Potential Role of Neutrophil Extracellular Traps in Cardio-Oncology.

Cardiovascular toxicity has emerged as the leading cause of death in patients undergoing cancer treatment. Thus, cardio-oncology (CO) care must also focus on the prevention and management of related cardiovascular (CV) complications caused by cancer therapy. Neutrophil extracellular traps (NETs)-entities with released DNA, proteases, proinflammatory and prooxidative substances from blasted neutrophils-play an important role in cancer proliferation, propagation metastasis, and incident CV events (acute coronary syndrome, thromboembolic events, and heart failure). Although NETs have been shown to be involved in cancer progression and incident CV events, little is known about their relationship with cardio-oncology, especially on cancer treatment-related cardiovascular toxicity (CTRCT). This review aims to explore the evidence of the impact of NETs on cancer, CV events, and CTRCT, and the possible solutions based on the mechanism of NETs activation and NETs released toxic substances.

Viral transmission and evolution dynamics of SARS-CoV-2 in shipboard quarantine.

OBJECTIVE: To examine transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in shipboard quarantine of the Diamond Princess cruise ship. METHODS: We obtained the full SARS-CoV-2 genome sequences of 28 samples from the Global Initiative on Sharing All Influenza Data database. The samples were collected between 10 and 25 February 2020 and came for individuals who had been tested for SARS-CoV-2 during the quarantine on the cruise ship. These samples were later sequenced in either Japan or the United States of America. We analysed evolution dynamics of SARS-CoV-2 using computational tools of phylogenetics, natural selection pressure and genetic linkage. FINDINGS: The SARS-CoV-2 outbreak in the cruise most likely originated from either a single person infected with a virus variant identical to the WIV04 isolates, or simultaneously with another primary case infected with a virus containing the 11083G > T mutation. We identified a total of 24 new viral mutations across 64.2% (18/28) of samples, and the virus evolved into at least five subgroups. Increased positive selection of SARS-CoV-2 were statistically significant during the quarantine (Tajima's D: -2.03, P < 0.01; Fu and Li's D: -2.66, P < 0.01; and Zeng's E: -2.37, P < 0.01). Linkage disequilibrium analysis confirmed that ribonucleic acid (RNA) recombination with the11083G > T mutation also contributed to the increase of mutations among the viral progeny. CONCLUSION: The findings indicate that the 11083G > T mutation of SARS-CoV-2 spread during shipboard quarantine and arose through de novo RNA recombination under positive selection pressure.

Successful treatment of corticosteroid-dependent drug reaction with eosinophilia and systemic symptoms with cyclosporine.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is an intractable drug hypersensitivity disease with high mortality. The current standard treatment requires high-dose and long-term systemic corticosteroids, which may lead to adverse effects and intolerability of patients. OBJECTIVE: To evaluate the efficacy and safety of cyclosporine in patients with corticosteroid-dependent DRESS or intolerance to systemic corticosteroids. METHODS: A retrospective review of 8 patients with corticosteroid-dependent DRESS who were treated with cyclosporine as an alternative treatment owing to suboptimal response to regular doses of systemic corticosteroids for at least 3 weeks, flare-ups when tapering corticosteroids, or experiencing intolerable adverse effects of corticosteroids. RESULTS: In all 8 patients (4 women and 4 men; age range, 15-75 years), either intractable skin eruptions, persistent eosinophilia, or elevated liver function was noted after at least 3 weeks of treatment with systemic corticosteroids. The patients had marked cutaneous improvement and normalization of liver function and eosinophil count after adding cyclosporine, and the systemic corticosteroid treatment was smoothly tapered down. The mean dosage of cyclosporine was 1.68 ± 0.73 mg/kg/d, and the mean duration of cyclosporine treatment was 76.13 ± 35.64 days. Their serum eosinophil counts, serum alanine aminotransferase levels, and serum thymus and activation-regulated chemokine levels were all elevated at baseline and then significantly decreased during the recovery stage after cyclosporine therapy (P < .05). No adverse events were reported after adding cyclosporine. CONCLUSION: Cyclosporine is an effective and safe therapeutic alternative as a steroid-sparing agent for corticosteroid-dependent DRESS. Further prospective randomized controlled studies are required to confirm these preliminary results.

