The largest genome-wide association study for breast cancer in Taiwanese Han population.

PURPOSE: Breast cancer is a molecularly heterogeneous disease, and multiple genetic variants contribute to its development and prognosis. Most of previous genome-wide association studies (GWASs) and polygenic risk scores (PRSs) analyses focused on studying breast cancers of Caucasian populations, which may not be applicable to other population. Therefore, we conducted the largest breast cancer cohort of Taiwanese population to fill in the knowledge gap. METHODS: A total of 152,534 Participants recruited by China Medical University Hospital between 2003 and 2019 were filtered by several patient selection criteria and GWAS quality control steps, resulting in the inclusion of 2496 cases and 9984 controls for this study. We then conducted GWAS for all breast cancers and PRS analyses for all breast cancers and the four breast cancer subtypes, including luminal A, luminal B, basal-like, and HER2-enriched. RESULTS: The GWAS analyses identified 113 SNPs, 50 of which were novel. The PRS models for all breast cancers and the luminal A subtype showed positively correlated trends between the PRS and the risk of developing breast cancer. The odds ratios (95% confidence intervals) for the groups with the highest PRS in all breast cancers and the luminal A subtype were 5.33 (3.79-7.66) and 3.55 (2.13-6.14), respectively. CONCLUSION: In summary, we explored the association of genetic variants with breast cancer in the largest Taiwanese cohort and developed two PRS models that can predict the risk of developing any breast cancer and the luminal A subtype in Taiwanese women.

Galectin-3 promotes noncanonical inflammasome activation through intracellular binding to lipopolysaccharide glycans.

Cytosolic lipopolysaccharides (LPSs) bind directly to caspase-4/5/11 through their lipid A moiety, inducing inflammatory caspase oligomerization and activation, which is identified as the noncanonical inflammasome pathway. Galectins, ß-galactoside-binding proteins, bind to various gram-negative bacterial LPS, which display ß-galactoside-containing polysaccharide chains. Galectins are mainly present intracellularly, but their interactions with cytosolic microbial glycans have not been investigated. We report that in cell-free systems, galectin-3 augments the LPS-induced assembly of caspase-4/11 oligomers, leading to increased caspase-4/11 activation. Its carboxyl-terminal carbohydrate-recognition domain is essential for this effect, and its N-terminal domain, which contributes to the self-association property of the protein, is also critical, suggesting that this promoting effect is dependent on the functional multivalency of galectin-3. Moreover, galectin-3 enhances intracellular LPS-induced caspase-4/11 oligomerization and activation, as well as gasdermin D cleavage in human embryonic kidney (HEK) 293T cells, and it additionally promotes interleukin-1ß production and pyroptotic death in macrophages. Galectin-3 also promotes caspase-11 activation and gasdermin D cleavage in macrophages treated with outer membrane vesicles, which are known to be taken up by cells and release LPSs into the cytosol. Coimmunoprecipitation confirmed that galectin-3 associates with caspase-11 after intracellular delivery of LPSs. Immunofluorescence staining revealed colocalization of LPSs, galectin-3, and caspase-11 independent of host N-glycans. Thus, we conclude that galectin-3 amplifies caspase-4/11 oligomerization and activation through LPS glycan binding, resulting in more intense pyroptosis-a critical mechanism of host resistance against bacterial infection that may provide opportunities for new therapeutic interventions.

Sialylation of cell surface glycoconjugates modulates cytosolic galectin-mediated responses upon organelle damage : Minireview.

Sialylation is an important terminal modification of glycoconjugates that mediate diverse functions in physiology and disease. In this review we focus on how altered cell surface sialylation status is sensed by cytosolic galectins when the integrity of intracellular vesicles or organelles is compromised to expose luminal glycans to the cytosolic milieu, and how this impacts galectin-mediated cellular responses. In addition, we discuss the roles of mammalian sialidases on the cell surface, in the organelle lumen and cytosol, and raise the possibility that intracellular glycan processing may be critical in controlling various galectin-mediated responses when cells encounter stress.

Targeted disruption of galectin 3 in mice delays the first wave of spermatogenesis and increases germ cell apoptosis.

Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3-/-) exhibited significantly decreased testicular weight in adulthood compared to controls. The transgenic mice also exhibited a delay to the first wave of spermatogenesis, a decrease in the number of germ cells at postnatal day 5 (P5) and P15, and defective Sertoli cell maturation. Mechanistically, we found that Insulin-like-3 (a Leydig cell marker) and enzymes involved in steroid biosynthesis were significantly upregulated in adult Lgals3-/- testes. These observations were accompanied by increased serum testosterone levels. To determine the underlying causes of the testicular atrophy, we monitored cellular apoptosis. Indeed, adult Lgals3-/- testicular cells exhibited an elevated apoptosis rate that is likely driven by downregulated Bcl-2 and upregulated Bax and Bak expression, molecules responsible for live/death cell balance. Moreover, the percentage of testicular macrophages within CD45+ cells was decreased in Lgals3-/- mice. These data suggest that galectin 3 regulates spermatogenesis initiation and Sertoli cell maturation in part, by preventing germ cells from undergoing apoptosis and regulating testosterone biosynthesis. Going forward, understanding the role of galectin 3 in testicular physiology will add important insights into the factors governing the development of germ cells and steroidogenesis and delineate novel biomarkers of testicular function.

Association of water intake and hydration status with risk of kidney stone formation based on NHANES 2009-2012 cycles.

OBJECTIVE: Evaluating the association of water intake and hydration status with nephrolithiasis risk at the population level. DESIGN: It is a cross-sectional study in which daily total plain water intake and total fluid intake were estimated together with blood osmolality, urine creatinine, urine osmolality, urine flow rate (UFR), free water clearance (FWC) and urine/blood osmolality ratio (Uosm:Bosm). The associations of fluid intake and hydration markers with nephrolithiasis were evaluated using multivariable logistic regression. SETTING: General US population. PARTICIPANTS: A total of 8195 adults aged 20 years or older from the National Health and Nutritional Examination Survey 2009-2012 cycles. RESULTS: The population medians (interquartile ranges, IQR) for daily total plain water intake and total fluid intake were 807 (336-1481) and 2761 (2107-3577) ml/d, respectively. The adjusted OR (95 % CI) of nephrolithiasis for each IQR increase in total plain water intake and total fluid intake were 0·92 (95 % CI 0·79, 1·06) and 0·84 (95 % CI 0·72, 0·97), respectively. The corresponding OR of nephrolithiasis for UFR, blood osmolality, Uosm:Bosm and urine creatinine were 0·87 (95 % CI 0·76, 0·99), 1·18 (95 % CI 1·06, 1·32), 1·38 (95 % CI 1·17, 1·63) and 1·27 (95 % CI 1·11, 1·45), respectively. A linear protective relationship of fluid intake, UFR and FWC with nephrolithiasis risk was observed. Similarly, positive dose-response associations of nephrolithiasis risk with markers of insufficient hydration were identified. Encouraging a daily water intake of >2500 ml/d and maintaining a urine output of 2 l/d was associated with a lower prevalence of nephrolithiasis. CONCLUSION: This study verified the beneficial role of general water intake recommendations in nephrolithiasis prevention in the general US population.

Photoreduction of carbon dioxide and photodegradation of organic pollutants using alkali cobalt oxides MCoO2 (M = Li or Na) as catalysts.

