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Leisure-time physical activity (LTPA) has been closely related to health improvement. The under-appreciation for energy output by nutritionists stems in part from limited data expressed in caloric equivalent. We converted the frequency, duration, and intensity of LTPA, reported from 15,390 adults in the Taiwan National Health Interview Survey 2001, into kilocalories (kcal). Half of Taiwanese adults admit to no LTPA. Women, lower education or income, younger age, smokers and chewers of betel quid; exercised significantly less than their counterparts. Less than 1/5 (18.9%) of the population in Taiwan was physically active at >or=750 kcal/week, and only 1/7 (13.9%) reached a more desirable goal of >or=1,000 kcal/week, compared with 1/3 in the U.S. The most disconcerting finding was the Taiwan unique U-shaped prevalence for males, with the 25-44 age group being the least active, >or=65 age group being the most active; and S-shaped for females, lowest at age 18-24 years and highest at the two older groups (45-64 and >or=65 years). LTPA was under-appreciated, particularly among the most productive work force (25-44-year group), who exercised with a prevalence only 1/4 of their U.S. counterparts. Expressing LTPA in kcal makes direct comparison easier. Invoking a goal of >or=750 kcal/week for Asians, attainable by exercising 4 hours/week, can facilitate nutritionists in assessing LTPA adequacy. Currently, 4/5 of adults in Taiwan failed to reach this goal. Recognizing the concept of cumulative energy expenditure, in contrast to disciplined daily work for 5 or more days, will encourage the infrequent exercisers such as 'weekend warriors' to continue with their activities. [ABSTRACT FROM AUTHOR]

Excellent castability, significantly refined microstructure, and good mechanical properties make eutectic high-entropy alloys (EHEAs) a natural fit for rapid solidification processes, e.g., additive manufacturing. Previous investigations have focused on developing EHEAs through trial and error and mixing known binary eutectic materials. However, eutectic compositions obtained from near-equilibrium conditions do not guarantee a fully eutectic microstructure under rapid solidifications. In this work, a thermodynamically guided high-throughput framework is proposed to design EHEAs for rapid solidification. Empirical formulas derived from past experimental observations and thermodynamic computations are applied and considered phase growth kinetics under rapid solidification (skewed phase diagram). The designed alloy candidate, Co 25.6 Fe 17.9 Ni 22.4 Cr 19.1 Ta 8.9 Al 6.1 (wt.%), contains nanostructured eutectic lamellar and shows a high Vickers hardness of 675 Hv. In addition to this specific composition, the alloy design toolbox enables the development of new EHEAs for rapid solidification without the limitation of previous knowledge., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes., (© 2024. The Author(s).)

Pulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)-approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti-proliferative and anti-migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet-derived growth factor (PDGF)-BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS-, Ang II- and PDGF-BB-induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF-BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down-regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Recent years have seen the development of a variety of mammalian library approaches for display and secretion mode. Advantages include library approaches for engineering, preservation of precious immune repertoires and their repeated interrogation, as well as screening in final therapeutic format and host. Mammalian display approaches for antibody optimization exploit these advantages, necessitating the generation of large libraries but in turn enabling early screening for both manufacturability and target specificity. For suitable libraries, high antibody integration rates and resulting monoclonality need to be balanced - we present a solution for sufficient transmutability and acceptable monoclonality by applying an optimized ratio of coding to non-coding lentivirus. The recent advent of microfluidic-assisted hit discovery represents a perfect match to mammalian libraries in secretion mode, as the lower throughput fits well with the facile generation of libraries comprising a few million functional clones. In the presented work, Chinese Hamster Ovary cells were engineered to both express the target of interest and secrete antibodies in relevant formats, and specific clones were strongly enriched by high throughput screening for autocrine cellular binding. The powerful combination of mammalian secretion libraries and microfluidics-assisted hit discovery could reduce attrition rates and increase the probability to identify the best possible therapeutic antibody hits faster.

This study evaluated the risks of childhood acute bronchitis and bronchiolitis (CABs) for children with asthma or allergic rhinitis (AR). Using insurance claims data of Taiwan, we identified, from children of ≤12 years old in 2000-2016, cohorts with and without asthma (N = 192,126, each) and cohorts with and without AR (N = 1,062,903, each) matched by sex and age. By the end of 2016, the asthma cohort had the highest bronchitis incidence, AR and non-asthma cohorts followed, and the lowest in the non-AR cohort (525.1, 322.4, 236.0 and 169.9 per 1000 person-years, respectively). The Cox method estimated adjusted hazard ratios (aHRs) of bronchitis were 1.82 (95% confidence interval (CI), 1.80-1.83) for the asthma cohort and 1.68 (95% CI, 1.68-1.69) for the AR cohort, relative to the respective comparisons. The bronchiolitis incidence rates for these cohorts were 42.7, 29.5, 28.5 and 20.1 per 1000 person-years, respectively. The aHRs of bronchiolitis were 1.50 (95% CI, 1.48-1.52) for the asthma cohort and 1.46 (95% CI, 1.45-1.47) for the AR cohort relative to their comparisons. The CABs incidence rates decreased substantially with increasing age, but were relatively similar for boys and girls. In conclusion, children with asthma are more likely to develop CABs than are children with AR.

Recently, there has been a co-evolution of mammalian libraries and diverse microfluidic approaches for therapeutic antibody hit discovery. Mammalian libraries enable the preservation of full immune repertoires, produce hit candidates in final format and facilitate broad combinatorial bispecific antibody screening, while several available microfluidic methodologies offer opportunities for rapid high-content screens. Here, we report proof-of-concept studies exploring the potential of combining microfluidic technologies with mammalian libraries for antibody discovery. First, antibody secretion, target co-expression and integration of appropriate reporter cell lines enabled the selection of in-trans acting agonistic bispecific antibodies. Second, a functional screen for internalization was established and comparison of autocrine versus co-encapsulation setups highlighted the advantages of an autocrine one cell approach. Third, synchronization of antibody-secreting cells prior to microfluidic screens reduced assay variability. Furthermore, a display to secretion switchable system was developed and applied for pre-enrichment of antibody clones with high manufacturability in conjunction with subsequent screening for functional properties. These case studies demonstrate the system's feasibility and may serve as basis for further development of integrated workflows combining manufacturability sorting and functional screens for the identification of optimal therapeutic antibody candidates.