Effects of electromagnetic waves on oocyte maturation and embryonic development in pigs.

Our living environment has been full of electromagnetic radiation (EMR) due to the prevailing electronic devices and equipment. Intermediate frequency electromagnetic field (IF-EMF) or waves constitute a significant part of EMR; therefore, an increasing number of household electrical appliances have become a source of IF-EMF, and concerns about IF-EMF on health are gaining more attention. However, little information is available about its impact on female reproductive traits, such as germ cell viability and early embryonic development, particularly at the cellular and molecular levels. In this study, we used porcine oocytes as a model system to explore the effect of IF-EMF at various intensities on the in vitro maturation (IVM) of oocytes and their subsequent embryonic development. Our results showed that no difference in oocyte maturation rates was detected among groups, but the cleavage and blastocyst rates of parthenotes derived from EMF-treated oocytes decreased with the weaker IF-EMF intensity (25 and 50 Gauss) groups compared to the control group (P < 0.05). For cytoplasmic maturation, the weaker IF-EMF intensity groups also showed a peripheral pattern of mitochondrial distribution resembling that of immature oocytes and increased autophagy activity. No obvious differences in cytoskeletal distribution and total cell numbers of blastocysts were investigated in the four IF-EMF treatments compared to those in the control group. Although the underlying mechanism associated with EMF effects on oocytes and embryos is still elusive, we have demonstrated that low intensity IF-EMF exerts harmful effects on porcine oocytes during the maturation stage, carrying over such effects to their subsequent embryonic development.

Dynactin helps target Polo-like kinase 1 to kinetochores via its left-handed beta-helical p27 subunit.

Dynactin is a protein complex required for the in vivo function of cytoplasmic dynein, a microtubule (MT)-based motor. Dynactin binds both dynein and MTs via its p150(Glued) subunit, but little is known about the 'pointed-end complex' that includes the protein subunits Arp11, p62 and the p27/p25 heterodimer. Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin-dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo-like kinase 1 (Plk1) at kinetochores. Removal of p27/p25 from dynactin results in reduced levels of Plk1 and its phosphorylated substrates at kinetochores in prometaphase, which correlates with aberrant kinetochore-MT interactions, improper chromosome alignment and abbreviated mitosis. To investigate the structural implications of p27 phosphorylation, we determined the structure of human p27. This revealed an unusual left-handed ß-helix domain, with the phosphorylation site located within a disordered, C-terminal segment. We conclude that dynactin plays a previously undescribed regulatory role in the spindle assembly checkpoint by recruiting Plk1 to kinetochores and facilitating phosphorylation of important downstream targets.

The conserved 5' apical hairpin stem loops of bamboo mosaic virus and its satellite RNA contribute to replication competence.

Satellite RNAs associated with Bamboo mosaic virus (satBaMVs) depend on BaMV for replication and encapsidation. Certain satBaMVs isolated from natural fields significantly interfere with BaMV replication. The 5' apical hairpin stem loop (AHSL) of satBaMV is the major determinant in interference with BaMV replication. In this study, by in vivo competition assay, we revealed that the sequence and structure of AHSL, along with specific nucleotides (C(60) and C(83)) required for interference with BaMV replication, are also involved in replication competition among satBaMV variants. Moreover, all of the 5' ends of natural BaMV isolates contain the similar AHSLs having conserved nucleotides (C(64) and C(86)) with those of interfering satBaMVs, suggesting their co-evolution. Mutational analyses revealed that C(86) was essential for BaMV replication, and that replacement of C(64) with U reduced replication efficiency. The non-interfering satBaMV interfered with BaMV replication with the BaMV-C64U mutant as helper. These findings suggest that two cytosines at the equivalent positions in the AHSLs of BaMV and satBaMV play a crucial role in replication competence. The downregulation level, which is dependent upon the molar ratio of interfering satBaMV to BaMV, implies that there is competition for limited replication machinery.

