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  • 1
    Online Resource
    Online Resource
    The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 14 ( 2022-07-14), p. 3435-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 14 ( 2022-07-14), p. 3435-
    Abstract: Patients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little is known about their molecular basis. To explore further, we used whole exome sequencing to explore the genetic changes in the granulocytes of 26 paired MPN patients with or without SC. We noticed that MPN–SC patients harbor genomic variants of distinct genes, among which a unique pattern of co-occurrence or mutual exclusiveness could be identified. We also found that mutated genes in MPN–SC samples were enriched in immune-related pathways and inflammatory networks, an observation further supported by their increased plasma levels of TGF-β and IL-23. Noteworthily, variants of KRT6A, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN–SC patients. Analysis through OncodriveCLUST disclosed that KRT6A replaces JAK2V617F as the more prominent disease driver in MPN–SC, whereas a major mutation in this gene (KRT6A c.745T 〉 C) in our patients is linked to human carcinoma and predicted to be pathogenic in COSMIC database. Overall, we demonstrate that inflammation could be indispensable in MPN–SC pathogenesis.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14143435
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Mutation-Driven S100A8 Overexpression Confers Aberrant Phenotypes in Type 1 CALR-Mutated MPN
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 10 ( 2023-05-14), p. 8747-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 10 ( 2023-05-14), p. 8747-
    Abstract: Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24108747
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    RAS Mediates BET Inhibitor-Endued Repression of Lymphoma Migration and Prognosticates a Novel Proteomics-Based Subgroup of DLBCL through Its Negative Regulator IQGAP3
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 19 ( 2021-10-07), p. 5024-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 19 ( 2021-10-07), p. 5024-
    Abstract: Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL migration. To explore further, we dissected the impacts of BET inhibition in DLBCL. We found that JQ1 abrogated amoeboid movement of DLBCL cells through both restraining RAS signaling and suppressing MYC-mediated RhoA activity. We also demonstrated that BET inhibition resulted in the upregulation of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3). IQGAP3 similarly exhibited an inhibitory effect on RAS activity in DLBCL cells. Through barcoded mRNA/protein profiling in clinical samples, we identified a specific subgroup of DLBCL tumors with enhanced phosphatidylinositol-3-kinase (PI3K) activity, which led to an inferior survival in these patients. Strikingly, a lower IQGAP3 expression level further portended those with PI3K-activated DLBCL a very dismal outcome. The inhibition of BET and PI3K signaling activity led to effective suppression of DLBCL dissemination in vivo. Our study provides an important insight into the ongoing efforts of targeting BET proteins as a therapeutic approach for DLBCL.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13195024
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 4
    Online Resource
    Online Resource
    Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 3 ( 2020-03-23), p. 755-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 3 ( 2020-03-23), p. 755-
    Abstract: Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93–28.32, p 〈 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12030755
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 5
    Online Resource
    Online Resource
    A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 3 ( 2023-02-03), p. 3021-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 3 ( 2023-02-03), p. 3021-
    Abstract: While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger’s hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10−7–7.31 × 10−6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10−7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10−6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D’ = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24033021
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Cancer Risks in Vitiligo Patients: A Nationwide Population-Based Study in Taiwan
    MDPI AG ; 2018
    In:  International Journal of Environmental Research and Public Health Vol. 15, No. 9 ( 2018-08-27), p. 1847-
    Details
    In: International Journal of Environmental Research and Public Health, MDPI AG, Vol. 15, No. 9 ( 2018-08-27), p. 1847-
    Abstract: Vitiligo is an autoimmune disease characterized by destruction of melanocytes and associated with other autoimmune disease. Whether the dysregulation of immune system enhances oncogenesis or not remains obscure. Until now, no nationwide population-based study has been conducted regarding this. As such, this paper aims to clarify cancer risk in vitiligo patients. A retrospective nationwide population-based cohort study between 2000 and 2010 was performed based on data from the National Health Insurance Research Database of Taiwan. Standardized incidence ratios (SIRs) of cancers were analyzed. Among the 12,391 vitiligo patients (5364 males and 7027 females) and 48,531.09 person-years of observation, a total of 345 cancers were identified. Significantly increased SIRs were observed for prostate cancer in male patients, thyroid cancer and breast cancer in female patients and bladder cancers in both male and female patients. Unfortunately, the low incidence rate of certain cancers limited the power of our statistical analyses. This study demonstrated the patterns of malignancies in vitiligo patients of Taiwan. Compared with the general population, male patients had higher risks of prostate cancer and female patients had higher risks of thyroid cancer and breast cancer. The risks of bladder cancer were also increased in both male and female patients.
