Acrylamide, an air pollutant, enhances allergen-induced eosinophilic lung inflammation via group 2 innate lymphoid cells.

Air pollution significantly impacts the aggravation of asthma. Exposure to acrylamide, a volatile organic compound in tobacco smoke, is associated with elevated risks of allergy-related outcomes among active smokers. As group 2 innate lymphoid cells (ILC2s) can act as an environmental sensor and significantly contribute to protease allergen-induced lung inflammation, we aimed to elucidate the causal relationship and how inhaled acrylamide worsens allergic lung inflammation via ILC2s. Intranasal acrylamide exposure at nanomolar levels significantly enhanced allergen-induced or recombinant mouse interleukin-33-induced lung inflammation in C57BL/6 mice or Rag1-/- mice, respectively. The cardinal features of lung inflammation included accumulated infiltration of ILC2s and eosinophils. Transcriptomic analysis revealed a gene expression pattern associated with proliferation-related pathways in acrylamide-treated ILC2s. Western blotting revealed significantly higher expression of Ras and phospho-Erk in acrylamide-treated ILC2s than the control, suggesting Ras-Erk signaling pathway involvement. Ex vivo and in vitro analysis showed that acrylamide treatment mainly increased Ki-67+ ILC2s and the cell number of ILC2s whereas PD98059, a highly selective Erk inhibitor, effectively counteracted the acrylamide effect. Intratracheal administration of acrylamide-treated ILC2s significantly enhanced eosinophil infiltration in Rag1-/- mice. This study suggests that airborne acrylamide may enhance the severity of allergen-induced airway eosinophilic inflammation, partly via altering ILC2 proliferative activity.

Differential item functioning for the Tendency of Avoiding Physical Activity and Sport Scale across two subculture samples: Taiwanese and mainland Chinese university students.

Aims: The aims of the study were to examine the differential item functioning (DIF) of the Tendency of Avoiding Physical Activity and Sport Scale (TAPAS) among three subgroups (gender, weight status, and region) and to test the construct and concurrent validities of the scale. Methods: Using an online survey, university students (608 Taiwanese and 2319 mainland Chinese) completed the TAPAS. Rasch analysis examined if all the 10 TAPAS items fitted the same construct and displayed no substantial DIF across three subgroups: gender (male vs. female), weight status (overweight vs. non-overweight), and region (Taiwan vs. China). Concurrent validity was examined using the scores on the Weight Self-Stigma Questionnaire (WSSQ) and Weight Bias Internalization Scale (WBIS). Results: All TAPAS items, except for Item 10 ("Prefer to participate in physical activity in a more private setting"), fitted the same construct. None of the TAPAS items displayed DIF in any of the subgroups except for Item 10 across participants from Taiwan and China (DIF contrast = -1.41). Conclusion: The TAPAS can appropriately assess the tendency to avoid physical activity and sport among both Taiwanese and mainland Chinese university students. However, Item 10 may need to be further examined.

Investigating the mechanisms underlying U46619-induced contraction on porcine lower esophageal sphincter.

Gastroesophageal reflux disease (GERD) is associated with an incompetent lower esophageal sphincter (LES), resulting in the reflux of gastric contents into the esophagus. U46619, a thromboxane A2 (TXA2) receptor agonist, induces contractions in various smooth muscles. Therefore, this study aimed to investigate the effects and mechanisms of action of U46619 on the porcine LES. To achieve this, contractions of the clasp and sling strips of the porcine LES, induced by U46619 were measured using isometric transducers. Furthermore, the contractile mechanism of U46619 in the porcine LES was investigated by pretreating the strips with atropine (a muscarinic receptor antagonist), tetrodotoxin (a neuronal sodium channel blocker), nifedipine (a calcium channel blocker), and Ca2+-free Krebs-Henseleit solution. Additionally, reverse transcription polymerase chain reaction and immunohistochemistry (IHC) were performed to determine the presence of the TXA2 receptor in porcine LES. The results of this study demonstrated that U46619 caused marked concentration-dependent contractions in both porcine sling and clasp strips. The mechanism of U46619-induced contraction of the porcine LES was found to be related to calcium channels. Furthermore, the reverse transcription PCR analysis and IHC revealed that the TXA2 receptor was expressed in the clasp and sling fibers of porcine LES. Consequently, this study suggests that U46619 mediates the contraction of porcine LES through calcium channels and has potential as a therapeutic approach for treating GERD. Significance Statement This study establishes that U46619 induces concentration-dependent contractions in porcine LES, primarily mediated by calcium channels. The presence of the TXA2 receptor in LES clasp and sling fibers is confirmed. These findings highlight U46619's potential as a GERD therapeutic by targeting calcium channels for LES contraction modulation.

