ACE2: the node connecting the lung cancer and COVID-19.

Angiotensin-converting Enzyme 2 (ACE2) collaborates with Angiotensin (Ang) 1-7 and Mas receptors to establish the ACE2-Ang (1-7)-Mas receptor axis. ACE2 impacts lung function and can cause lung injury due to its inflammatory effects. Additionally, ACE2 contributes to pulmonary vasculature dysfunction, resulting in pulmonary hypertension. In addition, ACE2 is a receptor for coronavirus entry into host cells, leading to coronavirus infection. Lung cancer, one of the most common respiratory diseases worldwide, has a high rate of infection. Elevated levels of ACE2 in lung cancer patients, which increase the risk of SARS-CoV-2 infection and severe disease, have been demonstrated in clinical studies and by molecular mechanisms. The association between lung cancer and SARS-CoV-2 is closely linked to ACE2. This review examines the basic pathophysiological role of ACE2 in the lung, the long-term effects of SARS-CoV-2 infection on lung function, the development of pulmonary fibrosis, chronic inflammation in long-term COVID patients, and the clinical research and mechanisms underlying the increased susceptibility of lung cancer patients to the virus. Possible mechanisms of lung cancer in SARS-CoV-2-infected individuals and the potential role of ACE2 in this process are also explored in this review. The role of ACE2 as a therapeutic target in the novel coronavirus infection process is also summarized. This will help to inform prevention and treatment of long-term pulmonary complications in patients.

Synergistic resistance of honeybee (Apis mellifera) and their gut microorganisms to fluvalinate stress.

Fluvalinate is widely used in the control of Varroa destructor, but its residues in colonies threaten honeybees. The effect of fluvalinate-induced dysbiosis on honeybee-related gene expression and the gut microenvironment of honeybees has not yet been fully elucidated. In this study, two-day-old larvae to seven-day-old adult worker bees were continuously fed different amounts of fluvalinate-sucrose solutions (0, 0.5, 5, and 50 mg/kg), after which the expression levels of two immune-related genes (Hymenoptaecin and Defensin1) and three detoxication-related genes (GSTS3, CAT, and CYP450) in worker bees (1, 7, and 20 days old) were measured. The effect of fluvalinate on the gut microbes of worker bees at seven days old also was explored using 16S rRNA Illumina deep sequencing. The results showed that exposure of honeybees to the insecticide fluvalinate affected their gene expression and gut microbial composition. As the age of honeybees increased, the effect of fluvalinate on the expression of Hymenoptaecin, CYP450, and CAT decreased, and the abundance of honeybee gut bacteria was affected by increasing the fluvalinate concentration. These findings provide insights into the synergistic defense of honeybee hosts against exogenous stresses in conjunction with honeybee gut microbes.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

Measuring adolescent health literacy in Taiwan: validation of the health literacy assessment scale for adolescents.

BACKGROUND: This study aimed to validate the Chinese version of the Health Literacy Assessment Scale for Adolescents (HAS-A) and conduct a comparative analysis of adolescent health literacy between Taiwan and other countries. METHODS: The Chinese version of the HAS-A was completed by 2,312 adolescents in the fifth and sixth grades of a primary school. Psychometric properties were examined using consistent internal reliability and confirmatory factor analysis. These assessments were compared with the results from different regions to explore health literacy inequality. RESULTS: Construct validity was good, and internal consistency was acceptable. The scale, particularly regarding communication health literacy, was associated with parents' socioeconomic status, and family income had a more significant impact on children's health literacy than community income. Health literacy disparities appear in different countries, with Taiwan exhibiting the lowest level of communication health literacy. CONCLUSION: The results indicate that the HAS-A is a valuable tool for assessing the health literacy of 10-11-year-old adolescents and can uncover health literacy inequality among different regions.