The recycling of lithium batteries should be prioritized, and the use of discarded alkali metal battery electrode materials as photocatalysts merits research attention. This study synthesized alkali metal cobalt oxide (MCoO2, M = Li or Na) as a photocatalyst for the photoreduction of CO2 and degradation of toxic organic substances. The optimized NaCoO2 and LiCoO2 photocatalysts increased the photocatalytic CO2-CH4 conversion rate to 21.0 and 13.4 µmol g-1 h-1 under ultraviolet light irradiation and to 16.2 and 5.3 µmol g-1 h-1 under visible light irradiation, which is 17 times higher than that achieved by TiO2 P25. The rate constants of the optimized reactions of crystal violet (CV) with LiCoO2 and NaCoO2 were 2.29 × 10-2 and 4.35 × 10-2 h-1, respectively. The quenching effect of the scavengers and electron paramagnetic resonance in CV degradation indicated that active O2•-, 1O2, and h+ play the main role, whereas •OH plays a minor role for LiCoO2. The hyperfine splitting of the DMPO-•OH and DMPO-•CH3 adducts was aN = 1.508 mT, aHß = 1.478 mT and aN = 1.558 mT, aHß = 2.267 mT, respectively, whereas the hyperfine splitting of DMPO+• was aN = 1.475 mT. The quenching effect also indicated that active O2•- and h+ play the main role and that •OH and 1O2 play a minor role for NaCoO2. The hyperfine splitting of the DMPO-•OH and DMPO+• adducts was aN = 1.517 mT, aHß = 1.489 mT and aN = 1.496 mT, respectively. Discarded alkali metal battery electrode materials can be reused as photocatalysts to address environmental pollution.

Helminth-Induced Production of TGF-ß and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells.

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-ß and is associated with TGF-ß-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-ß-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-ß secretion, TGF-ß-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-ß. In contrast, TGF-ß is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3- CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-ß generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

STAT6 and Furin Are Successive Triggers for the Production of TGF-ß by T Cells.

Production of TGF-ß by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-ß generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-ß generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-ß propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-ß-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-ß requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-ß production by T cells, our results support a two-step model, composed of STAT6 and furin.

Intracellular galectins control cellular responses commensurate with cell surface carbohydrate composition.

Galectins are ß-galactoside-binding animal lectins primarily found in the cytosol, while their carbohydrate ligands are mainly distributed in the extracellular space. Cytosolic galectins are anticipated to accumulate on damaged endocytic vesicles through binding to glycans initially displayed on the cell surface and subsequently located in the lumen of the vesicles, and this can be followed by cellular responses. To facilitate elucidation of the mechanism underlying this process, we adopted a model system involving induction of endocytic vesicle damage with light that targets the endocytosed amphiphilic photosensitizer disulfonated aluminum phthalocyanine. We demonstrate that the levels of galectins around damaged endosomes are dependent on the composition of carbohydrates recognized by the proteins. By super resolution imaging, galectin-3 and galectin-8 aggregates were found to be distributed in distinct microcompartments. Importantly, galectin accumulation is significantly affected when cell surface glycans are altered. Furthermore, accumulated galectins can direct autophagy adaptor proteins toward damaged endocytic vesicles, which are also significantly affected following alteration of cell surface glycans. We conclude that cytosolic galectins control cellular responses reflect dynamic modifications of cell surface glycans.

Milk-whey diet substantially suppresses seizure-like phenotypes of paraShu, a Drosophila voltage-gated sodium channel mutant.

The Drosophila mutant paraShu harbors a dominant, gain-of-function allele of the voltage-gated sodium channel gene, paralytic (para). The mutant flies display severe seizure-like phenotypes, including neuronal hyperexcitability, spontaneous spasms, ether-induced leg shaking, and heat-induced convulsions. We unexpectedly found that two distinct food recipes used routinely in the Drosophila research community result in a striking difference in severity of the paraShu phenotypes. Namely, when paraShu mutants were raised on the diet originally formulated by Edward Lewis in 1960, they showed severe neurological defects as previously reported. In contrast, when they were raised on the diet developed by Frankel and Brousseau in 1968, these phenotypes were substantially suppressed. Comparison of the effects of these two well-established food recipes revealed that the diet-dependent phenotypic suppression is accounted for by milk whey, which is present only in the latter. Inclusion of milk whey in the diet during larval stages was critical for suppression of the adult paraShu phenotypes, suggesting that this dietary modification affects development of the nervous system. We also found that milk whey has selective effects on other neurological mutants. Among the behavioral phenotypes of different para mutant alleles, those of paraGEFS+ and parabss were suppressed by milk whey, while those of paraDS and parats1 were not significantly affected. Overall, our study demonstrates that different diets routinely used in Drosophila labs could have considerably different effects on neurological phenotypes of Drosophila mutants. This finding provides a solid foundation for further investigation into how dietary modifications affect development and function of the nervous system and, ultimately, how they influence behavior.

Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes.

While glycans are generally displayed on the cell surface or confined within the lumen of organelles, they can become exposed to the cytosolic milieu upon disruption of organelle membrane by various stresses or pathogens. Galectins are a family of ß-galactoside-binding animal lectins synthesized and predominantly localized in the cytosol. Recent research indicates that some galectins may act as "danger signal sensors" by detecting unusual exposure of glycans to the cytosol. Galectin-8 was shown to promote antibacterial autophagy by recognizing host glycans on ruptured vacuolar membranes and interacting with the autophagy adaptor protein NDP52. Galectin-3 also accumulates at damaged phagosomes containing bacteria; however, its functional consequence remains obscure. By studying mouse macrophages infected with Listeria monocytogenes (LM), we showed that endogenous galectin-3 protects intracellular LM by suppressing the autophagic response through a host N-glycan-dependent mechanism. Knock out of the galectin-3 gene resulted in enhanced LC3 recruitment to LM and decreased bacterial replication, a phenotype recapitulated when Galectin-8-deficient macrophages were depleted of N-glycans. Moreover, we explored the concept that alterations in cell surface glycosylation by extracellular factors can be deciphered by cytosolic galectins during the process of phagocytosis/endocytosis, followed by rupture of phagosomal/endosomal membrane. Notably, treatment of cells with sialidase, which removes sialic acid from glycans, resulted in increased galectin-3 accumulation and decreased galectin-8 recruitment at damaged phagosomes, and led to a stronger anti-autophagic response. Our findings demonstrate that cytosolic galectins may sense changes in glycosylation at the cell surface and modulate cellular response through differential recognition of glycans on ruptured phagosomal membranes.

MicroRNA-130a can inhibit hepatitis B virus replication via targeting PGC1α and PPARγ.

In hepatitis B virus (HBV)-replicating hepatocytes, miR-130a expression was significantly reduced. In a reciprocal manner, miR-130a reduced HBV replication by targeting at two major metabolic regulators PGC1α and PPARγ, both of which can potently stimulate HBV replication. We proposed a positive feed-forward loop between HBV, miR-130a, PPARγ, and PGC1α. Accordingly, HBV can significantly enhance viral replication by reducing miR-130a and increasing PGC1α and PPARγ. NF-κB/p65 can strongly stimulate miR-130a promoter, while miR-130a can promote NF-κB/p65 protein level by reducing PPARγ and thus NF-κB/p65 protein degradation. We postulated another positive feed-forward loop between miR-130a and NF-κB/p65 via PPARγ. During liver inflammation, NF-κB signaling could contribute to viral clearance via its positive effect on miR-130a transcription. Conversely, in asymptomatic HBV carriers, persistent viral infection could reduce miR-130a and NF-κB expression, leading to dampened inflammation and immune tolerance. Finally, miR-130a could contribute to metabolic homeostasis by dual targeting PGC1α and PPARγ simultaneously.

Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-ß-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-ß-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-ß-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-ß-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.

Domperidone, cytochrome P450 3A4 isoenzyme inhibitors and ventricular arrhythmia: a nationwide case-crossover study.