Studies have associated the human respiratory syncytial virus which causes seasonal childhood acute bronchitis and bronchiolitis (CABs) with climate change and air pollution. We investigated this association using the insurance claims data of 3,965,560 children aged ≤ 12 years from Taiwan from 2006−2016. The monthly average incident CABs increased with increasing PM2.5 levels and exhibited an inverse association with temperature. The incidence was 1.6-fold greater in January than in July (13.7/100 versus 8.81/100), declined during winter breaks (February) and summer breaks (June−August). The highest incidence was 698 cases/day at <20 °C with PM2.5 > 37.0 μg/m3, with an adjusted relative risk (aRR) of 1.01 (95% confidence interval [CI] = 0.97−1.04) compared to 568 cases/day at <20 °C with PM2.5 < 15.0 μg/m3 (reference). The incidence at ≥30 °C decreased to 536 cases/day (aRR = 0.95, 95% CI = 0.85−1.06) with PM2.5 > 37.0 μg/m3 and decreased further to 392 cases/day (aRR = 0.61, 95% CI = 0.58−0.65) when PM2.5 was <15.0 μg/m3. In conclusion, CABs infections in children were associated with lowered ambient temperatures and elevated PM2.5 concentrations, and the high PM2.5 levels coincided with low temperature levels. The role of temperature should be considered in the studies of association between PM2.5 and CABs.

Background: Evidences have shown that the stroke risk associated with long-term exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM 2.5 ) varies among people in North America, Europe and Asia, but studies in Asia rarely evaluated the association by stroke type. We examined whether long-term exposure to PM 2.5 is associated with developing all strokes, ischemic stroke and hemorrhagic stroke., Methods: The retrospective cohort study consisted of 1,362,284 adults identified from beneficiaries of a universal health insurance program in 2011. We obtained data on air pollutants and meteorological measurements from air quality monitoring stations across Taiwan in 2010-2015. Annual mean levels of all environmental measurements in residing areas were calculated and assigned to cohort members. We used Cox proportional hazards models to estimate hazard ratio (HR) and 95% confidence interval (CI) of developing stroke associated with 1-year mean levels of PM 2.5 at baseline in 2010, and yearly mean levels from 2010 to 2015 as the time-varying exposure, adjusting for age, sex, income and urbanization level., Results: During a median follow-up time of 6.0 years, 12,942 persons developed strokes, 9919 (76.6%) were ischemic. The adjusted HRs (95% CIs) per interquartile range increase in baseline 1-year mean PM 2.5 were 1.03 (1.00-1.06) for all stroke, 1.06 (1.02-1.09) for ischemic stroke, and 0.95 (0.89-1.10) for hemorrhagic stroke. The concentration-response curves estimated in the models with and without additional adjustments for other environmental measurements showed a positively linear association between baseline 1-year mean PM 2.5 and ischemic stroke at concentrations greater than 30 μg/m 3 , under which no evidence of association was observed. There was an indication of an inverse association between PM 2.5 and hemorrhagic stroke, but the association no longer existed after controlling for nitrogen dioxide or ozone. We found similar shape of the concentration-response association in the Cox regression models with time-varying PM 2.5 exposures., Conclusion: Long-term exposure to PM 2.5 might be associated with increased risk of developing ischemic stroke. The association with high PM 2.5 concentrations remained significant after adjustment for other environmental factors., (© 2022. The Author(s).)

No study has ever investigated how ambient temperature and PM 2.5 mediate rotavirus infection (RvI) in children. We used insurance claims data from Taiwan in 2006-2012 to evaluate the RvI characteristics in children aged ≤ 9. The RvI incidence rates were higher in colder months, reaching the highest in March (117.0/100 days), and then declining to the lowest in July (29.2/100 days). The age-sex-specific average incident cases were all higher in boys than in girls. Stratified analysis by temperature (<20, 20-24, and ≥25 °C) and PM 2.5 (<17.5, 17.5-31.4, 31.5-41.9, and ≥42.0 μg/m 3 ) showed that the highest incidence was 16.4/100 days at average temperatures of <20 °C and PM 2.5 of 31.5-41.9 μg/m 3 , with Poisson regression analysis estimating an adjusted relative risk (aRR) of 1.26 (95% confidence interval (CI) = 1.11-1.43), compared to the incidence at the reference condition (<20 °C and PM 2.5 < 17.5 μg/m 3 ). As the temperature increased, the incident RvI cases reduced to 4.84 cases/100 days (aRR = 0.40, 95% CI = 0.35-0.45) when it was >25 °C with PM 2.5 < 17.5 μg/m 3 , or to 9.84/100 days (aRR = 0.81, 95% CI = 0.77-0.93) when it was >25 °C with PM 2.5 > 42 μg/m 3 . The seasonal RvI is associated with frequent indoor personal contact among children in the cold months. The association with PM 2.5 could be an alternative assessment due to temperature inversion.

For facilitating risk communication in clinical management, such a ratio-based measure becomes easier to understand if expressed as a loss of life expectancy. The cohort, consisting of 543,410 adults in Taiwan, was recruited between 1994 and 2008. Health risks included lifestyle, biomarkers, and chronic diseases. A total of 18,747 deaths were identified. The Chiang's life table method was used to estimate a loss of life expectancy. We used Cox regression to calculate hazard ratios (HRs) for health risks. The increased mortality from cardio-metabolic risks such as high cholesterol (HR=1.10), hypertension (HR=1.48) or diabetes (HR=2.02) can be converted into a loss of 1.0, 4.4, and 8.9 years in life expectancy, respectively. The top 20 of the 30 risks were associated with a loss of 4 to 10 years of life expectancy, with 70% of the cohort having at least two such risk factors. Smoking, drinking, and physical inactivity each had 5-7 years loss. Individuals with diabetes or an elevated white count had a loss of 7-10 years, while prolonged sitting, the most prevalent risk factor, had a loss of 2-4 years. Those with diabetes (8.9 years) and proteinuria (9.1 years) present at the same time showed a loss of 16.2 years, a number close to the sum of each risk. Health risks, expressed as life expectancy loss, could facilitate risk communication. The paradigm shift in expressing risk intensity can help set public health priorities scientifically to promote a focus on the most important ones in primary care.

Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the antibiotic G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized that an antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing P. aeruginosa bacteria with high local concentrations of G2637 antibiotic in the intracellular environment of phagocytes. Using a novel technology of screening for hybridomas recognizing intact bacteria, we identified monoclonal antibody 26F8, which binds to lipopolysaccharide O antigen on the surface of P. aeruginosa bacteria. This antibody was engineered to contain 6 cysteines and was conjugated to the G2637 antibiotic via a lysosomal cathepsin-cleavable linker, yielding a drug-to-antibody ratio of approximately 6. The resulting AAC delivered a high intracellular concentration of free G2637 upon phagocytosis of AAC-bound P. aeruginosa by macrophages, and potently cleared viable P. aeruginosa bacteria intracellularly. The molar concentration of AAC-associated G2637 antibiotic that resulted in elimination of bacteria inside macrophages was approximately 2 orders of magnitude lower than the concentration of free G2637 required to eliminate extracellular bacteria. This study demonstrates that an anti-P. aeruginosa AAC can locally concentrate antibiotic and kill P. aeruginosa inside phagocytes, providing additional therapeutic options for antibiotics that are moderately active or have an unfavorable pharmacokinetics or toxicity profile. IMPORTANCE Antibiotic treatment of life-threatening P. aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological in vitro assays, affirming the need for new therapeutic approaches. Antibiotics often fail in the preclinical stage due to insufficient efficacy against P. aeruginosa. One potential strategy is to enhance the local concentration of antibiotics with limited inherent anti-P. aeruginosa activity. This study presents proof of concept for an antibody-antibiotic conjugate, which releases a high local antibiotic concentration inside macrophages upon phagocytosis, resulting in potent intracellular killing of phagocytosed P. aeruginosa bacteria. This approach may provide new therapeutic options for antibiotics that are dose limited.

This animal study aimed to elucidate the relationship of low-dose, narrow-band UVB at 308 nm with vitamin D synthesis. C57BL/6 female mice, at 3 weeks-of-age, were randomly divided into the following six groups (n = 6 at each time point of vitamin D measurement), which were: (1) normal diet without UVB irradiation; (2) VDd diet without UVB irradiation; and (3)-(6) VDd diet with 308 nm-UVB irradiation of 12.5, 25, 50, and 100 μω/cm 2 , respectively. All of the groups needing UVB irradiation received an exposure of 10 min per day, five days per week, and a duration of 3-5 weeks. The mice recovering from severe VDd (plasma total 25-hydroxyvitamin D level increasing from approximately 3 to over 30 ng/mL) only occurred in groups with a UVB irradiation dosage of either 50 or 100 μω/cm 2 . The optimal, estimated dosage for mice to recover from severe VDd was 355 mJ/cm 2 within 3 weeks. Low-dose, narrow-band UVB irradiation at 308 nm is effective in improving VDd in mice. The results obtained, in addition to the especially small side effects of the above UVB irradiation formula, could be further translated to treating VDd-related disorders.

Pigeon circovirus (PiCV) is the most recurrent virus diagnosed in pigeons and is among the major causative agents of young pigeon disease syndrome (YPDS). Due to the lack of an established laboratory protocol for PiCV cultivation, development of prophylaxis is hampered. Alternatively, virus-like particles (VLPs), which closely resemble native viruses but lack the viral genetic material, can be generated using a wide range of expression systems and are shown to have strong immunogenicity. Therefore, the use of VLPs provides a promising prospect for vaccine development. In this study, transfected human embryonic kidney (HEK-293) cells, a mammalian expression system, were used to express the PiCV capsid protein (Cap), which is a major component of PiCV and believed to contain antibody epitopes, to obtain self-assembled VLPs. The VLPs were observed to have a spherical morphology with diameters ranging from 12 to 26 nm. Subcutaneous immunization of pigeons with 100 µg PiCV rCap-VLPs supplemented with water-in-oil-in-water (W/O/W) adjuvant induced specific antibodies against PiCV. Observations of the cytokine expression and T-cell proliferation levels in spleen samples showed significantly higher T-cell proliferation and IFN- γ expression in pigeons immunized with VLPs compared to the controls ( p < 0.05). Experimentally infected pigeons that were vaccinated with VLPs also showed no detectable viral titer. The results of the current study demonstrated the potential use of PiCV rCap-VLPs as an effective vaccine candidate against PiCV.

In the United States, maternal mortality, defined as all deaths during pregnancy, childbirth, and up to 365 days after the end of pregnancy, is among the highest of all developed nations. For every 1 maternal death, there are more than 100 life-threatening complications that occur related to pregnancy. However, maternal morbidity and mortality do not affect all mothers equally. Black and indigenous people are at the highest risk for pregnancy-related complications and death-they are up to 5 times as likely to die from childbearing than white women. To understand this nationwide epidemic, cases of maternal death must be thoroughly reviewed, including the medical, social, and societal circumstances surrounding them. The state of Hawai'i formed the Maternal Mortality Review Committee in 2016 to review cases of maternal mortality, collect accurate data, and develop strategies for prevention. Twenty-five maternal deaths occurred in the state of Hawai'i from 2015 to 2017. More than half of these deaths were deemed preventable. Combined data show that mental health disorders played a significant role in maternal mortality, and approximately a quarter of cases involved substance use. Twenty-three percent of maternal deaths occurred in Native Hawaiian and Pacific Islander women, even though they make up a smaller proportion of women in the state. The collection and analysis of these data are the first steps toward understanding and reducing maternal morbidity and mortality in Hawai'i. Most notably, the striking ethnic disparities in maternal deaths and the preventable nature of many cases demand our immediate attention., (©Copyright 2020 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