Weight stigma is associated with body mass index among college students in Taiwan: the mediated role of internalized weight stigma.

BACKGROUND: Weight stigma is an issue often studied in Western countries; however, such information is scarce in Asian studies. METHODS: This study aimed to examine the role of internalized weight stigma as a mediator in the relationship between perceived weight stigma and changes in body mass index (BMI). The data were collected through a longitudinal online survey with two phases (n = 974; Phase 1: August and September 2021; Phase 2: November and December 2021). The Perceived Weight Stigma Scale (PWSS), Weight Self-Stigma Questionnaire (WSSQ), and Depression, Anxiety, Stress Scale - 21 (DASS-21) were administered to assess perceived weight stigma, internalized weight stigma, and psychological distress. Hierarchical regressions were used to examine the proposed model, and Hayes' Process Macro was used to test a mediation model. RESULTS: The changes in perceived weight stigma and internalized weight stigma were significantly and positively associated with changes in BMI. There were significant and positive associations between perceived weight stigma, internalized weight stigma and psychological distress over time. Change in internalized weight stigma was found to be a significant mediator in the association of change in perceived weight stigma with change in BMI for the entire sample (unstandardized coefficient = 0.04; 95% CI = 0.02, 0.06), female subgroup (unstandardized coefficient = 0.05; 95% CI = 0.02, 0.08), and male subgroup (unstandardized coefficient = 0.03; 95% CI = 0.01, 0.06). Change in perceived weight stigma also had significant effects on change in BMI for the entire sample and the female subgroup, but not for the male subgroup. CONCLUSION: Because perceived weight stigma may significantly impact changes in BMI through internalized weight stigma, treatment strategies to ameliorate self-stigma may enhance the results of weight-reduction programs. Such treatment strategies should be considered for inclusion in weight-loss interventions.

Weight stigma is commonly studied in Western countries rather than in Asian ones. To further explore how internalized weight stigma mediates the relationship between perceived weight stigma and the changes in body mass index (BMI), the study collected data through a longitudinal online survey with two phases by applying the Perceived Weight Stigma Scale (PWSS), Weight Self-Stigma Questionnaire (WSSQ) and Depression, Anxiety, Stress Scale − 21 (DASS-21) to assess perceived weight stigma, internalized weight stigma, and psychological distress. The changes in perceived and internalized weight stigma were significantly and positively associated with changes in BMI. There were significantly positive associations between perceived weight stigma, internalized weight stigma, and psychological distress over time. Based on the findings, treatment strategies to alleviate self-stigma may enhance the results of weight-reduction programs and should be considered for inclusion in weight-loss interventions.

Validation of the Thai Assessment of Criteria for Specific Internet-use Disorders (ACSID-11) among young adults.

BACKGROUND: The Assessment of Criteria for Specific Internet-use Disorders (ACSID-11) is a consistent and comprehensive instrument to assess symptoms of specific internet-use disorders including those related to gaming, shopping, pornography use disorder, social networks use and gambling considering criteria in the eleventh revision of the International Classification of Diseases (ICD-11). However, to date, there is little evidence supporting instruments assessing major types of specific internet use disorders in Thailand. The aim of this present study was to assess the psychometric properties of the ACSID-11 among Thai young adults. METHODS: A total of 612 participants were recruited. A confirmatory factor analysis (CFA) examined construct validity of the ACSID-11. Cronbach's α and McDonald's ω were used to assess reliability of the ACSID-11. Pearson correlations examined relationships between ACSID-11 domains and Internet Gaming Disorder Scale-Short Form (IGDS9-SF) scores. RESULTS: The CFA supported validity of the Thai version of the ACSID-11 and a four-factor structure. Specific domains of the Thai ACSID-11, particularly gaming, were positively and significantly correlated with IGDS9-SF scores. CONCLUSIONS: Data indicate that the Thai version of the ACSID-11 is a valid and reliable instrument to assess major types of specific internet use disorders. Additional studies are needed to further examine the validity and reliability of the Thai ACSID-11.