HemU and TonB1 contribute to hemin acquisition in Stenotrophomonas maltophilia.

Introduction: The hemin acquisition system is composed of an outer membrane TonB-dependent transporter that internalizes hemin into the periplasm, periplasmic hemin-binding proteins to shuttle hemin, an inner membrane transporter that transports hemin into the cytoplasm, and cytoplasmic heme oxygenase to release iron. Fur and HemP are two known regulators involved in the regulation of hemin acquisition. The hemin acquisition system of Stenotrophomonas maltophilia is poorly understood, with the exception of HemA as a TonB-dependent transporter for hemin uptake. Methods: Putative candidates responsible for hemin acquisition were selected via a homolog search and a whole-genome survey of S. maltophilia. Operon verification was performed by reverse transcription-polymerase chain reaction. The involvement of candidate genes in hemin acquisition was assessed using an in-frame deletion mutant construct and iron utilization assays. The transcript levels of candidate genes were determined using quantitative polymerase chain reaction. Results: Smlt3896-hemU-exbB2-exbD2-tonB2 and tonB1-exbB1-exbD1a-exbD1b operons were selected as candidates for hemin acquisition. Compared with the parental strain, hemU and tonB1 mutants displayed a defect in their ability to use hemin as the sole iron source for growth. However, hemin utilization by the Smlt3896 and tonB2 mutants was comparable to that of the parental strain. HemA expression was repressed by Fur in iron-replete conditions and derepressed in iron-depleted conditions. HemP negatively regulated hemA expression. Like hemA, hemU was repressed by Fur in iron-replete conditions; however, hemU was moderately derepressed in response to iron-depleted stress and fully derepressed when hemin was present. Unlike hemA and hemU, the TonB1-exbB1-exbD1a-exbD1b operon was constitutively expressed, regardless of the iron level or the presence of hemin, and Fur and HemP had no influence on its expression. Conclusion: HemA, HemU, and TonB1 contribute to hemin acquisition in S. maltophilia. Fur represses the expression of hemA and hemU in iron-replete conditions. HemA expression is regulated by low iron levels, and HemP acts as a negative regulator of this regulatory circuit. HemU expression is regulated by low iron and hemin levels in a hemP-dependent manner.

National safety surveillance of quadrivalent recombinant influenza vaccine in Taiwan during NH 20/21.

BACKGROUND: During the COVID-19 pandemic, the need for influenza vaccine significantly increased in the initial weeks of the 2020-2021 influenza vaccination campaign season in Taiwan. To meet this demand, the Taiwanese government therefore purchased additional influenza vaccines via special import, including 350,000 doses of quadrivalent recombinant influenza vaccines (RIV4, Flublok Quadrivalent). Approved in the United States since 2016, there were limited numbers of published studies regarding RIV4 outside America. We utilized the national passive surveillance system consisting adverse event (AE) reports following RIV4 immunization to describe its safety profiles in Taiwan. METHODS: We obtained the database from the Taiwan National Adverse Drugs Reactions Reporting System and collected reports from January 2021 to July 2021, which was at least one month after RIV4 immunization. AE reporting rates were calculated based on the total administered doses. RESULTS: Eight AEs were reported among 200,287 administered doses, which led to a reporting rate of 3.99 AEs per 100,000 doses administered. The mean age of the reported individuals were 47.53 years, and women (75%) were the predominant gender. Most adverse events started within the first day after immunization, with one reported as starting 4 days after vaccination. Among the 8 cases, 75% (n = 6) were non-serious and the most common symptoms were erythematous skin rashes with pruritus. Two cases were listed as serious based on the criteria of "other clinically significant medical conditions", but neither was judged to have a causal relationship with RIV4 immunization. CONCLUSION: The Taiwan national passive surveillance data supported the safety profiles of RIV4 in Taiwan population.

