulfur-containing aroma compounds such as 4MMP.

Background According to a WHO report, nearly 15% of adults aged 60 and over suffer from a mental disorder, constituting 6.6% of the total disability for this age group. Taipei City faces rapid transformation towards an aging society, with the proportion of elderly in the total population rising from 12% in 2008 to 16% in 2016. The aim of this study is to identify the prevalence of mental disorders among the elderly in Taipei City and to elucidate risk factors contributing to mental disorders. Methods The elderly health examination database was obtained from the Department of Health, Taipei City government, from 2005 to 2012. A total of 86,061 people underwent publicly funded health examinations, with 348,067 visits. Each year, there are around 43,000 elderly persons in Taipei City using this service. We used a mental health questionnaire including five questions to estimated relative risks among potential risk factors with the generalized estimating equations (GEE) model to measure the mental health status of the elderly. Mood disorders were measured with the Brief Symptom Rating Scale (BSRS-5) questionnaire. Age, education level, gender, marital status, living alone, drinking milk, eating vegetables and fruits, long-term medication, smoking status, frequency of alcohol consumption, frequency of physical activity, BMI, and number of chronic diseases were included as covariates. Results The results show that being male (odds ratio (OR) 0.57; 95% CI = 0.56, 0.59), higher education (OR 0.88; 95% CI = 0.82, 0.95), no long-term medication (OR 0.57; 95% CI = 0.56, 0.58), and exercising three or more times per week (OR 0.94; 95% CI = 0.91, 0.98) were all positively correlated with better emotional status. However, being divorced (OR = 1.22, 95% CI = 1.09, 1.36), not drinking milk (OR = 1.12, 95% CI = 1.09, 1.14), not eating enough vegetables and fruits every day (OR = 1.78, 95% CI = 1.73, 1.83), daily smoking (OR = 1.15, 95% CI = 1.01, 1.32), and having more chronic diseases (OR = 1.02, 95% CI = 1.01, 1.03) were all correlated with poor mental status among the elderly. Conclusions The findings of this research can both estimate the prevalence of mood disorders at the community level, and identify risk factors of mood disorders at the personal level.

This chapter re-examines the relationship between Rabindranath Tagore and China, which was previously understood through the poet’s 1924 controversial trip to China and thus subject to rather fixed interpretation. It argues that while it is important to explore how Tagore’s contemporary Chinese thinkers responded, usually emotionally, to his proposal of the ‘revival of Eastern culture’ according to their respective stances, more depth and dimensions can be restored to the event to sustain a fuller understanding of how cultural debate was conducted in the early twentieth-century world. To this end, starting from a thought-provoking conversation between Tagore and Feng Youlan, a to-be prominent philosopher who was a PhD researcher at Columbia University in 1920, this chapter seeks to demonstrate a philosophical reading of ‘Tagore and China’ and goes further to expand the intellectual web, covering both Chinese and Western thinkers of distinction, to reveal the world historical significance of Tagore’s uneasy interaction with China.

Gastric cancer is one of the leading causes of cancer death worldwide. Previous studies demonstrated that activation of STAT3 is crucial for the development and progression of gastric cancer. However, the role of STAT3 in neuronal related gene methylation in gastric cancer has never been explored. In this study, by using DNA methylation microarray, we identified a potential STAT3 target, C11orf87, showing promoter hypomethylation in gastric cancer patients with lower STAT3 activation and AGS gastric cancer cell lines depleted with STAT3 activation. Although C11orf87 methylation is independent of its expression, ectopic expression of a constitutive activated STAT3 mutant upregulated its expression in gastric cancer cell line. Further bisulfite pyrosequencing demonstrated a progressive increase in DNA methylation of this target in patient tissues from gastritis, intestinal metaplasia, to gastric cancer. Intriguingly, patients with higher C11orf87 methylation was associated with better survival. Furthermore, hypermethylation of C11orf87 was also frequently observed in other GI cancers, as compared to their adjacent normal tissues. These results suggested that C11orf87 methylation may serve as a biomarker for diagnosis and prognosis of GI cancers, including gastric cancer. We further postulated that constitutive activation of STAT3 might be able to epigenetically silence C11orf87 as a possible negative feedback mechanism to protect the cells from the overactivation of STAT3. Targeted inhibition of STAT3 may not be appropriate in gastric cancer patients with promoter hypermethylation of C11orf87.