Early-Term Neonates Demonstrate a Higher Likelihood of Requiring Phototherapy Compared to Those Born Full-Term.

Early-term neonates (with a gestational age (GA) of 37 and 0/7 weeks to 38 and 6/7 weeks) face higher morbidities, including respiratory and neurodevelopmental issues, than full-term (39 and 0/7 weeks to 40 and 6/7 weeks) infants. This study explores whether hyperbilirubinemia necessitating phototherapy also differs between these groups. A retrospective study was conducted on neonates born from January 2021-June 2022, excluding those with specific conditions. Evaluated factors included GA, birth weight, bilirubin levels, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and feeding type, with phototherapy given as per AAP guidelines. Of 1085 neonates, 356 met the criteria. When stratifying the neonates based on the need for phototherapy, a higher proportion of early-term neonates required phototherapy compared to full-term (p < 0.05). After factoring in various risks (GA; birth weight; gender; feeding type; G6PD deficiency; transcutaneous bilirubin levels at 24 h and 24-48 h postpartum; maternal diabetes; and the presence of caput succedaneum or cephalohematoma), early-term neonates were more likely to need phototherapy than full-term babies (OR: 2.15, 95% CI: 1.21 to 3.80). The optimal cut-off for transcutaneous bilirubin levels 24-48 h postpartum that were used to predict phototherapy need was 9.85 mg/dl. In conclusion, early-term neonates are at a greater risk for developing jaundice and requiring phototherapy than full-term neonates. Monitoring bilirubin 24-48 h postpartum enhances early prediction and intervention.

Comprehensive Analysis of Risk Factors for Bronchopulmonary Dysplasia in Preterm Infants in Taiwan: A Four-Year Study.

Bronchopulmonary dysplasia (BPD) is a major respiratory condition mainly affecting premature infants. Although its occurrence is global, risk factors may differ regionally. This study, involving 3111 infants with birth weight ≤ 1500 gm or gestational age (GA) < 30 weeks, aimed to identify risk factors for BPD and BPD/mortality in Taiwan using data from the Taiwan Neonatal Network. The BPD criteria were based on the National Institute of Child Health and Human Development standards. Average GA was 27.5 weeks, with 23.7% classified as small for GA (SGA). Multivariate analysis highlighted low GA, low birth weight, and other perinatal factors as significant risk indicators for BPD. For moderate-to-severe BPD, additional risk factors included male gender and SGA, endotracheal intubation (ETT) or cardiopulmonary cerebral resuscitation (CPCR) in initial resuscitation. In the moderate-to-severe BPD/death group, SGA and ETT or CPCR in initial resuscitation remained the only additional risk factors. The study pinpoints male gender, SGA and ETT or CPCR as key risk factors for moderate-to-severe BPD/death in low-birth-weight infants in Taiwan, offering a basis for focused interventions and further research.

Integrins and Actions of Androgen in Breast Cancer.

Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells via different types of receptors and different mechanisms. Androgen-induced cancer growth and metastasis link with different types of integrins. Integrin αvß3 is predominantly expressed and activated in cancer cells and rapidly dividing endothelial cells. Programmed death-ligand 1 (PD-L1) also plays a vital role in cancer growth. The part of integrins in action with androgen in cancer cells is not fully mechanically understood. To clarify the interactions between androgen and integrin αvß3, we carried out molecular modeling to explain the potential interactions of androgen with integrin αvß3. The androgen-regulated mechanisms on PD-L1 and its effects were also addressed.

Age and gender differences in misperceptions of body shape in a Taiwanese population.