BACKGROUND: Recent evidence suggested that oral form of domperidone may possess pro-arrhythmic effects and increase the risk of ventricular arrhythmia. The concomitant use of cytochrome P450 (CYP) 3A4 isoenzyme inhibitors may further potentiate this association. Nevertheless, empirical data supporting these associations are very limited. The aim of this study was to investigate the association between oral domperidone, CYP 3A4 inhibitors, and ventricular arrhythmia. METHODS: We identified 25,356 patients who were admitted or were seen in the emergency room for ventricular arrhythmia between 2000 and 2011 from Taiwan's Longitudinal Health Insurance Database. We adopted a case-crossover study design to compare the exposure to oral domperidone for the same patient within a "case period" and within a "control period". RESULTS: Conditional logistic regression models showed that domperidone use was significantly associated with an increased odds of ventricular arrhythmia (aOR 1.56, 95%CI [1.41-1.72]). The association was stronger with a higher daily dose of domperidone (>30 mg, aOR 1.98, 95%CI [1.50-2.63]). Furthermore, the co-exposure of domperidone and CYP 3A4 inhibitors was significantly associated with an increased odds of ventricular arrhythmia, especially considering the lasting effect of CYP 3A4 inhibitors (1 day apart: aOR 1.91, 95%CI [1.33-2.75], 3 days apart: aOR 1.90, 95%CI [1.33-2.71], 7 days apart: aOR 1.80, 95%CI [1.28-2.54]). CONCLUSIONS: Our results suggested that oral domperidone was significantly associated with an increased odds of ventricular arrhythmia and that the association was stronger with exposure to >30 mg of domperidone. In addition, our study reported increased odds of ventricular arrhythmia among those who concomitantly used domperidone and CYP 3A4 inhibitors.

The role of galectins in the regulation of autophagy and inflammasome in host immunity.

Galectins, a family of glycan-binding proteins have been shown to bind a wide range of glycans. In the cytoplasm, these glycans can be endogenous (or "self"), originating from damaged endocytic vesicles, or exogenous (or "non-self"), found on the surface of invading microbial pathogens. Galectins can detect these unusual cytosolic exposures to glycans and serve as critical regulators in orchestrating immune responses in innate and adaptive immunity. This review provides an overview of how galectins modulate host cellular responses, such as autophagy, xenophagy, and inflammasome-dependent cell death program, to infection.

Galectin-3 aggravates microglial activation and tau transmission in tauopathy.

Alzheimer's disease is characterized by the accumulation of amyloid-ß plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a ß-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.

Dietary Supplementation with Milk Lipids Leads to Suppression of Developmental and Behavioral Phenotypes of Hyperexcitable Drosophila Mutants.

Dietary modifications often have a profound impact on the penetrance and expressivity of neurological phenotypes that are caused by genetic defects. Our previous studies in Drosophila melanogaster revealed that seizure-like phenotypes of gain-of-function voltage-gated sodium (Nav) channel mutants (paraShu, parabss1, and paraGEFS+), as well as other seizure-prone "bang-sensitive" mutants (eas and sda), were drastically suppressed by supplementation of a standard diet with milk whey. In the current study we sought to determine which components of milk whey are responsible for the diet-dependent suppression of their hyperexcitable phenotypes. Our systematic analysis reveals that supplementing the diet with a modest amount of milk lipids (0.26% w/v) mimics the effects of milk whey. We further found that a minor milk lipid component, α-linolenic acid, contributed to the diet-dependent suppression of adult paraShu phenotypes. Given that lipid supplementation during the larval stages effectively suppressed adult paraShu phenotypes, dietary lipids likely modify neural development to compensate for the defects caused by the mutations. Consistent with this notion, lipid feeding fully rescued abnormal dendrite development of class IV sensory neurons in paraShu larvae. Overall, our findings demonstrate that milk lipids are sufficient to ameliorate hyperexcitable phenotypes in Drosophila mutants, providing a foundation for future investigation of the molecular and cellular mechanisms by which dietary lipids modify genetically induced abnormalities in neural development, physiology, and behavior.

Galectin-12 Regulates Immune Responses in the Skin through Sebaceous Glands.

Sebaceous glands (SGs) are holocrine glands that produce sebum, which primarily contains lipids that help to maintain the barrier function of the skin. Dysregulated lipid production contributes to the progression of some diseases characterized by dry skin, including atopic dermatitis. Although the lipid production of SGs has been well-studied, few studies have assessed their role in skin immune responses. We found that SGs and sebocytes expressed IL-4 receptor and produced high levels of T helper 2-associated inflammatory mediators after IL-4 treatment, suggesting immunomodulatory effects. Galectin-12 is a lipogenic factor expressed in sebocytes that affects their differentiation and proliferation. Using galectin-12-knockdown sebocytes, we showed that galectin-12 regulated the immune response in cells exposed to IL-4 and promoted CCL26 expression by upregulating peroxisome proliferator-activated receptor-γ. Moreover, galectin-12 suppressed the expression of endoplasmic reticulum stress-response molecules, and CCL26 upregulation by IL-4 was reversed after sebocyte treatment with inducers of endoplasmic reticulum stress, suggesting that galectin-12 controls IL-4 signaling by suppressing endoplasmic reticulum stress. Using galectin-12-knockout mice, we showed that galectin-12 positively regulated the IL-4-induced enlargement of SGs and the development of an atopic dermatitis-like phenotype. Thus, galectin-12 regulates the skin immune response by promoting peroxisome proliferator-activated receptor-γ expression and suppressing endoplasmic reticulum stress in SGs.