Identification and validation of immunogenic cell death-related score in uveal melanoma to improve prediction of prognosis and response to immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) could activate innate and adaptive immune response. In this work, we aimed to develop an ICD-related signature in uveal melanoma (UVM) patients and facilitate assessment of their prognosis and immunotherapy. METHODS: A set of machine learning methods, including non-negative matrix factorization (NMF) method and least absolute shrinkage and selection operator (LASSO) logistic regression model, and bioinformatics analytic tools were integrated to construct an ICD-related risk score (ICDscore). CIBERSORT and ESTIMATE algorithms were used to evaluate the infiltration of immune cells. The Genomics of Drug Sensitivity in Cancer (GDSC), cellMiner and tumor immune dysfunction and exclusion (TIDE) databases were used for therapy sensitivity analyses. The predictive performance between ICDscore with other mRNA signatures was also compared. RESULTS: The ICDscore could predict the prognosis of UVM patients in both the training and four validating cohorts. The ICDscore outperformed 19 previously published signatures. Patients with high ICDscore exhibited a substantial increase in immune cell infiltration and expression of immune checkpoint inhibitor-related genes, leading to a higher response rate to immunotherapy. Furthermore, the downregulation of poly (ADP-ribose) polymerase family member 8 (PARP8), a critical gene involved in the development of the ICDscore, resulted in decreased cell proliferation and slower migration of UVM cells. CONCLUSION: In conclusion, we developed a robust and powerful ICD-related signature for evaluating the prognosis and benefits of immunotherapy that could serve as a promising tool to guide decision-making and surveillance for UVM patients.

The effects of combined high-frequency repetitive transcranial magnetic stimulation and cervical nerve root magnetic stimulation on upper extremity motor recovery following stroke.

Introduction: Upper limb motor impairments after stroke cause patients partial or total loss of the capability of performing daily living, working, and social activities, which significantly affects the quality of life (QoL) of patients and brings a heavy burden to their families and society. As a non-invasive neuromodulation technique, transcranial magnetic stimulation (TMS) can act not only on the cerebral cortex, but also on peripheral nerves, nerve roots, and muscle tissues. Previous studies have shown that magnetic stimulation on the cerebral cortex and peripheral tissues has a positive effect on the recovery of upper limb motor function after stroke, however, few studies have reported the combination of the two. Objective: This study was to investigate whether high frequency repetitive transcranial magnetic stimulation (HF-rTMS) combined with cervical nerve root magnetic stimulation more effectively ameliorates upper limb motor function in stroke patients. We hypothesized that the combination of the two can achieve a synergistic effect and further promotes functional recovery. Methods: Sixty patients with stroke were randomly divided into four groups and received real or sham rTMS stimulation and cervical nerve root magnetic stimulation consecutively before other therapies, once daily over five fractions per week for a total of 15 times. We evaluated the upper limb motor function and activities of daily living of the patients at the time of pre-treatment, post-treatment, and 3-month follow up. Results: All patients completed study procedures without any adverse effects. The upper limb motor function and activities of daily living improved in patients of each group were improved after treatment (post 1) and 3 months after treatment (post 2). Combination treatment was significantly better than single treatments alone or sham. Conclusion: Both rTMS and cervical nerve root magnetic stimulation effectively promoted upper limb motor recovery in patients with stroke. The protocol combining the two is more beneficial for motor improvement and patients can easily tolerate it. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2100048558.

The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.

Mitophagy is a vital process that controls mitochondria quality, dysregulation of which can promote cancer. Oncoprotein mucin 1 (MUC1) targets mitochondria to attenuate drug-induced apoptosis. However, little is known about whether and how MUC1 contributes to mitochondrial homeostasis in cancer cells. We identified a novel role of MUC1 in promoting mitophagy. Increased mitophagy is coupled with the translocation of MUC1 to mitochondria, where MUC1 interacts with and induces degradation of ATPase family AAA domain-containing 3A (ATAD3A), resulting in protection of PTEN-induced kinase 1 (Pink1) from ATAD3A-mediated cleavage. Interestingly, MUC1-induced mitophagy is associated with increased oncogenicity of cancer cells. Similarly, inhibition of mitophagy significantly suppresses MUC1-induced cancer cell activity in vitro and in vivo. Consistently, MUC1 and ATAD3A protein levels present an inverse relationship in tumor tissues of breast cancer patients. Our data validate that MUC1/ATAD3A/Pink1 axis-mediated mitophagy constitutes a novel mechanism for maintaining the malignancy of cancer cells, providing a novel therapeutic approach for MUC1-positive cancers.

MUC1 triggers lineage plasticity of Her2 positive mammary tumors.

Aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant MUC1/HER2 in the development of breast cancer has not been fully illustrated. Following analysis of public microarray datasets that revealed a correlation between double MUC1 and HER2 positivity and a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD conferred a growth advantage and promoted the development of spontaneous mammary tumors. Genomic analysis revealed that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity, which is supported by gene reprogramming and mammary stem cell enrichment. Through gain- and loss-of-function strategies, we show that coexpression of Her2 and MUC1-CD is associated with downregulation of tricarboxylic acid (TCA) cycle genes in tumors. Importantly, the reduction in TCA cycle genes induced by MUC1-CD was found to be significantly connected to poor prognosis in HER2+ breast cancer patients. In addition, MUC1 augments the Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping the mammary tumor landscape and highlight the prognostic and therapeutic implications of MUC1 in patients with HER2+ breast cancer.