Recombination shapes the 2022 monkeypox (mpox) outbreak.

Monkeypox (Mpox) is a global health emergency. Yeh et al. analyze tandem repeats and linkage disequilibrium in monkeypox virus (MPXV) sequences from the 2022 pandemic to determine the virus evolution, showing that these are useful tools to monitor and track phylogenetic dynamics and recombination of MPXV.

Immunogenicity and safety of high-dose quadrivalent influenza vaccine in older adults in Taiwan: A phase III, randomized, multi-center study.

BACKGROUND: High-dose influenza vaccine offers better protection against influenza/associated complications compared with standard-dose formulation. We evaluated immunogenicity and safety of high-dose influenza vaccine (QIV-HD) and standard-dose (QIV-SD) in older adults (≥ 65 years) in Taiwan. METHODS: This was a phase III, randomized, modified double-blind, active-controlled, multi-center, descriptive study in older adults. Participants (N = 165) were randomized 1:1 to receive QIV-HD or QIV-SD vaccine (clinicaltrials.gov#NCT04537234). RESULTS: For all four influenza strains, geometric means titers (GMTs) of hemagglutination inhibition were higher for the QIV-HD than QIV-SD with adjusted GMT ratios (95 % CI) of 2.65 (1.87-3.75) for A/H1N1; 1.76 (1.31-2.38) for A/H3N2; 2.60 (1.90-3.56) for B/Victoria; and 2.01 (1.57-2.56) for B/Yamagata. The seroconversion was higher for QIV-HD than QIV-SD with similar safety profiles across both groups. CONCLUSION: QIV-HD was highly immunogenic for four influenza strains and have acceptable safety profile in older adults aged ≥ 65 years in Taiwan.

Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity.

Abnormal accumulation of acrolein, an α, ß unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. In the present study, the neuroprotective effect of selumetinib (a MEK-ERK inhibitor) on acrolein-induced neurotoxicity was investigated in vitro using primary cultured cortical neurons. Incubation of acrolein consistently increased phosphorylated ERK levels. Co-treatment of selumetinib blocked acrolein-induced ERK phosphorylation. Furthermore, selumetinib reduced acrolein-induced increases in heme oxygenase-1 (a redox-regulated chaperone protein) and its transcriptional factor, Nrf-2 as well as FDP-lysine (acrolein-lysine adducts) and α-synuclein aggregation (a pathological biomarker of neurodegeneration). Morphologically, selumetinib attenuated acrolein-induced damage in neurite outgrowth, including neuritic beading and neurite discontinuation. Moreover, selumetinib prevented acrolein-induced programmed cell death via decreasing active caspase 3 (a hallmark of apoptosis) as well as RIP (receptor-interacting protein) 1 and RIP3 (biomarkers for necroptosis). In conclusion, our study showed that selumetinib inhibited acrolein-activated Nrf-2-HO-1 pathway, acrolein-induced protein conjugation and aggregation as well as damage in neurite outgrowth and cell death, suggesting that selumetinib, a MEK-ERK inhibitor, may be a potential neuroprotective agent against acrolein-induced neurotoxicity in the CNS neurodegenerative diseases.

The dynein light chain Tctex-1 has a dynein-independent role in actin remodeling during neurite outgrowth.

Coordinated microtubule and microfilament changes are essential for the morphological development of neurons; however, little is know about the underlying molecular machinery linking these two cytoskeletal systems. Similarly, the indispensable role of RhoGTPase family proteins has been demonstrated, but it is unknown how their activities are specifically regulated in different neurites. In this paper, we show that the cytoplasmic dynein light chain Tctex-1 plays a key role in multiple steps of hippocampal neuron development, including initial neurite sprouting, axon specification, and later dendritic elaboration. The neuritogenic effects elicited by Tctex-1 are independent from its cargo adaptor role for dynein motor transport. Finally, our data suggest that the selective high level of Tctex-1 at the growth cone of growing axons drives fast neurite extension by modulating actin dynamics and also Rac1 activity.