We have recently shown that exogenous administration of extracellular heat shock protein HSC70, a previously recognized intracellular chaperone protein, can protect against LPS-induced cardiac dysfunction through anti-inflammatory actions. However, whether it can also exert anti-hypertrophic effect is unknown. The present study was aimed to investigate the efficacy of HSC70 against cardiac hypertrophy and its underlying molecular mechanisms. Cardiomyocytes were isolated from the cardiac ventricles of neonatal Wistar rats and LPS (1 μg/mL) was used to induce the hypertrophic responses. We found that HSC70 (0.1, 1 and 5 μg/mL) pretreatment attenuated LPS-induced cardiomyocyte hypertrophy dose-dependently. In addition, HSC70 mitigated LPS-induced inflammatory mediators including TNF-α, IL-6, NO, iNOS and COX-2, with down-regulated protein expression of MMP-2 and MMP-9. Moreover, HSC70 repressed LPS-induced signaling of MAPK and Akt. Finally, HSC70 inhibited NF-κB subunit p65, and the DNA binding activity of NF-κB. Taken together, these findings suggest that in vitro HSC70 can exert anti-hypertrophic effects through inhibition of pro-inflammatory mediators, which are potential mediated by the down-regulation of MAPK, Akt and NF-κB signaling pathways. In conclusion, extracellular HSC70 may be a novel pharmacologic strategy in the management of cardiac hypertrophy., Competing Interests: Declaration of Competing Interest To the best of our knowledge, all authors have no conflict of interest, financial or otherwise., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Haemophilia A and B are disorders caused by the lack of clotting factors VIII and IX, respectively. Repeated bleeding into the same joint leads to haemophilic arthropathy (HA). Interleukin (IL)-1β is responsible for the pro-inflammatory response and IL-37 is induced by IL-1β stimuli to have an anti-inflammatory response and prevent uncontrolled inflammation and tissue damage. Our objective was to investigate plasma levels of IL-1β and IL-37 in patients with severe haemophilia with different severities of HA., Methods: Peripheral blood samples were collected from 14 patients with severe haemophilia A and 6 with severe haemophilia B, and 18 healthy individuals. Plasma levels of IL-1β and IL-37 were detected by immunoassay, and severity of HA was evaluated using the Pettersson scoring system. Plasma levels of IL-1β and IL-37 were analysed in patients with severe haemophilia grouped by Pettersson score and in healthy individuals., Results: Plasma levels of IL-1β and IL-37 were significantly higher in patients with severe haemophilia compared with healthy individuals and significantly lower in those with moderate to severe HA than in those with no or mild HA., Conclusions: Plasma levels of IL-1β and IL-37 may be useful to track HA progression in patients with severe haemophilia.

For antibody-drug conjugates to be efficacious and safe, they must be stable in circulation to carry the payload to the site of the targeted cell. Several components of a drug-conjugated antibody are known to influence stability: 1) the site of drug attachment on the antibody, 2) the linker used to attach the payload to the antibody, and 3) the payload itself. In order to support the design and optimization of a high volume of drug conjugates and avoid unstable conjugates prior to testing in animal models, we wanted to proactively identify these potential liabilities. Therefore, we sought to establish an in vitro screening method that best correlated with in vivo stability. While traditionally plasma has been used to assess in vitro stability, our evaluation using a variety of THIOMAB TM antibody-drug conjugates revealed several disconnects between the stability assessed in vitro and the in vivo outcomes when using plasma. When drug conjugates were incubated in vitro for 24 h in mouse whole blood rather than plasma and then analyzed by affinity capture LC-MS, we found an improved correlation to in vivo stability with whole blood (R 2 = 0.87, coefficient of determination) compared to unfrozen or frozen mouse plasma (R 2 = 0.34, 0.01, respectively). We further showed that this whole blood assay was also able to predict in vivo stability of other preclinical species such as rat and cynomolgus monkey, as well as in human. The screening method utilized short (24 h) incubation times, as well as a custom analysis software, allowing increased throughput and in-depth biotransformation characterization. While some instabilities that were more challenging to identify remain, the method greatly enhanced the process of screening, optimizing, and lead candidate selection, resulting in the substantial reduction of animal studies.

In Taiwan, most students with disabilities receive education in an inclusive setting. Literature has documented the effects of interventions in increasing students' positive behaviors in inclusive settings, including students with disabilities in Western countries; however, effectiveness of such interventions in an Asian context remains unclear. The Class-Wide Function-Related Intervention Teams (CW-FIT) is one of the interventions that applies reinforcement-based strategies and provides multi-tiered supports to students with various severity of challenging behaviors. This study investigates the effects of CW-FIT Tier I (i.e. class-wide intervention) and Tier II (i.e. self-management) on the on-task and disruptive behaviors of a student with Autism Spectrum Disorder in an inclusive elementary classroom in Taiwan. Across nine weeks of intervention, the researchers used a reversal single-case design A-B-C-B-C to demonstrate experimental control over five phases. In addition, the researchers administered interviews and questionnaires to collect social validity data from the teacher and peers' perceptions toward the intervention. Findings from this study support that the CW-FIT is an effective intervention in increasing a student's on-task behaviors and decreasing disruptive behaviors in an inclusive classroom in an Asian context. The effect of implementing multiple tiers of CW-FIT was much more effective than implementing solely Tier I (class-wide intervention). The intervention was also well-received by the general education teacher and students., (© The British Society of Developmental Disabilities 2019.)

O-acetyl-ADP-ribose (AAR) is a metabolic small molecule relevant in epigenetics that is generated by NAD-dependent histone deacetylases, such as Sir2. The formation of silent heterochromatin in yeast requires histone deacetylation by Sir2, structural rearrangement of SIR complexes, spreading of SIR complexes along the chromatin, and additional maturation processing. AAR affects the interactions of the SIR-nucleosome in vitro and enhances the chromatin epigenetic silencing effect in vivo. In this study, using isothermal titration calorimetry (ITC) and dot blotting methods, we showed the direct interaction of AAR with Sir3. Furthermore, through chromatin immunoprecipitation (ChIP)-on-chip and chromatin affinity purification (ChAP)-on chip assays, we discovered that AAR is capable of increasing the extended spreading of Sir3 along telomeres, but not Sir2. In addition, the findings of a quantitative real-time polymerase chain reaction (qRT-PCR) and examinations of an in vitro assembly system of SIR-nucleosome heterochromatin filament were consistent with these results. This study provides evidence indicating another important effect of AAR in vivo. AAR may play a specific modulating role in the formation of silent SIR-nucleosome heterochromatin in yeast., Competing Interests: The authors declare no conflict of interest.

Background: The genetic background of patients with hemoglobin (Hb) H disease in Taiwan has been investigated; however, the clinical features and treatment outcomes were not reported., Objective: To analyze the clinical features and genotypes of patients with HbH who reside in Taiwan., Methods: We conducted a retrospective analysis of the clinical and molecular characteristics of 38 patients with HbH disease who were undergoing treatment at Kaohsiung Medical University Hospital, Taiwan., Results: Initial Hb levels were lower and the numbers of patients requiring iron-chelation therapy were higher in the nondeletional HbH group than in the deletional HbH group (P <.05). Compared with the healthy population, the patients with HbH disease exhibited short body length, low body weight, and low body mass index (BMI)., Conclusions: Patients with nondeletional HbH disease had lower Hb levels and a higher requirement for splenectomy and iron-chelation therapy than did those with deletional HbH disease. Also, growth status was compromised in patients with HbH disease., (© American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuregulin 1 (NRG1) is required for development of the central and peripheral nervous system and regulates neurotransmission in the adult. NRG1 and the gene encoding its receptor, ERBB4, are risk genes for schizophrenia, although how alterations in these genes disrupt their function has not been fully established. Studies of knockout and transgenic mice have yielded conflicting results, with both gain and loss of function resulting in similar behavioral and electrophysiological phenotypes. Here, we used high affinity antibodies to NRG1 and ErbB4 to perturb the function of the endogenous proteins in adult mice. Treatment with NRG1 antibodies that block receptor binding caused behavioral alterations associated with schizophrenia, including, hyper-locomotion and impaired pre-pulse inhibition of startle (PPI). Electrophysiological analysis of brain slices from anti-NRG1 treated mice revealed reduced synaptic transmission and enhanced paired-pulse facilitation. In contrast, mice treated with more potent ErbB4 function blocking antibodies did not display behavioral alterations, suggesting a receptor independent mechanism of the anti-NRG1-induced phenotypes. We demonstrate that anti-NRG1 causes accumulation of the full-length transmembrane protein and increases phospho-cofilin levels, which has previously been linked to impaired synaptic transmission, indicating enhancement of non-canonical NRG1 signaling could mediate the CNS effects.