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients' survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10-21.66), hemoglobin less than 8 g/dl (adjusted HR 3.34, 95% CI 1.32-8.42), serum albumin 3.5 g/dl (adjusted HR 3.24, 95% CI 1.09-9.68), and having received allogeneic stem cell transplantation (allo-SCT) (adjusted HR 5.98, 95% CI 1.62-22.03) were significantly associated with IFI in the multivariate analysis. Contracting IFI was in turn associated with early mortality (adjusted HR 11.60, 95% CI 1.26-106.74). Light chain disease, anemia, hypoalbuminemia, and receiving allo-SCT were independent predictors of IFI in MM patients. The early mortality risk is much higher in those encountering IFI. Physicians must be aware of the rare but potentially lethal infections.

We investigated the risk and impact of mycobacterium tuberculosis (TB) infection in patients with multiple myeloma (MM). We identified 3979 MM patients from Taiwan's National Health Insurance database between 2000 and 2011 and compared the incidence rates of TB infection in these patients with 15,916 randomly selected age-, sex-, and comorbidity-matched subjects without MM. The risk of TB was higher in the myeloma cohort (adjusted hazard ratio [HR] 3.11, 95% confidence interval [CI] 2.41-4.02). Risk factors for MM patients contracting TB were age ≥65 (adjusted HR 1.93, 95% CI 1.19-3.15), alcohol use disorder (adjusted HR 2.86, 95% CI 1.24-6.62), and steroid daily dose equivalent to prednisone 5 mg or more (adjusted HR 2.38, 95% CI 1.50-3.77). MM patients with TB had a higher mortality risk than those without (adjusted HR 2.03, 95% CI 1.54-2.67). The incidence of TB is significantly higher in MM patients.

IntroductionPositive fluid balance is a prognostic factor for mortality in patients with sepsis; however, the association between cumulated fluid balance (CFB) and sepsis-induced multi-organ dysfunction syndrome (MODS) has yet to be elucidated. In this study, we sought to determine whether CFB is correlated with MODS and mortality in cases of septic shock.MethodsThe study retrospectively recruited patients with septic shock from the intensive care unit of a tertiary care hospital. Multiple organ dysfunction syndrome (MODS) was identified as sequential organ failure assessment (SOFA) score ≥ 2 in more than one organ system. The CFB is the sum of all daily intake and output. An independent t-test, single and multivariate logistic regression, the receiver operating characteristic (ROC) curves, and the Pearson correlation coefficient were used to determine whether a relationship exists between CFB and the development of MODS and mortality.ResultsAmong the 104 patients enrolled in the study, 58 (55.8%) survived more than 28 days, and 73 (70.2%) developed MODS on day 3. The values of CFB in the first 24 hours and 72 hours after diagnosis of septic shock in patients with MODS were higher than these in patients without MODS (1086.6 ± 176.3 vs. 325.5 ± 205.7 ml, p = 0.013 and 2408 ± 361 vs. 873.1 ± 489 ml, p < 0.0001). In a multivariate logistic regression, the independent factors associated with the development of MODS on day 3 were APACHE II score at ICU admission (27.6 ± 7.6 in patients with MODS vs. 20.5 ± 6.4 in those without; O.R. 1.18; 95% C.1 I. 1.08-1.30; p < 0.001), disseminated intravascular coagulopathy (DIC) (n = 28; 38.4% vs. n = 2; 6.5%; O.R. 23.67; 95% C.I. 3.58-156.5; p = 0.001), and CFB in the first 72 hours (72-hr CFB) > median (1767.50ml) (n = 41; 56.2% vs. n = 11; 35.5%; O.R. 3.67; 95% C.I., 1.18-11.40; p = 0.024). Moreover, a multivariate logistic regression also identified neoplasm (n = 25; 54.3% vs. n = 17; 29.3%; O.R. 3.45; 95% C.I. 1.23-10.0; p = 0.019) and 72-hr CFB > median (n = 30; 65.2% vs. n = 21; 36.2%; O.R. 4.13; 95% C.I. 1.34-12.66; p = 0.013) as independent factors associated with 28-day mortality. 72-hr CFB values were strongly correlated with the SOFA score (r = 0.445, p < 0.0001). The area under the ROC curve revealed that 72-hr CFB has good discriminative power in associating the development of MODS (0.644, p = 0.002) and predicting subsequent 28-day mortality (0.704, p < 0.0001).Conclusions72-hr CFB appears to be correlated with the likelihood of developing MODS and mortality in patients with septic shock. Thus, it appears that 72-hr CFB could perhaps be used as an indicator for MODS and a predictor for mortality in those patients.