Allopurinol in dermatology.

Off-label use is common in dermatology, and is inevitable for rare cutaneous diseases such as perforating dermatosis. Allopurinol is traditionally considered to be a drug for hyperuricemia only, but the recent demonstration of its efficacy in congestive heart failure has spurred renewed interest in its application in other clinical specialties. In dermatology, allopurinol is best known for its severe cutaneous adverse reactions. Recent genomic studies conducted in Taiwan have discovered useful HLA markers for determining the susceptibility of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with allopurinol. Allopurinol has also been used in a number of dermatologic disorders including acquired reactive perforating collagenosis, sarcoidosis, psoriasis and granulomas caused by methacrylate microspheres, silicon and tattoos. Allopurinol may express its therapeutic effects via its antioxidation or anti-inflammatory properties, or its ability to improve vascular function.

XerD-dependent integration of a novel filamentous phage Cf2 into the Xanthomonas citri genome.

Filamentous Inoviridae phages integrate into the chromosome of plant pathogens Xanthomonas as prophages, but their diversity and integrative mechanism are not completely understood. A proviral Cf2 sequence of 6454 bases from Xanthomonas citri genome was revived as infectious virions able to lysogenize its host. Unlike other Xanthomonas phages (Cf1c, φLf, Xf109, XacF1), Cf2 phage has RstA/RstB replication protein, and its attP has XerD binding arm and dif central region but lacks XerC binding arm. XerC+/Xf109 and XerD+/Cf2 attPs are in the opposite direction in phage genomes. Moreover, XerCD binding and XerD catalysis for strand exchange are necessary for site-specific integration of XerD+/Cf2 and XerC+/Xf109 attPs. Taken together, these results provide a new insight into the mechanism of XerCD-mediated recombination at XerD + attP.

Prolonged viral shedding and new mutations of COVID-19 could complicate the control of the pandemic.

The studies of coronavirus disease 2019 (COVID-19) have mainly focused on epidemiological and clinical features of patients, but transmission dynamics of SARS-CoV-2 virus after patients have recovered is still poorly understood. Here we report a case with prolonged viral shedding of COVID-19 in Kaohsiung, Taiwan. This patient started to show myalgia and malaise in Wuhan, and the onset of the fever was on days 7-14 of the illness. All clinical and radiological results returned to normal after day 26, however, viral shedding was still evident 14 days later. Sequence analysis of the genome of the Taiwanese SARS-CoV-2 isolate from this patient reveals new mutations in viral replicase and ORF3a, indicating that COVID-19 evolves very quickly. Prolonged viral shedding and new mutations in the viral genome could potentially complicate the control of the COVID-19 pandemic.

Family members' concerns about relatives in long-term care facilities: Acceptance of visiting restriction policy amid the COVID-19 pandemic.

AIM: The policy enforcing visiting restriction during the COVID-19 pandemic may cause feelings of social isolation among residents in long-term care facilities. This study aimed to explore family members' concerns for their relatives during the lockdown period, assess their level of acceptance of the visiting restriction policy and determine the associated factors. METHODS: From the 156 family members interviewed, demographic data, satisfaction with overall care quality, worry and concerns for their relatives, acceptance of the visiting restriction and arrangement for the residents if cluster infections occur in the facility were recorded. RESULTS: Among the members interviewed, 83 (53.2%) were men; mean age of members was 56.3 ± 9.8; most were offspring of residents in the facility (n = 121, 77.6%), most visited the residents at least once a week (n = 113, 72.4%) before the lockdown. The most common concerns of the family members for their relatives were psychological stress (38.5%), followed by nursing care (26.9%) and daily activity (21.1%). Nearly 84.6% of those interviewed accepted the visiting restriction policy, and a higher satisfaction rating independently associated with acceptance of the visiting restriction policy (odds ratio 2.15). CONCLUSIONS: During the lockdown period, staff members should provide more psychological information about residents to their family members. Higher satisfaction rating was found to be independent of the acceptance of the visiting restriction policy. Therefore, good quality of care of the facility wins the trust of family members, and this might mitigate the tension between the family members and staff during a major crisis. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2020; 20: 938-942.