Age-specific percentile-based prostate-specific antigen cutoff values predict the risk of prostate cancer: A single hospital observation.

Background: Testing for prostate-specific antigen (PSA) is often recommended for men with a potential risk of prostate cancer (PCa) before requiring advanced examination. However, the best PSA cutoff value remains controversial. Object: We compared the predictive performance of age-specific percentile-based PSA thresholds with a conventional cutoff of >4 ng/mL for the risk of PCa. Methods: We included men who received PSA measurements between 2003 and 2017 in a medical center in Taiwan. Logistic regression modeling was used to assess the association between age-specific percentile-based PSA thresholds and PCa risk in age subgroups. We further applied C-statistic and decision curve analysis to compare the predictive performance of age-specific percentile-based PSA with that of a conventional cutoff PSA. Results: We identified 626 patients with PCa and 40 836 patients without PCa. The slope of PSA in patients >60-year-old was almost 3 times that of those <60-year-old (0.713 vs 0.259). The risk effect sizes of the 75th percentile PSA cutoff (<60-year-old: 2.19; 60-70-year-old: 4.36; >70-year-old: 5.84 ng/mL) were comparable to those observed based on the conventional cutoff in all age groups. However, the discrimination performance of the 75th percentile PSA cutoff was better than that of the conventional cutoff among patients aged <60-year-old (C-statistic, 0.783 vs. 0.729, p < 0.05). The 75th percentile cutoffs also correctly identified an additional 2 patients with PCa for every 100 patients with PSA screening at the threshold probability of 20%. Conclusions: Our data support the use of the 75th percentile PSA cutoff to facilitate individualized risk assessment, particularly for patients aged <60-year-old.

Association between coronary artery calcium and all-cause mortality: A large single-center retrospective cohort study.

OBJECTIVE: Previous studies have revealed that coronary artery calcium is related to cardiovascular diseases and mortality. However, most studies have been conducted in Western countries and have excluded patients with pre-existing heart disease. We investigated the association between coronary artery calcium (CAC) and all-cause mortality in an Asian cohort and in subgroups stratified by age, sex, smoking, obesity, diabetes, cardiovascular disease, blood pressure, and biochemical parameters. METHODS: We conducted a retrospective cohort study on 4529 health examinees who underwent multidetector computed tomography in a tertiary medical center in Taiwan between 2011 and 2016. The mean follow-up was 3.5 years. Cox regression was used to estimate the relative hazards of death. Stratified analyses were performed. RESULTS: The all-cause mortality rates were 2.94, 4.88, 17.6, and 33.1 per 1000 person-years for CAC scores of 0, 1-100, 101-400, and >400, respectively. The multivariable adjusted hazard ratios (95% confidence intervals [CIs]) for all-cause mortality were 0.95 (0.53, 1.72), 1.87 (0.89, 3.90), and 3.05 (1.46, 6.39) for CAC scores of 1-100, 101-400, and >400, respectively, relative to a CAC score of 0. Compared with CAC ≤ 400, the HRs (95% CIs) for CAC > 400 were 6.46 (2.44, 17.15) and 1.94 (1.00, 3.76) in younger and older adults, respectively, indicating that age was a moderating variable (p = 0.02). CONCLUSION: High CAC scores were associated with increased all-cause mortality. Although older adult patients had higher risks of death, the relative risk of death for patients with CAC > 400 was more prominent in people younger than 65 years.