Background Bladder cancer is a disease frequently seen in the elderly. Frail and elderly patients with muscle-invasive bladder cancer (MIBC) are often unfit for surgery. While concurrent chemoradiotherapy (CCRT) is a well-established alternative treatment modality, only a small proportion of elderly patients receive CCRT. The purpose of this article is to review our experience with CCRT in elderly MIBC patients. Methods Between January 1, 2007 and December 31, 2013, we retrospectively reviewed patients aged >75 who were treated with CCRT at Taipei Veterans General Hospital. Patients' characteristics, therapeutic strategy, clinical outcomes, and treatment-related toxicities were assessed. Results Nineteen patients (4 females and 15 males) were identified. The median age was 79.5 years (range, 78.5–84.0 years) and the median follow-up was 33.7 months (interquartile range, 19.1–51.8 months). The major adverse event was grade 3 or grade 4 neutropenia, which developed in 10 of the 19 patients. No treatment-related mortality occurred. We found no association between prognosis and the chemotherapy regimen. Chemotherapy with a conventional dose of gemcitabine (800–1000 mg/m2) was well tolerated. The two-year and three-year estimated overall survival rates were 74% and 60%, respectively. Conclusion CCRT after complete transurethral resection of the bladder tumor is feasible for elderly patients with MIBC. The conventional dose of gemcitabine as a chemosensitizer is adequate in the elderly population, but further investigation is needed.

Cerebrovascular events are a common complication among patients with cancer, increasing morbidity and mortality. However, the association between multiple myeloma and cerebrovascular events remains unclear. We therefore investigated multiple myeloma patients' risk factors for stroke to devise a better stroke-prevention strategy. This study includes consecutive patients 20 years and older who were newly diagnosed with symptomatic multiple myeloma at Taipei Veterans General Hospital, a tertiary medical center, between January 1, 2002 and December 31, 2014. The primary outcome was stroke development. Patients with head injuries, brain tumors, brain parenchymal invasions, or antecedent malignancies were excluded. Hazard ratios (HRs) of stroke risk factors for multiple myeloma patients were estimated by Cox proportional regression analysis. Overall, 395 patients with a median age of 70 years were investigated. In the median follow-up period of 18 months, cerebrovascular events occurred in 16 patients, including 10 ischemic strokes and 6 hemorrhagic strokes. The 5-year estimated cumulative incidence rate was 7.45%. In the multivariate analysis, the κ light chain isotype (adjusted HR, 8.37; 95% confidence interval [CI], 1.91-39.8), previous cerebrovascular accidents (adjusted HR, 5.16; 95% CI, 1.48-17.9), and serum creatinine > 2 mg/dL (adjusted HR, 4.21; 95% CI, 1.10-16.0) were identified as independent risk factors for stroke. Subgroup analysis showed that atrial fibrillation (adjusted HR, 8.07) and previous cerebrovascular accident (adjusted HR, 4.89) are significant risk factors for ischemic stroke. Serum creatinine > 2 mg/dL (adjusted HR, 30.6) and previous cerebrovascular accident (adjusted HR, 13.9) are significant for hemorrhagic stroke. Moreover, therapeutic strategies for multiple myeloma were not associated with stroke in our study. This study demonstrates that risk of stroke increases in myeloma patients with a κ light chain isotype, previous cerebrovascular events, and renal impairment. Further prospective clinical studies to clarify the relationship between multiple myeloma and stroke are warranted.