Ultrastructural Characterization of Porcine Growing and In Vitro Matured Oocytes.

This study aimed to investigate ultrastructural changes of growing porcine oocytes and in vitro maturated oocytes. Light microscopy was used to characterize and localize the primordial, primary, secondary, and tertiary follicles. During oocyte growth and maturation, the morphology of mitochondria was roundish or ovoid in shape depending on the differentiation state, whereas their mean diameters oscillated between 0.5 and 0.7 µm, respectively, from primary and secondary follicles. Hooded mitochondria were found in the growing oocytes of the tertiary follicles. In addition to the pleomorphism of mitochondria, changes in the appearance of lipid droplets were also observed, along with the alignment of a single layer of cortical granules beneath the oolemma. In conclusion, our study is apparently the first report to portray morphological alterations of mitochondria that possess the hooded structure during the growth phase of porcine oocytes. The spatiotemporal and intrinsic changes during oogenesis/folliculogenesis are phenomena at the ultrastructural or subcellular level of porcine oocytes, highlighting an in-depth understanding of oocyte biology and impetus for future studies on practical mitochondrion replacement therapies for oocytes.

Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein.

Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Available inhibitors target Smoothened (Smo), which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smo are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and pseudoprometaphase delay. Dynarrestin reversibly inhibits cytoplasmic dynein 2-dependent intraflagellar transport (IFT) of the cargo IFT88 and flux of Smo within cilia without interfering with ciliogenesis and suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. As such, dynarrestin is a valuable tool for probing cytoplasmic dynein-dependent cellular processes and a promising compound for medicinal chemistry programs aimed at development of anti-cancer drugs.

Epidemiology and Medication Utilization Pattern of Aortic Dissection in Taiwan: A Population-Based Study.

Acute aortic dissection (AD) is a catastrophic condition associated with a high rate of mortality. However, current epidemiological information regarding AD remains sparse. The objective of the present study was to investigate the current epidemiological profile and medication utilization patterns associated with aortic dissection in Taiwan.In this population-based study, we identified cases of AD diagnosed during 2005 to 2012 in the complete Taiwan National Health Insurance (NHI) Research Database. Patients with AD were identified using the International Classification of Disease, Ninth Revision (ICD-9) code 441.0, and surgical interventions were defined using NHI procedure codes.A total of 9092 individuals with a mean age of 64.4 ±â€Š15.1 years were identified. The cases were divided into 3 groups: Group A included 2340 patients (25.74%) treated surgically for type A AD; Group B included 1144 patients (12.58%) treated surgically for type B AD, and Group C included 5608 patients (61.68%) with any type of AD treated with medical therapy only. The average annual incidence of AD was 5.6 per 100,000 persons, and the average prevalence was 19.9 per 100,000 persons. Hypertension was the most common risk factor, followed by coronary artery disease and chronic obstructive pulmonary disease. Within 1 year of AD diagnosis, 92% of patients were taking antihypertensive medication. Calcium channel blockers were the most frequently prescribed antihypertensive medication for long-term observation in Taiwan.The annual trends revealed statistically significant increases in the numbers and percentages of prevalence, incidence, and mortality. Changes in patients' drug utilization in patterns were observed after AD diagnosis. Our study provides a local profile that supports further in-depth analyses in AD-affected populations.