Sublethal fluvalinate negatively affect the development and flight capacity of honeybee (Apis mellifera L.) workers.

Fluvalinate has been heavily used to control the pest Varroa destructor and residues in honeybee colony causing long-term exposure threat for bees. But, little is known about the lifetime trips and homing ability of worker bees under fluvalinate stresses during the development period. In this study, honeybees from 2-day-old larvae to 7-day-old adults were continuously fed with different concentrations of fluvalinate (0, 0.5, 5 and 50 mg/kg) and the effects of fluvalinate on the development of larvae were examined. And then, all the treated bees were reintroduced into the original source colony and were monitored, and the homing ability of 20 days old bees at 1000 and 2000 m away from the beehive were tested using the radio frequency identification (RFID). We found that fluvalinate significantly activates the superoxide dismutase (SOD) activities of larvae and 5 mg/kg fluvalinate reduced the homing rate of workers at 2000 m away from colony. 50 mg/kg fluvalinate reduced proportion of capped worker cells, activated Cytochrome P450 (CYP450) activity of larvae, affected the foraging times, influenced the homing rate and homing time of one trip at 2000 m away from colony. Our results showed that the larvae can activate the activities of SOD and detoxification enzymes in detoxification of fluvalinate and reduce the influence on honeybees. But, when the concentration is higher than 5 mg/kg fluvalinate, it is difficult for bees to detoxify fluvalinate completely, which affect the homing rate. The results reflect the potential risk for honeybees in the development stage continuously exposed to fluvalinate.

QKI 6 ameliorates CIRI through promoting synthesis of triglyceride in neuron and inhibiting neuronal apoptosis associated with SIRT1-PPARγ-PGC-1α axis.

BACKGROUND: The stroke induced by ischemia of brain remains high incidence and death rate. The study wanted to confirm the effects of Quaking 6 (QKI 6) on the protection role in neurons of rat model of cerebral ischemia/reperfusion injury (CIRI). MATERIAL AND METHODS: The rat model with CIRI induced by middle cerebral artery occlusion was well established and rat neurons were isolated to characterize the effects of QKI 6 mediated by sirtuin 1 (SIRT1) on synthesis of triglyceride in neuron and neuronal apoptosis via activation of SIRT1-peroxisome proliferater-activated receptor (PPAR)γ- peroxisome proliferator-activated receptor coactivator (PGC)-1α signaling pathway. RESULTS: The expression levels of SIRT1 or QKI 6, and acetylation level of QKI 6 were decreased in neurons of rat model with CIRI. QKI 6 deacetylated and mediated by SIRT1 that contributed to suppressing the progression of neuronal apoptosis in rat through promoting synthesis of triglyceride in vivo and in vitro via SIRT1-PPARγ-PGC-1α signaling pathway, then inhibiting CIRI. CONCLUSIONS: Our results demonstrated SIRT1 deacetylates QKI 6, the RNA-binding protein, that affects significantly the synthesis of triglyceride in neurons of CIRI rat model. Moreover, it activated transcription factor peroxisome proliferator-activated receptorγ coactivator-1α (PGC-1α) through post-transcriptional regulation of the expression of PPARγ, and further enhanced synthesis of triglyceride, thereby restrained the progression of neural apoptosis and CIRI.

Tapering of Biological Agents in Juvenile ERA Patients in Daily Clinical Practice.