This study aimed to identify the excess risks associated with diabetic patients with early kidney involvement (early diabetic kidney disease). The mortality risks of early diabetic kidney disease, defined as diabetes in early stages 1-3 chronic kidney disease (CKD), were assessed from a cohort of 512,700 adults in Taiwan participating in a health surveillance program from 1994-2008. Three related groups were identified and compared: diabetes without CKD, early diabetic kidney disease, and early CKD without diabetes. Deaths were ascertained through the National Death Registry. One-third of diabetics had early kidney disease, and approximately two-thirds of patients were classified with early CKD due to proteinuria. Patients with early diabetic kidney disease had more lifestyle risks such as inactivity or obesity, which characteristically amplified excess mortality by up to five times. The three-fold increase in all-cause mortality (hazard ratio 3.16) and a 16-year loss in life expectancy made early diabetic kidney disease a serious and yet often overlooked disease, with most patients unaware of their kidney involvement. Mortality for early diabetic kidney disease was nearly twice as high as that for early CKD (hazard ratio 2.01) or diabetes without CKD (hazard ratio 1.79). The 16-year life span loss is much worse than individually from early CKD (six years) or diabetes (ten years). Thus, identifying early proteinuria among diabetic patients and realizing the importance of reducing lifestyle risks like inactivity is a clinical challenge, but can save lives., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Previous studies have reported inconsistent results of the associations of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) with incident type 2 diabetes (diabetes hereafter). We aimed to resolve the controversy by taking nonalcoholic fatty liver disease (NAFLD) into account. The study population comprised 132,377 non-diabetic individuals (64,875 men and 67,502 women) aged 35-79 who had two or more health examinations during 1996-2014. A total of 6,555 incident diabetes (3,734 men and 2,821 women) were identified, on average, over 5.8 years of follow-up. Cox regression was used to calculate the hazard ratio (HR) for incident diabetes, adjusting for classical confounders. The risk of incident diabetes was significantly associated with NAFLD [HR = 2.08 (men) and 2.65 (women)]. Elevated ALT, AST, GGT and ALP were also significantly associated with the increased risk of diabetes, with HRs of 1.27, 1.23, 1.58 and 1.37, respectively, in men, and 1.56, 1.18, 1.48 and 1.44, respectively in women. Our results suggest that NAFLD, ALT, AST, GGT and ALP are independent predictors for incident diabetes in both men and women.

Background/aims: Transfusion dependent subjects are at a great risk of viral hepatitis infection. We aimed to evaluate the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among transfusion-dependent patients in Taiwan., Methods: A total of 140 patients (67 thalassemic patients, 70 hemophilic patients, two patients with hereditary spherocytosis and one patient with von Willebrand disease) were prospectively enrolled to evaluate the prevalence and factors associated with viral hepatitis and spontaneous HCV clearance. All patients were tested for HBV and HCV serology and virology. Two consecutive serum samples, at least 1 year apart, were collected to clarify HCV seroclearance., Results: The seropositivity rate of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and both HBsAg/anti-HCV were 6.4%, 45.7% and 5%, respectively. Logistic regression analysis of factors associated with anti-HCV seropositivity included age (odds ratio/95% confidence interval [OR/CI]: 1.12/1.07-1.18, P<0.001), serum alanine aminotransferase (ALT) (OR/CI: 1.04/1.02-1.06, P<0.001) and platelet counts (OR/CI: 0.995/0.991-0.998, P = 0.002). Age was the only factor independently associated with HBsAg seropositivity (OR/CI: 1.08/1.02-1.14.4, P = 0.007). Compared to patients born before 1992, the seroprevalence of HCV among thalassemic patients decreased dramatically in those born after 1992 (46.0% vs. 11.8%, p = 0.012). The seroprevalence of HCV among hemophilic patients also decreased significantly when comparing patients born before 1987 to those born after 1987 (79.5% vs. 11.5%, p<0.001). Similarly, the seroprevalence of HBV decreased significantly in the post-vaccination cohort compared to its counterpart (13.1%, vs. 1.3%, p = 0.005). The spontaneous clearance of HCV was observed in 25.4% (15/59) of patients, and ALT was the only factor associated with it (OR/CI 0.98/0.96-1.00, P = 0.02)., Conclusions: Both HBV and HCV infections are prevalent among transfusion-dependent thalassemic and hemophilic patients in Taiwan. Nevertheless, seroprevalence decreased significantly and dramatically for HCV after universal blood screening and for HBV after implementation of a universal mass vaccination program.

Yeast silent heterochromatin provides an excellent model with which to study epigenetic inheritance. Previously we developed an in vitro assembly system to demonstrate the formation of filament structures with requirements that mirror yeast epigenetic gene silencing in vivo. However, the properties of these filaments were not investigated in detail. Here we show that the assembly system requires Sir2, Sir3, Sir4, nucleosomes, and O-acetyl-ADP-ribose. We also demonstrate that all Sir proteins and nucleosomes are components of these filaments to prove that they are SIR-nucleosome filaments. Furthermore, we show that the individual localization patterns of Sir proteins on the SIR-nucleosome filament reflect those patterns on telomeres in vivo. In addition, we reveal that magnesium exists in the SIR-nucleosome filament, with a role similar to that for chromatin condensation. These results suggest that a small number of proteins and molecules are sufficient to mediate the formation of a minimal yeast silent pre-heterochromatin in vitro., (© 2017 Tung et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

The goal of this paper is to analyse the effect of adding Al on the non-steady pearlite growth occurring in a Fe-C-Mn system. The results are discussed in terms of the partitioning of elements across the austenite/ferrite and austenite/cementite interfaces, and the modification of the pearlite driving force related to the change in carbon activity in austenite.