    Type of Medium: Online Resource
    ISSN: 1660-4601
    URL: Article
    DOI: 10.3390/ijerph15091847
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2175195-X
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  • 7
    Online Resource
    Online Resource
    The Association between General Anesthesia and New Postoperative Uses of Sedative–Hypnotics: A Nationwide Matched Cohort Study
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 12 ( 2022-06-11), p. 3360-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 12 ( 2022-06-11), p. 3360-
    Abstract: Sedative–hypnotic misuse is associated with psychiatric diseases and overdose deaths. It remains uncertain whether types of anesthesia affect the occurrence of new postoperative uses of sedative–hypnotics (NPUSH). We used reimbursement claims data of Taiwan’s National Health Insurance and conducted propensity score matching to compare the risk of NPUSH between general and neuraxial anesthesia among surgical patients who had no prescription of oral sedative–hypnotics or diagnosis of sleep disorders within the 12 months before surgery. The primary outcome was NPUSH within 180 days after surgery. Multivariable logistic regression models were used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 92,222 patients were evaluated after matching. Among them, 15,016 (16.3%) had NPUSH, and 2183 (4.7%) were made a concomitant diagnosis of sleep disorders. General anesthesia was significantly associated both with NPUSH (aOR: 1.17, 95% CI: 1.13–1.22, p 〈 0.0001) and NPUSH with sleep disorders (aOR: 1.11, 95% CI: 1.02–1.21, p = 0.0212) compared with neuraxial anesthesia. General anesthesia was also linked to NPUSH that occurred 90–180 days after surgery (aOR: 1.12, 95% CI: 1.06–1.19, p = 0.0002). Other risk factors for NPUSH were older age, female, lower insurance premium, orthopedic surgery, specific coexisting diseases (e.g., anxiety disorder), concurrent medications (e.g., systemic steroids), postoperative complications, perioperative blood transfusions, and admission to an intensive care unit. Patients undergoing general anesthesia had an increased risk of NPUSH compared with neuraxial anesthesia. This finding may provide an implication in risk stratification and prevention for sedative–hypnotic dependence after surgery.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11123360
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 8
    Online Resource
    Online Resource
    Life in a New Normal with a Self-Care Routine: A Cross-Sectional Study of Older Adults’ Daily Health Behaviors (DHB) Performance during the Initial Outbreak of COVID-19 in China
    MDPI AG ; 2022
    In:  Nutrients Vol. 14, No. 8 ( 2022-04-18), p. 1678-
    Details
    In: Nutrients, MDPI AG, Vol. 14, No. 8 ( 2022-04-18), p. 1678-
    Abstract: For older adults, self-care begins with daily health behaviors (DHB), which refers to a series of basic behaviors beneficial to health in daily life; it is the foundation for promoting health, preventing disease, and maintaining health with or without the support of a healthcare provider. Thus, this study aimed to observe the changes in DHB among older adults when the COVID-19 pan-demic first erupted in China (at the beginning of 2020) and explore the impact factors on self-care routines in daily life. We applied a cross-sectional study among 1256 (83.7%) valid older Chinese from 19 February 2020 to 19 March 2020, the score of DHB changes (mean ± SD, 14.70 ± 2.140; range, 8–18) presented a significant growth (t1256 = 44.636, p 〈 0.001) during COVID-19. From 3 hierarchical linear regression models, the older Chinese who received a higher education include high school (β = 0.403, 95% CI [0.009, 0.797], p = 0.045) and college degree and above (β = 0.488, 95% CI [0.034, 0.943] , p = 0.035), and lived in the eastern China (β = 0.771, 95% CI [0.392, 1.151], p 〈 0.001) took DHB more frequently. However, the high-risk infection (β = −0.740, 95% CI [−1.248, −0.231], p = 0.004), overweight/obese character (β = −0.265, 95% CI [−0.526, −0.004] , p = 0.047), and alcohol consumption (β = −0.350, 95% CI [−0.634, −0.065], p = 0.016) are significant factors in decreasing a senior’s DHB performance. For China, self-care offers a straightforward strategy among the range of measures required to combat COVID-19 and future health threats. In summary, findings in this study can build a foundation for developing healthcare policy and services for the relevant government and departments on prompting DHB and the importance of self-care among the older population.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu14081678
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2518386-2
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  • 9