Objectives: We aim to evaluate the proportion and characteristics of enthesitis-related arthritis (ERA) patients in whom medications can be withdrawn in daily practice and to analyze the factors associated with flare-ups during medication tapering of these patients. Methods: We retrospectively reviewed records of patients under 16 years old diagnosed with ERA from April 2001 to March 2020 in one tertiary medical center in Taiwan. Patients were categorized by different medication uses: conventional disease modifying anti-rheumatic drugs (cDMARDs) only and cDMARDs plus biologics. Demographics, laboratory data, presence of uveitis, and medication withdrawal rate were analyzed. Subgroup analysis was performed in the patients with cDMARDs plus biologics to identify factors associated with flare-ups during medication tapering of these patients. Statistical analysis was performed using R (v3.6.0). Results: There were 75 juvenile ERA patients with a median onset age of 10.28 years old. Nineteen (25.3%) patients used cDMARDs for disease control; 56 (74.7%) patients depended on cDMARDs plus biologics. Poly-articular involvement was noted in 29 (38.7%) patients, and it occurred more frequently in the cDMARDs plus biologics subgroup (cDMARDs only, 5.3%; cDMARDs plus biologics, 53.6%; P = 0.0001). ANA positivity was observed in 18 (24.0%) patients, and it occurred more frequently in the cDMARDs plus biologics subgroup (cDMARDs, 0%; cDMARDs plus biologics, 32.1%; P = 0.0038). The overall medication withdrawal rate was 34.7%, and it occurred more frequently in patients with cDMARDs only (cDMARDs only, 84.2%; cDMARDs plus biologics, 17.9%; P < 0.001). In the subgroup analysis of patients with cDMARDs plus biologics, patients on biologics tapering with flare-up had a significantly longer time interval between disease onset and initiation of cDMARDs (biologics tapering without flare-up: 0.27 (0.11-0.73) years; biologics tapering with flare-up: 1.14 (0.39-2.02) years; ever withdrawing biologics: 0.26 (0.18-0.42) years, P = 0.0104). Conclusion: Juvenile ERA patients with polyarticular involvement had a higher risk of developing cDMARDs refractory and progressing to biologics use. Patients with a long time interval between disease onset and initiation of cDMARDs were prone to experience flare-up during tapering of biologics.

Utilizing ultrasound findings of a single indicator joint to assess non-systemic juvenile idiopathic arthritis.

BACKGROUND: Musculoskeletal ultrasound (MSUS) has been used worldwide in adult patients with rheumatoid arthritis (RA) but is beginning to play an increasing role in patients with juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the application of MSUS findings of a single indicator joint in JIA to assess the disease activity and classify disease subtype. METHODS: Thirty-five non-systemic JIA patients with a total of 62 visits were retrospectively recruited in this study. Among the involved joints, the joint with highest value of grey-scale (GS) plus power Doppler (PD) (=GSPD) was selected as the indicator joint at each visit. The correlations between each MSUS parameter (GS, PD, GSPD) of indicator joints and the Physician Global Assessment (PGA) score, the Childhood Health Assessment Questionnaire-disability index (CHAQ-DI), and laboratory data were analyzed. The ultrasound features in different subtypes of JIA were also compared. RESULTS: PD was weakly correlated with the PGA score (rho = 0.323, p = 0.010), while both GS and GSPD were moderately correlated with the PGA score (rho = 0.405, p = 0.001; rho = 0.434, p = 0.000). On the other hand, GS, PD, and GSPD were weakly correlated with CHAQ-DI. Although erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) had a weak correlation with PGA, they were not statistically correlated with GS, PD, or GSPD. The proportions of effusion, synovial hypertrophy, and enthesopathy in three different subtypes, showed significant differences (Fisher's exact test, p = 0.037; p = 0.004; p = 0.019). Enthesopathy was only seen in joints of enthesitis-related arthritis (ERA), but not in joints of polyarthritis and oligoarthritis. CONCLUSIONS: MSUS is an acceptable non-invasive tool for the patients with JIA, particularly for those with non-systemic JIA, that might assist disease classification, and whose parameters of the indicator joints may potentially contribute to the evaluation of disease activity.

Experience of the use of hydroxychloroquine on patients with COVID-19: A perspective on viral load and cytokine kinetics.

Until now, there are no approved treatment against COVID-19. Hydroxychloroquine (HCQ) was hypothesized to be active against SARS-CoV2 via antiviral and anti-inflammatory effect; however, HCQ for COVID-19 in clinical use remained debating. In this preliminary report, we presented six patients with mild to moderate COVID-19. They were treated with HCQ for 14 days from the day of COVID-19 diagnosis. Serial viral load from respiratory specimens were performed every other day. Cytokine profile was checked before HCQ initiation and on the 14th day of HCQ treatment. All patients receiving HCQ completed 14-day course without complication. Among the six patients, the mean duration from symptom onset to last detectable viral load was 34 ± 12 days, which was similar to those without specific treatment in previous reports. Low level of interferon-gamma was noted in all patients of different stage of infection and three patients had elevation of IL-17 level. Prolonged virus shedding is still observed regardless HCQ. The impact of HCQ on cytokine kinetics remained unclear; however, IL-17 could be an inflammatory marker for disease status monitor and a potential therapeutic target.

Onset age is a risk factor for refractory pediatric IgA vasculitis: a retrospective cohort study.