Hemophilic arthropathy is the most common chronic complication in patients with hemophilia. The pathogenesis of hemophilic arthropathy involves the inflammatory processes associated with rheumatoid arthritis (RA). Determining the severity and/or progression of joint damage is crucial when evaluating the effect of treatment modalities. Identifying reliable biomarkers in the peripheral blood of patients with hemophilic arthropathy may be beneficial in clinical practice. Circulating soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin, and P-selectin levels are elevated in patients with RA. Our study investigated whether these soluble adhesion molecules can be used as biological indicators in the course of joint damage in patients with hemophilia A.Patients with hemophilia A (mild, moderate, and severe) were enrolled. The plasma levels of sVCAM-1, E-selectin, and P-selectin in patients with hemophilia A and control were measured using specific enzyme-linked immunosorbent assay kits. Joint damages were evaluated using Pettersson scores.No statistically significant differences were observed in E-selectin and P-selectin levels between patients and controls. The sVCAM-1 level was significantly higher in patients with hemophilia A than in controls. The differences remained significant in patients with severe hemophilia A but not in patients with mild or moderate hemophilia A. The degree of hemophilic arthropathy was evaluated using Pettersson scores, and a score higher than 5 indicated marked arthropathy. Patients with more than 1 joint with marked arthropathy showed significantly higher sVCAM-1 levels.sVCAM-1 levels in patients with hemophilia A are associated with the severity of hemophilic arthropathy., Competing Interests: The authors have no conflicts of interest to disclose.

Widowhood has been increasingly encountered because of increasing longevity of women, often characterized by social stigmatization and poor physical and mental health. However, applied research to overcome its adversity has been quite limited. The goal of this study is to explore the role of physical activity in improving the health of widows.A cohort of 446,582 adults in Taiwan who successively participated in a comprehensive medical screening program starting in 1994, including 232,788 women, was followed up for mortality until 2008. Each individual provided detailed health history, and extensive lab tests results.The number of widows increased with time trend. Every other woman above age 65 was a widow (44%). Widows were less active, more obese, and smoked and drank more, had sleep problems, were more depressed with taking sedatives or psychoactive drugs, leading to more suicides. In the global development of health policies by World Health Organization (WHO), physical activity is one of the main factors to reverse poor health. The poor health of inactive widow was mitigated when becoming fully active in this study. Exercise not only reduced the observed 18% increase in all-cause mortality, but also gained 4 years and as much as 14% mortality advantage over the married but inactive. More importantly, becoming physically active energized their mental status, improved sleep quality and quantity, reduced depressions and the need for psychoactive drugs, and increased socialization circles.Widows, a rapidly growing and socially stigmatized group, suffered from social and financial inequality and tended to develop poorer health. Sustained physical activity could be one of the ways for them to overcome and reverse some of the physical and mental adversities of widowhood, and improve their quality and quantity of life.

Purpose: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody., Experimental Design: The F(ab')2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab')2) was generated and assessed in efficacy and toxicity studies., Results: Anti-DLL4 F(ab')2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab')2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition., Conclusions: PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab')2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans., (©2015 American Association for Cancer Research.)

Purpose: Antibody-drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium-phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies., Experimental Design: The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non-small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys., Results: We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression., Conclusions: Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments., (©2015 American Association for Cancer Research.)

Objective: To estimate the impact of trends in smoking and obesity prevalence on productivity loss among petrochemical employees from 1980 to 2009., Methods: Smoking and obesity informations were collected during company physical examinations. Productivity loss was calculated as differential workdays lost between smokers and non-smokers, and obese and normal-weight employees., Results: During 1980-2009, smoking prevalence decreased from 32% to 17%, while obesity prevalence increased from 14% to 42%. In 1982, lost productivity from obesity was an estimated 43 days/100 employees, and for smoking, 65 days/100 employees, but by 1987, workdays lost due to obesity exceeded that attributable to smoking. In 2007, workdays lost from obesity were 3.7 times higher than for smoking., Conclusions: Owing to the increasing trend in obesity, the productivity impact on employers from obesity will continue to rise without effective measures supporting employee efforts to achieve healthy weight through sustainable lifestyle changes.

Hemophilia B (HB) is an X-linked recessive disorder characterized by mutations in the clotting factor IX (FIX) gene that result in FIX deficiency. Previous studies have shown a wide variation of FIX gene mutations in HB. Although the quality of life in HB has greatly improved mainly because of prophylactic replacement therapy with FIX concentrates, there exists a significant burden on affected families and the medical care system. Accurate detection of FIX gene mutations is critical for genetic counseling and disease prevention in HB. In this study, we used denaturing high-performance liquid chromatography (DHPLC), which has proved to be a highly informative and practical means of detecting mutations, for the molecular diagnosis of our patients with HB. Ten Taiwanese families affected by HB were enrolled. We used the DHPLC technique followed by direct sequencing of suspected segments to detect FIX gene mutations. In all, 11 FIX gene mutations (8 point mutations, 2 small deletions/insertions, and 1 large deletion), including two novel mutations (exon6 c.687-695, del 9 mer and c.460-461, ins T) were found. According to the HB pedigrees, 25% and 75% of our patients were defined as familial and sporadic HB cases, respectively. We show that DHPLC is a highly sensitive and cost-effective method for FIX gene analysis and can be used as a convenient system for disease prevention., (Copyright © 2013. Published by Elsevier B.V.)

Delta-like-4 ligand (DLL4) plays an important role in vascular development and is widely expressed on the vasculature of normal and tumor tissues. Anti-DLL4 is a humanized IgG1 monoclonal antibody against DLL4. The purpose of these studies was to characterize the pharmacokinetics (PK), tissue distribution, and anti-tumor efficacy of anti-DLL4 in mice over a range of doses. PK and tissue distribution of anti-DLL4 were determined in athymic nude mice after administration of single intravenous (IV) doses. In the tissue distribution study, radiolabeled anti-DLL4 (mixture of (125)Iodide and (111)Indium) was administered in the presence of increasing amounts of unlabeled anti-DLL4. Dose ranging anti-DLL4 anti-tumor efficacy was evaluated in athymic nude mice bearing MV522 human lung tumor xenografts. Anti-DLL4 had nonlinear PK in mice with rapid serum clearance at low doses and slower clearance at higher doses suggesting the involvement of target mediated clearance. Consistent with the PK data, anti-DLL4 was shown to specifically distribute to several normal tissues known to express DLL4 including the lung and liver. Maximal efficacy in the xenograft model was seen at doses ≥ 10 mg/kg when tissue sinks were presumably saturated, consistent with the PK and tissue distribution profiles. These findings highlight the importance of mechanistic understanding of antibody disposition to enable dosing strategies for maximizing efficacy.