OBJECTIVES: Most studies of body size perception have been performed in adolescents, and most focus on gender differences in accurate perception of body size. This study investigated misperceptions of body sizes among males and females at different stages of adulthood in Taiwan. DESIGNS: In-person home interviews were used to proportionally and randomly select 2095 adult men and women to answer the East Asian Social Survey. Participants were divided into 18-39, 40-64, and 65 + age groups. The main variables analyzed were self-perceived body size and standardized BMI. RESULTS: Women, unlike men, were more likely to misperceive their body size as being overweight (OR = 2.92; p < .001). People with higher self-perceived social status were less likely to misperceive themselves as overweight (OR = 0.91; p = .01). People with college educations were 2.35 times more likely to overestimate their body size as being heavier than they were (p < .001) and less likely to underestimate it as being thinner than they were (OR = 0.45; p < .001). Women 18-35 and 36-64 years old were 6.96 and 4.31 times more likely (p < .001) to misperceive themselves as being overweight than women 65 or older, who were more likely to misperceive themselves as being too thin. There were no significant differences in body size misperceptions among the three age groups of adult men (p > .05). We found no different significant discrepancies between self-perceived body size and actual BMI between the older men and women (p = .16). However, younger and middle-aged men were 6.67 and 3.1 times more likely to misperceive themselves as being too thin than women in their same age groups (OR = 0.15 and OR = 0.32, respectively). CONCLUSIONS: Age and gender affect self-perceptions of body size in Taiwan. Overall, women are more likely than men to misperceive themselves as being too big, and men are more likely than women to misperceive themselves as too thin. Older women, however, were more likely to misperceive themselves as being too thin. Clinicians and health educators should know that people's perceptions and concerns regarding their body size vary by age and gender.

Psychometric properties and development of the Chinese versions of Gaming Disorder Test (GDT) and Gaming Disorder Scale for Adolescents (GADIS-A).

Currently, six instruments have been developed using the 11th revision of the International Classification of Diseases (ICD-11) criteria for Gaming Disorder (GD). Two of these are the Gaming Disorder Test (GDT) and Gaming Disorder Scale for Adolescents (GADIS-A). The present study validated both the GDT and GADIS-A among a large sample of Chinese emerging adults. Via an online survey, 3381 participants (56.6% females; mean age = 19.56 years) completed the Chinese versions of the GDT, GADIS-A, Internet Gaming Disorder-Short Form (IGDS9-SF), and Bergen Social Media Addiction Scale (BSMAS). Confirmatory factor analysis was used to examine the factor structure of the Chinese GDT and GADIS-A. Pearson correlations were computed to examine the convergent validity (with IGDS9-SF) and divergent validity (with BSMAS) of the Chinese GDT and Chinese GADIS-A. The GDT had a unidimensional structure, which was invariant across sex and disordered gaming severity subgroups. The GADIS-A had a two-factor structure, which was also invariant across gender and gaming severity subgroups. Both the GDT and GADIS-A had significant associations with both IGDS9-SF and with BSMAS. Both the Chinese GDT and GADIS-A are valid instruments to assess GD among emerging adults in mainland China, enabling healthcare providers to adopt these tools in their efforts to prevent and examine GD severity among Chinese youth.

Execution of anticipatory guidance and the knowledge and practice gap among caregivers in Southern Taiwan: A retrospective study.

BACKGROUND/PURPOSE: This study examined the practice rate of Anticipatory Guidance (AG) and the gap between knowledge and practice among caregivers. METHODS: We retrospectively collected data from caregivers who brought their children for seven age-based well-child visits (birth to 7 years old) and seven corresponding AG checklists for practice (each ranged from 16 to 19 guidance items, 118 items in total) between 2015 and 2017. Practice rates of guidance items and their association with children's sex, age, residence, and body mass index were collected and analyzed. RESULTS: We enrolled 2310 caregivers (330 per well-child visit). Average practice rates of guidance items in the seven AG checklists were 77.6%-95.1%, generally without significant differences between urban/rural or male/female children. However, lower (<80%) rates were observed for 32 items, including dental check-ups (38.9%), use of fluoride toothpaste (44.6%), screen time (69.4%), and drinking less sugar-sweetened beverages (SSBs) (75.5%), with corresponding knowledge-to-practice gap rates of 55.5%, 47.9%, 30.3%, and 23.8%, respectively. "Drinking less SSBs" was the only item with a higher obesity rate in the non-achieved group versus the achieved group (16.7% vs. 7.4%, p = 0.036; odds ratio: 3.509, 95% CI: 1.153-10.677, p = 0.027). CONCLUSION: Caregivers in Taiwan practiced most AG recommendations. However, dental check-ups, fluoride toothpaste use, drinking less SSBs, and limiting screen time were less executed items. A higher obesity rate was found among 3-7-year-old children whose caregivers failed to practice the "Drink less SSBs" guidance. Strategies to overcome the gap between knowledge and practice are needed to improve these less-achieved guidance items.