BACKGROUND: Though outcome differences between children and adults with immunoglobulin A vasculitis (IgAV) has been well documented, it remains unclear if disease features in pediatric IgAV patients vary with onset age. We aimed to explore clinical features and prognosis of pediatric IgAV stratified by onset age. METHODS: We retrospectively reviewed records of patients under 18 years old diagnosed with IgAV from January 1999 to December 2018 in one tertiary medical center in Taiwan. Patients were grouped by onset age: ≤ 6 years old, 6-12 years old (> 6, ≤ 12), and 12-18 years old (> 12, < 18). Demographics, laboratory data, incidence of gastrointestinal, renal, and joint involvement, corticosteroid dependence, recurrence, and refractory disease were analyzed. Recurrence was defined as disease flare-up after complete remission and discontinuation of all medications for at least 3 months. Corticosteroid dependence was defined by more than 6 weeks of daily oral corticosteroid intake. Refractory disease was defined as not achieving complete remission 6 months after disease onset. Statistical analysis was performed using R software (v3.6.0). RESULTS: There were 484 IgAV patients, with an onset age of 6.10 (4.72-8.58) (median (IQR)) years old. There were 234 (48.3%) patients ≤6 years old, 210 (43.4%) 6-12 years old, and 40 (8.3%) 12-18 years old. One hundred and thirty (26.9%) patients had renal involvement, which was more frequent in older children (≤ 6 years old, 18.4%; 6-12 years old, 31.0%; 12-18 years old, 55.0%; p <  0.001). There were 361 patients (74.6%) with joint involvement; younger children were affected more frequently (≤ 6 years old, 82.1%; 6-12 years old, 71.9%; 12-18 years old, 45.0%; p <  0.001). Gastrointestinal involvement was present in 311 (64.3%) patients, showing no difference among age groups. There were 46 patients (9.5%) with recurrent IgA vasculitis, 136 (28.1%) with corticosteroid dependent and 76 (15.7%) with refractory disease. Corticosteroid dependence and refractory disease occurred more frequently as onset age increased (p <  0.001). CONCLUSION: Pediatric IgAV with different onset ages are associated with distinct clinical manifestations and outcomes. The risk of developing corticosteroid dependence, refractory disease and renal involvement increased with onset age.

Exposure to acetamiprid influences the development and survival ability of worker bees (Apis mellifera L.) from larvae to adults.

In most cases, honey bees experience pesticide pollution in a long-term period through direct or indirect exposure, such as the development process from larvae to the pre-harvest stage. At present, little is known about how honey bees respond to pesticide stresses during the continuous development period. This study aims to examine effects of long-term acetamiprid exposure on the development and survival of honey bees, and further present the expression profile in larvae, 1-day-old, and 7-day-old adult worker bees that related to immune, detoxification, acetylcholinesterase (AChE) and memory. Honey bees from 2-day-old larvae to 14-day-old adults except the pupal stage were continuously fed with different acetamiprid solutions (0, 5, and 25 mg/L). We found that acetamiprid over 5 mg/L disturbed the development involving birth weight and emergence rate of newly emerged bees, and reduced the proportion of capped cells of larvae at 25 mg/L; gene expression related to immune and detoxification of worker bees exposed to acetamiprid was roughly activated, returned and then inhibited from larval to emerged and to the late adult stage, respectively. Moreover, lifespans of bees treated with acetamiprid at 25 mg/L were significantly reduced. The present study reflects the potential risk for honey bees continuously exposed to acetamiprid in the development stage.

Sublethal acetamiprid doses negatively affect the lifespans and foraging behaviors of honey bee (Apis mellifera L.) workers.

The neonicotinoid insecticide acetamiprid is applied widely for pest control in agriculture production. However, little is known about the effects of acetamiprid on the foraging behavior of nontarget pollinators. This study aims to investigate effects of sublethal acetamiprid doses on lifespans and foraging behaviors of honey bees (Apis mellifera L.) under natural swarm conditions. Newly emerged worker bees of each treatment received a drop of 1.5 µL acetamiprid solution (containing 0, 0.5, 1, and 2 µg/bee acetamiprid, diluted by water) on the thorax respectively. Bees from 2-day-old to deadline were monitored on foraging behaviors involving the age of bee for first foraging flights, rotating day-off status and the number of foraging flights using the radio frequency identification (RFID) system. We found that acetamiprid at 2 µg/bee significantly reduced the lifespan, induced precocious foraging activity, influenced the rotating day-off status and decreased foraging flights of worker bees. The abnormal behaviors of worker bees may be associated with a decline in lifespan. This work may provide a new perspective into the neonicotinoids that accelerate the colony failure.