Protein tyrosine phosphatases (PTPs) are a group of tightly regulated enzymes that coordinate with protein tyrosine kinases to control protein phosphorylation during various cellular processes. Using genetic analysis in Drosophila non-transmembrane PTPs, we identified one role that Myopic (Mop), the Drosophila homolog of the human His domain phosphotyrosine phosphatase (HDPTP), plays in cell adhesion. Depletion of Mop results in aberrant integrin distribution and border cell dissociation during Drosophila oogenesis. Interestingly, Mop phosphatase activity is not required for its role in maintaining border cell cluster integrity. We further identified Rab4 GTPase as a Mop interactor in a yeast two-hybrid screen. Expression of the Rab4 dominant-negative mutant leads to border cell dissociation and suppression of Mop-induced wing-blade adhesion defects, suggesting a critical role of Rab4 in Mop-mediated signaling. In mammals, it has been shown that Rab4-dependent recycling of integrins is necessary for cell adhesion and migration. We found that human HDPTP regulates the spatial distribution of Rab4 and integrin trafficking. Depletion of HDPTP resulted in actin reorganization and increased cell motility. Together, our findings suggest an evolutionarily conserved function of HDPTP-Rab4 in the regulation of endocytic trafficking, cell adhesion and migration.

Homologous recombination (HR) represents a major error-free pathway to eliminate pre-carcinogenic chromosomal lesions. The DNA strand invasion reaction in HR is mediated by a helical filament of the Rad51 recombinase assembled on single-stranded DNA that is derived from the nucleolytic processing of the primary lesion. Recent studies have found that the human and mouse Swi5 and Sfr1 proteins form a complex that influences Rad51-mediated HR in cells. Here, we provide biophysical evidence that the mouse Swi5-Sfr1 complex has a 1:1 stoichiometry. Importantly, the Swi5-Sfr1 complex, but neither Swi5 nor Sfr1 alone, physically interacts with Rad51 and stimulates Rad51-mediated homologous DNA pairing. This stimulatory effect stems from the stabilization of the Rad51-ssDNA presynaptic filament. Moreover, we provide evidence that the RSfp (rodent Sfr1 proline rich) motif in Sfr1 serves as a negative regulatory element. These results thus reveal an evolutionarily conserved function in the Swi5-Sfr1 complex and furnish valuable information as to the regulatory role of the RSfp motif that is specific to the mammalian Sfr1 orthologs.

Antibodies against epidermal growth factor receptor (EGFR)--cetuximab and panitumumab--are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

Nanocavity resonators in metals acting as nanofluidic refractive-index sensors were analyzed theoretically. With the illumination of transverse electric polarized light, the proposed refractive index sensor structure acts as a pure electromagnetic resonator without the excitation of surface plasmons. The reflected signal from the nanocavity resonators can be very sensitive to the refractive index of the fluids inside the nanocavities due to the enhancement of the electric field of the resonant mode inside the cavities. Such a sensor configuration can be a useful tool for probing the refractive index change of the fluid inside the nanocavities using the spectral, angular or intensity interrogation schemes. The wavelength sensitivity of 430 nm/RIU, angular sensitivity of 200-1,000 deg/RIU and intensity sensitivity of 25.5 RIU(-1) can be achieved in the proposed sensor configuration.

Objectives: This cohort study is to assess the extent of cancer risks of betel quid chewing (without tobacco added) beyond oral cancer, as such information was limited from case-control studies., Methods: The cohort, selected from participants in a medical screening program since 1994, consisted of 177,271 adult men with 19.2% chewers of betel quid. As of 2006, out of 4,840 deaths, 1,901 cancer deaths were identified. Mortality hazard ratios (HR) were estimated by Cox proportional hazard model. Life expectancy was calculated by life table method., Results: One-third of smokers chewed (33%) but most of chewers smoked (90%). Risk for all cancer doubled among chewers (HR = 2.00). Risks of at least six cancer sites were increased among chewers: oral cavity (HR = 12.52), esophagus (HR = 5.64), liver (HR = 2.27), pancreas (HR = 2.67), larynx (HR = 6.24), and lung (HR = 2.43) with risks increased with increasing betel quid amount consumed. All-cancer age-adjusted mortality rates in Taiwan increased 25%, including 223% increase in oral cancer, during the last 20 years when chewing rate increased five- to tenfolds. Chewing on top of smoking increased the risks synergistically, and these two were responsible for at least half (50%) of all cancer deaths among 2 million chewers in Taiwan. Life expectancy of chewers was shorter than non-chewers by 5.93 years at age 20 and 5.55 years at age 40., Conclusion: In addition to oral cancer, significant increases were seen among chewers for cancer of the esophagus, liver, pancreas, larynx, lung, and all cancer. Chewing and smoking, as combined by most chewers, interacted synergistically and was responsible for half of all cancer deaths in this group. They were responsible for the recent increases in oral, esophageal, pancreatic, and liver cancer in Taiwan. Chewing and smoking shortened their life span by nearly 6 years.

Background: Smoking is known to aggravate tuberculosis (TB), but such information has been ignored in clinical practice, as it was not thought to be relevant. The aim of this study is to assess the benefits of smoking cessation on TB mortality reduction., Methods: The study attempts to quantify smokers' risks on subsequent TB mortality and the change in such risks after smokers quit smoking. In this prospective cohort study, the TB mortality risks of smokers, never smokers and former smokers were compared, by using the Cox proportional model to estimate the hazard ratio (HR) of TB.The cohort, consisting of 486,341 adults, participated in standard medical screening programs since 1994, including 5,036 with self-reported TB history. Of 15,268 deaths identified as of 2007, 77 were coded as TB., Results: Smokers with self-reported TB history (1.2%) had very high TB mortality (HR = 44.02). Among those without self-reported TB history, smoking increased TB mortality by nine-fold (HR = 8.56), but when they quit smoking, the risk was reduced by more than half (65%), to a level not different from those who had never smoked. The overwhelming majority of TB deaths (83%) occurred among those without self-reported TB history. Given the high smoking prevalence and the high HR, smoking accounted for more than one-third (37.7%) of TB mortality in Taiwan. Smokers reported less TB history but died more from TB than those who had never smoked., Conclusions: Smokers had very high TB mortality, as much as nine times those who had never smoked, but once they quit, the risk reduced substantially and was similar to those who never smoked. Smoking cessation has benefits to the smokers far beyond reducing TB risk, but successful tobacco control could favorably impact the TB mortality rate and reduce this public health burden, which has long haunted the Taiwanese population. Smoking cessation could reduce nearly one-third of tuberculosis deaths.