The effect of time spent sitting and excessive gaming on the weight status, and perceived weight stigma among Taiwanese young adults.

Background: During the COVID-19 pandemic, physical inactivity and sedentary behaviors (i.e., longer sitting time and excessive gaming) increased because governments across the globe adopted stringent mitigation strategies such as social distancing and lockdowns to curb the spread of the virus. Excessive gaming was one of the coping mechanisms used to deal with the pressure associated with the pandemic. Moreover, perceived weight stigma (PWS) and weight status became more salient concerns among young adults during the COVID-19 pandemic. The current study sought to investigate the relationship between time spent sitting, excessive gaming, weight status, and PWS of Taiwanese Young adults. Additionally, weight status and PWS were examined as mediators between both sedentary behaviors. Methods: This cross-sectional study involved 600 participants who were recruited through Taiwan universities. All participants completed a demographic questionnaire (including weight and height) and self-report measures including the International Physical Activity Questionnaire short form (IPAQ-SF), the Perceived Weight Stigma Scale (PWSS), and the Internet Gaming Disorder Scale-short form (IGDS9-SF). PROCESS model was performed to test the potential mediation roles of weight status and PWS. Moreover, we categorized participants into two groups based on the sitting-time item in the IPAQ-SF: students whose sitting time was less than 8 h daily, and those more than 8 h daily. Results: The group that had less than 8 h had significantly higher PWS and IGDS9-SF scores than the other group. Sitting time was negatively associated with weight status, PWS, and IGDS9-SF. Additionally, we found a significantly direct effect between time spent sitting and excessive gaming. Both weight status and PWS were significant mediators in the association between time spent sitting and excessive gaming.Conclusions: The present study demonstrated important negative correlates of excessive sedentary behaviors. Prevention efforts should focus on promoting physical activity and providing information to decrease sedentary behavior among university students.

Unnecessary radiation exposure during diagnostic radiography in infants in a neonatal intensive care unit: a retrospective cohort study.

Unnecessary radiation exposure (URE) during radiographic examination is an issue among infants in neonatal intensive care units (NICUs). The causes of URE have not been fully explored. This study investigated the incidence and identified the causes of URE in infants during diagnostic radiography in a NICU. This was a retrospective cohort study. We retrieved and analysed requests and radiographs taken at a tertiary NICU between September and November 2018. URE was defined as the rate of discordance between requests and images taken (DisBRI) and unnecessary radiation exposure in irrelevant regions (UREIR) during radiography. We compared the rates of URE between very low-birth-weight (VLBW, birth weight < 1500 g) infants and non-VLBW infants. A total of 306 radiographs from 88 infants were taken. The means ± standard deviations (SDs) of gestational age and birth weight were 35.7 ± 3.6 weeks and 2471 ± 816 g, respectively. Each infant underwent an average of 3.5 radiographs. The DisBRI rate was 1.3% and was mostly related to poor adherence to requests. The UREIR rates in thoraco-abdominal babygrams were 89.6% for the head, 14.8% for the elbows and 18.4% for the knee and were mainly related to improper positioning of and collimation in infants while performing radiography. The UREIR rates for the head, knee and ankle were higher in VLBW infants than in non-VLBW infants (94.6% vs. 85.6%, 27.0% vs. 11.5% and 5.4% vs. 0.7%, respectively, p < 0.05). CONCLUSIONS: URE during diagnostic radiography is common in sick infants and is mainly related to improper positioning and collimation during examinations. Adherence to protocols when performing radiographic examination or using ultrasonography may be a solution to reduce URE in infants in NICUs. WHAT IS KNOWN: • The risk of unnecessary radiation exposure (URE) during radiography has been a common and important issue in sick infants in neonatal intensive care units (NICUs). • The new point-of-care ultrasound (POCUS) technique decreases the need for chest films and prevents radiation exposure in neonates. WHAT IS NEW: • In the NICU, URE is still a common issue in critically ill infants during radiographic examinations. The causes of URE during diagnostic radiography are mainly due to improper positioning and collimation during examinations. • The incidence of URE in irrelevant regions is higher in very low-birth-weight (VLBW) infants than in non-VLBW infants.