    Online Resource
    Online Resource
    Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson's Disease
    MDPI AG ; 2020
    In:  Brain Sciences Vol. 10, No. 4 ( 2020-04-01), p. 206-
    Details
    In: Brain Sciences, MDPI AG, Vol. 10, No. 4 ( 2020-04-01), p. 206-
    Abstract: Parkinson’s disease (PD) is one of the common long-term degenerative disorders that primarily affect motor systems. Gastrointestinal (GI) symptoms are common in individuals with PD and often present before motor symptoms. It has been found that gut dysbiosis to PD pathology is related to the severity of motor and non-motor symptoms in PD. Probiotics have been reported to have the ability to improve the symptoms related to constipation in PD patients. However, the evidence from preclinical or clinical research to verify the beneficial effects of probiotics for the motor functions in PD is still limited. An experimental PD animal model could be helpful in exploring the potential therapeutic strategy using probiotics. In the current study, we examined whether daily and long-term administration of probiotics has neuroprotective effects on nigrostriatal dopamine neurons and whether it can further alleviate the motor dysfunctions in PD mice. Transgenic MitoPark PD mice were chosen for this study and the effects of daily probiotic treatment on gait, beam balance, motor coordination, and the degeneration levels of dopaminergic neurons were identified. From the results, compared with the sham treatment group, we found that the daily administration of probiotics significantly reduced the motor impairments in gait pattern, balance function, and motor coordination. Immunohistochemically, a tyrosine hydroxylase (TH)-positive cell in the substantia nigra was significantly preserved in the probiotic-treated PD mice. These results showed that long-term administration of probiotics has neuroprotective effects on dopamine neurons and further attenuates the deterioration of motor dysfunctions in MitoPark PD mice. Our data further highlighted the promising possibility of the potential use of probiotics, which could be the relevant approach for further application on human PD subjects.
    Type of Medium: Online Resource
    ISSN: 2076-3425
    URL: Article
    DOI: 10.3390/brainsci10040206
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2651993-8
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  • 10
    Online Resource
    Online Resource
    The Autophagosomes Containing Dengue Virus Proteins and Full-Length Genomic RNA Are Infectious
    MDPI AG ; 2021
    In:  Viruses Vol. 13, No. 10 ( 2021-10-09), p. 2034-
    Details
    In: Viruses, MDPI AG, Vol. 13, No. 10 ( 2021-10-09), p. 2034-
    Abstract: Autophagic machinery is involved in selective and non-selective recruitment as well as degradation or exocytosis of cargoes, including pathogens. Dengue virus (DENV) infectioninduces autophagy that enhances virus replication and vesicle release to evade immune systemsurveillance. This study reveals that DENV2 induces autophagy in lung and liver cancer cells andshowed that DENV2 capsid, envelope, NS1, NS3, NS4B and host cell proinflammatory high mobilitygroup box 1 (HMGB1) proteins associated with autophagosomes which were purified by gradientcentrifugation. Capsid, NS1 and NS3 proteins showing high colocalization with LC3 protein in thecytoplasm of the infected cells were detected in the purified double-membrane autophagosome byimmunogold labeling under transmission electron microscopy. In DENV infected cells, the levels ofcapsid, envelope, NS1 and HMGB1 proteins are not significantly changed compared to the dramaticaccumulation of LC3-II and p62/SQSTM1 proteins when autophagic degradation was blocked bychloroquine, indicating that these proteins are not regulated by autophagic degradation machinery.We further demonstrated that purified autophagosomes were infectious when co-cultured withuninfected cells. Notably, these infectious autophagosomes contain DENV2 proteins, negativestrandand full-length genomic RNAs, but no viral particles. It is possible that the infectivity ofthe autophagosome originates from the full-length DENV RNA. Moreover, we reveal that DENV2promotes HMGB1 exocytosis partially through secretory autophagy. In conclusion, we are the firstto report that DENV2-induced double-membrane autophagosomes containing viral proteins andfull-length RNAs are infectious and not undergoing autophagic degradation. Our novel findingwarrants further validation of whether these intracellular vesicles undergo exocytosis to becomeinfectious autophagic vesicles.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v13102034
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2516098-9
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