Objectives: To assess whether overweight Asians, assessed on the basis of WHO criteria, are at greater mortality risk than overweight Caucasians, and to determine whether alternative cut-off points (BMI = 23.0-24.9 kg/m2 for overweight and BMI >or= 25.0 kg/m2 for obesity) suggested by the WHO Western Pacific Regional Office are appropriate., Design: The cohort was followed prospectively until the end of 2001. All-cause and CVD mortality risks of the overweight and obese group, relative to the reference group (BMI = 18.5-24.9 or 18.5-22.9 kg/m2), were assessed using Cox regression analysis, adjusting for age, smoking and gender. Excess deaths were estimated with a method proposed by the US Centers for Disease Control and Prevention., Setting: National Health Interview Survey (NHIS 2001) and a middle-aged perspective cohort in Taiwan., Subjects: Subjects comprised 36 386 civil servants and school teachers, aged 40 years and older, who underwent a medical examination during 1989-1992., Results: In the WHO-defined overweight group, Asians showed a significant increase in all-cause mortality risk compared with Caucasians. Asians showed risks equivalent to Caucasians' at lower BMI (around 5 units). Every unit of BMI increase, at 25.0 kg/m2 or above, was associated with a 9 % increase in relative mortality risk from all causes. Applying a cut-off point of 25.0 kg/m2 for obesity would result a prevalence of 27.1 %, while the traditional WHO cut-off point of 30.0 kg/m2 yielded obesity prevalence of 4.1 %. Excess deaths due to obesity accounted for 8.6 % of all deaths and 21.1 % of CVD deaths, based on the alternative cut-offs., Conclusions: In this Asian population, significant mortality risks started at BMI >or= 25.0 kg/m2, rather than at BMI >or= 30.0 kg/m2. The study supports the use of BMI >or= 25.0 kg/m2 as a new cut-off point for obesity and BMI = 23.0-24.9 kg/m2 for overweight. The magnitude of obesity-attributable deaths has been hitherto under-appreciated among Asians.

The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through IGF-I receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-II binding and by inducing cell surface receptor down-regulation via internalization and degradation, with the extracellular and intracellular domains of IGF-IR being differentially affected by the proteasomal and lysosomal inhibitors. In vitro, h10H5 exhibits antiproliferative effects on cancer cell lines. In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti-vascular endothelial growth factor antibody. Antitumor activity of h10H5 is associated with decreased AKT activation and glucose uptake and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors and furthermore illustrate a new method of monitoring its activity noninvasively in vivo via 2-fluoro-2-deoxy-d-glucose-positron emission tomography imaging.

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.

BR3, which is expressed on all mature B cells, is a specific receptor for the B-cell survival and maturation factor BAFF (B-cell-activating factor belonging to the tumor necrosis factor [TNF] family). In order to investigate the consequences of targeting BR3 in murine models and to assess the potential of BR3 antibodies as human therapeutics, synthetic antibody phage libraries were employed to identify BAFF-blocking antibodies cross-reactive to murine and human BR3, which share 52% identity in their extracellular domains. We found an antibody, CB1, which exhibits muM affinity for murine BR3 and very weak affinity for the human receptor. CB3s, an affinity-matured variant of CB1, has sub-nM affinity for BR3 from both species. Alanine scanning and crystallographic structural analysis of the CB3s/BR3 complex reveal that CB3s mimics BAFF by interacting with a similar region of the BR3 surface. Despite this similarity in binding epitopes, CB1 variants antagonize BAFF-dependent human B-cell proliferation in vitro and are effective at reducing murine B-cell populations in vivo, showing significant promise as therapeutics for human B-cell-mediated diseases.

Objectives: To assess the magnitude of cigarette smuggling after the market opened in Taiwan., Methods: Review of tobacco industry documents for references to smuggling activities related to Taiwan and government statistics on seizure of smuggled cigarettes., Results: The market opening in 1987 led to an increase in smuggling. Contraband cigarettes became as available as legal ones, with only a small fraction (8%) being seized. Being specifically excluded from the market-opening, Japan entered the Taiwan market by setting up a Swiss plant as a legal cover for smuggling 10-20 times its legal quota of exports to Taiwan. Smuggling in Taiwan contributed to increased consumption of foreign brands, particularly by the young. Taiwan, not a member of the World Health Organization, was excluded from the East Asian 16-member "Project Crocodile", a regional anti-smuggling collaborative effort to implement the Framework Convention on Tobacco Control., Conclusions: Taiwan showed a sharp increase in smuggling after market liberalisation. Being excluded from the international community, Taiwan faces an uphill battle to fight smuggling alone. If Taiwan remained as its weakest link, global efforts to reduce tobacco use will be undermined, particularly for countries in the East Asian region.

Objective: The objective of this article was to assess mortality risks at different levels of fasting blood glucose (FBG) in Taiwan, with particular attention to those pre-diabetic subjects with impaired fasting glucose (IFG)., Research Design and Methods: Governmental employees and schoolteachers were followed up for an average of 11 years. With the use of Cox regression analyses, mortality risks were calculated for 36,386 subjects, aged 40-69., Results: FBG > or =110 mg/dl was associated with increased mortality risks for all causes, cardiovascular diseases (CVD), and diabetes. IFG, when defined as 110-125 mg/dl, was associated with a significant increase for CVD and/or diabetes mortality. These mortality risks remained elevated when known CVD risk factors were adjusted for. The IFG group shared risk factor characteristics more with the FBG > or =126 mg/dl group than with the FBG <110 mg/dl group. When IFG was defined as 100-125 mg/dl, the number of subjects quadrupled, but mortality risks diminished substantially because of the inclusion of 100-109 mg/dl group. The lowest FBG group, 50-75 mg/dl, had a significant 2-fold risk from all causes., Conclusions: There was an overall J-shaped relationship between all-cause mortality and FBG. IFG, when defined as 110-125 mg/dl, is an independent risk factor and should be aggressively treated as a disease because its subsequent mortality risks for CVD and diabetes were significantly increased. The newly defined IFG at 100-125 mg/dl did not have the predictive power for later increases in CVD or diabetes mortality.