Problematic Use of Internet Among Indonesia University Students: Psychometric Evaluation of Bergen Social Media Addiction Scale and Internet Gaming Disorder Scale-Short Form.

OBJECTIVE: Social media addiction and internet gaming disorder may cause mental health problems among a minority of university students. The Bergen Social Media Addiction Scale (BSMAS) and the 9-item Internet Gaming Disorder Scale-Short Form (IGDS9-SF) are commonly used worldwide. However, they have not been translated or validated into Indonesian. The present study aimed to translate and validate the BSMAS and IGDS9-SF in an Indonesian context among young adults. METHODS: A multi-center, web-based cross-sectional study was conducted among 458 university students (74% female; mean age 22.5 years) in Indonesia from June to December 2021. The BSMAS and IGDS9-SF were translated into Indonesian. Internal consistency (using Cronbach's α and McDonald's ω) and factor structure (using confirmatory factor analysis) of the two instruments were examined. Concurrent validity of BSMAS and IGDS9-SF was examined using their correlations with two external concepts: nomophobia and psychological distress. RESULTS: Internal consistency of the Indonesian BSMAS and IGDS9-SF were both acceptable (Cronbach's α=0.80 and 0.90; McDonald's ω=0.86 and 0.92). Both instruments were unidimensional with good factor loadings (0.54-0.78 for BSMAS; 0.63-0.79 for IGDS9-SF). Moreover, BSMAS and IGDS9-SF had stronger associations with nomophobia (r=0.58 and 0.12; p<0.001) than with psychological distress (r=0.43 and 0.15; p<0.001). CONCLUSION: The Indonesian versions of the BSMAS and IGDS9-SF had good psychometric properties in terms of linguistic validity, unidimensionality, and reliability. The findings indicate the tools are appropriate for assessing the risk of social media addiction and internet gaming disorder among university students in Indonesia.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside improves female ovarian aging.

Reduced fertility associated with normal aging may reflect the over-maturity of oocytes. It is increasingly important to reduce aging-induced infertility since recent trends show people marrying at later ages. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, has been reported to have anti-inflammatory and anti-aging properties. To evaluate whether THSG can reduce aging-related ovarian damage in a female mouse model of aging, THSG was administered by gavage at a dose of 10 mg/kg twice weekly, starting at 4 weeks of age in a group of young mice. In addition, the effect of THSG in a group of aged mice was also studied in mice starting at 24 weeks of age. The number of oocytes in the THSG-fed group was higher than in the untreated control group. Although the percentage of secondary polar bodies (PB2) decreased during aging in the THSG-fed group, it decreased much more slowly than in the age-matched control group. THSG administration increased the quality of ovaries in young mice becoming aged. Western blotting analyses also indicated that CYP19, PR-B, and ER-ß expressions were significantly increased in 36-week-old mice. THSG also increased oocyte numbers in aged mice compared to mice without THSG fed. Studies of qPCR and immunohistochemistry (IHC) analyses of ovaries in the aged mice groups were conducted. THSG increased gene expression of anti-Müllerian hormone (AMH), a biomarker of oocyte number, and protein accumulation in 40-week-old mice. THSG increased the expression of pgc1α and atp6, mitochondrial biogenesis-related genes, and their protein expression. THSG also attenuated the fading rate of CYP11a and CYP19 associated with sex hormone synthesis. And THSG maintains a high level of ER-ß expression, thereby enhancing the sensitivity of estrogen. Our findings indicated that THSG increased or extended gene expression involved in ovarian maintenance and rejuvenation in young and aged mice. On the other hand, THSG treatments significantly maintained oocyte quantity and quality in both groups of young and aged mice compared to each age-matched control group. In conclusion, THSG can delay aging-related menopause, and the antioxidant properties of THSG may make it suitable for preventing aging-induced infertility.

Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells.

Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvß3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.

Posterior Sagittal Anorectoplasty for Acquired Imperforate Anus Complicated by Anorectal Necrosis: A Case Report.