Acetohydroxyacid synthase (AHAS) inhibitors are highly successful commercial herbicides. New kinetic data show that the binding of these compounds leads to reversible accumulative inhibition of AHAS. Crystallographic data (to a resolution of 2.17 Å) for an AHAS-herbicide complex shows that closure of the active site occurs when the herbicidal inhibitor binds, thus preventing exchange with solvent. This feature combined with new kinetic data shows that molecular oxygen promotes an accumulative inhibition leading to the conclusion that the exceptional potency of these herbicides is augmented by subversion of an inherent oxygenase side reaction. The reactive oxygen species produced by this reaction are trapped in the active site, triggering oxidation reactions that ultimately lead to the alteration of the redox state of the cofactor flavin adenine dinucleotide (FAD), a feature that accounts for the observed reversible accumulative inhibition.

Y1-xEuxMn2O5 nanorod samples (x = 0, 0.5, and 1) were prepared and crystallized in an orthorhombic structure with the Pbam space group. Magnetic susceptibility experiments revealed that the size effect reduced the effective magnetic moment and interaction among magnetic moments. All six samples exhibited AFM ordering and canted AFM domain below 50 K, and adjustable by varying the size of the nanorods. Hysteresis experiments revealed the size effect induced exchange bias. Room-temperature Raman spectra revealed a red-shift in all of x = 0 and x = 1 samples in an applied magnetic field, indicating that a spin-phonon interaction existed at room temperature.

The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (K(i) values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.

BACKGROUND Patients with colorectal cancer (CRC) who undergo cancer surgeries with higher-volume providers may have better outcomes. The current debate focuses on whether it is hospital volume or surgeon volume that matters more. METHODS The authors conducted a nationwide population-based study in Taiwan that enrolled all patients who underwent definitive surgery for newly diagnosed CRC between 2005 and 2011. All patients were divided into 4 quartiles according to hospital and surgeon volume. The main outcome was the 5-year mortality rate, which was analyzed using a frailty model for Cox regression. The authors also conducted fixed and random effects multivariate regression models to examine short-term outcomes and resource use, including operative mortality, hospital stay, emergency department visits within 30 days, and medical expenses. Analyses were adjusted for patient and provider characteristics. RESULTS A total of 61,728 patients with CRC were included in the current study. The 5-year mortality rates were 38.7%, 32.8%, 32.0%, and 29.1% in descending order of hospital volume quartiles and were 41.4%, 34.1%, 29.8%, and 27.4% in descending order of surgeon volume quartiles. After adjustment for the individual and provider characteristics, surgeon volume, but not hospital volume, remained a significantly predictive factor of death (P

Vertebral fractures affect approximately 30% of myeloma patients and lead to a poor impact on survival and life quality. In general, age and body mass index (BMI) are reported to have an important role in vertebral fractures. However, the triangle relationship among age, BMI, and vertebral fractures is still unclear in newly diagnosed multiple myeloma (NDMM) patients. This study recruited consecutive 394 patients with NDMM at Taipei Veterans General Hospital between January 1, 2005 and December 31, 2015. Risk factors for vertebral fractures in NDMM patients were collected and analyzed. The survival curves were demonstrated using Kaplan-Meier estimate. In total, 301 (76.4%) NDMM patients were enrolled in the cohort. In the median follow-up period of 18.0 months, the median survival duration in those with vertebral fractures ≥ 2 was shorter than those with vertebral fracture 75 years and BMI < 18.5 kg/m2 (adjusted RR, 12.22; 95% CI, 3.02-49.40). This is the first study that demonstrated that age had a significant impact on vertebral fractures in NDMM patients with low BMI. Elder patients with low BMI should consider to routinely receive spinal radiographic examinations and regular follow-up.