Anorectal necrosis is an uncommon lethal disease in children, characterized by necrosis of the mucosa of the anus and rectum. The difference between anorectal necrosis and Fournier's gangrene is that anorectal necrosis does not affect the genital organs. The treatment for anorectal necrosis includes debridement of the anus, colostomy, and the use of broad-spectrum antibiotics. However, anorectal necrosis may lead to anal stricture, anal malfunction, or even acquired atresia of the anus. There is no consensus on the treatment for acquired imperforate anus. Herein, we report a case of a four-month-old boy with acquired imperforate anus complicated by anorectal necrosis. We describe our experience performing posterior sagittal anorectoplasty to reconstruct a neo-anus in such a rare case.

Role of Integrin αvß3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells.

Doxycycline, an antibiotic, displays the inhibition of different signal transduction pathways, such as anti-inflammation and anti-proliferation, in different types of cancers. However, the anti-cancer mechanisms of doxycycline via integrin αvß3 are incompletely understood. Integrin αvß3 is a cell-surface anchor protein. It is the target for estrogen, androgen, and thyroid hormone and plays a pivotal role in the proliferation, migration, and angiogenic process in cancer cells. In our previous study, thyroxine hormones can interact with integrin αvß3 to activate the extracellular signal-regulated kinase 1/2 (ERK1/2), and upregulate programmed death-ligand 1 (PD-L1) expression. In the current study, we investigated the inhibitory effects of doxycycline on proliferation in two breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Doxycycline induces concentration-dependent anti-proliferation in both breast cancer cell lines. It regulates gene expressions involved in proliferation, pro-apoptosis, and angiogenesis. Doxycycline suppresses cell cyclin D1 (CCND1) and c-Myc which play crucial roles in proliferation. It also inhibits PD-L1 gene expression. Our findings show that modulation on integrin αvß3 binding activities changed both thyroxine- and doxycycline-induced signal transductions by an integrin αvß3 inhibitor (HSDVHK-NH2). Doxycycline activates phosphorylation of focal adhesion kinase (FAK), a downstream of integrin, but inhibits the ERK1/2 phosphorylation. Regardless, doxycycline-induced FAK phosphorylation is blocked by HSDVHK-NH2. In addition, the specific mechanism of action associated with pERK1/2 inhibition via integrin αvß3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of PD-L1 expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvß3 inhibitor (HSDVHK-NH2) or a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase (MAPK/ERK, MEK) inhibitor (PD98059). The results imply that doxycycline may interact with integrin αvß3 and inhibits ERK1/2 activation, thereby regulating cell proliferation and downregulating PD-L1 gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.

Determining programmed cell death ligand 1 expression in circulating tumor cells of patients with clear cell renal cell carcinoma and its correlation with response to programmed cell death protein 1 inhibitors.

OBJECTIVE: There is a great interest in determining whether the expression of the programmed cell death ligand 1 is correlated with the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma; however, primary tumor biopsies can only provide limited information. Therefore, we explored the expression of programmed cell death ligand 1 on circulating tumor cells, which is a potential predictor of therapeutic response. METHODS: Circulating tumor cells were isolated from 20 clear cell renal cell carcinoma patients based on cell surface markers targeting clear cell renal cell carcinoma using IsoFlux device, followed by identification according to cell morphology and immunofluorescence studies. Programmed cell death ligand 1 expression status and clinical correlations were also analyzed. RESULTS: Before treatment with programmed cell death protein 1 inhibitors, circulating tumor cells were detected in all patients, ranging from 1 to 22 (median 7), with 75% (15/20) of the patients having programmed cell death ligand 1 + circulating tumor cells. Circulating tumor cell programmed cell death ligand 1 expression did not correlate with the immunohistochemical staining of programmed cell death ligand 1 in primary tumors. During treatment with programmed cell death protein 1 inhibitors, the disease control rate was much higher in the patients harboring programmed cell death ligand 1 + circulating tumor cells (73%, 11/15) than others (20%, 1/5). We also found that changes in total circulating tumor cell numbers and programmed cell death ligand 1 + circulating tumor cell counts correlated well with the disease outcome. CONCLUSION: We showed that the presence of programmed cell death ligand 1 + circulating tumor cells before programmed cell death protein 1 inhibition treatment could be a prognosis predictive factor and that the dynamic changes in circulating tumor cell numbers may be used to monitor the therapeutic response. Our study confirms the possibility of programmed cell death ligand 1 + circulating tumor cell detection in clear cell renal cell carcinoma patients' blood samples, which can potentially be used as an individualized immunotherapy molecular biomarker for real-time exploration.