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Hsing-Ching Huang,1,* Liu-Ing Bih,1,* Ming-Miau Tsai,1 Tzu-Ling Chang,1 Wan-Chun Liao,1 Chung-Liang Lai2 1Department of Physical Medicine and Rehabilitation, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 2Department of Occupational Therapy, Asia University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Chung-Liang Lai, Department of Occupational Therapy, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, Email laipeter57@yahoo.com.twBackground: Traumatic brain injury (TBI) can result in functional impairments. Many patients with TBI require post-acute care to improve their functional skills and allow for greater self-independence and a better quality of life. Taiwan’s National Health Insurance proposed a nationwide post-acute care program in 2017 for patients with traumatic brain injury. The program’s goal was to maximize patients’ functional recovery and make it possible for them to return to their homes and communities. This study aimed to explore the effectiveness of such programs in Taiwan.Methods: This pilot study retrospectively evaluated a de-identified database that contained the scores of various assessments evaluated at admission and discharge. It used the data to determine the functional improvement of patients with traumatic brain injury after participating in post-acute care programs.Results: This study collected complete data from 27 patients. After an average of 45.11 days in the program, the patients showed significant improvement in the Barthel Activity Daily Living Index, the Lawton–Brody Instrumental Activity Daily Living Scale, the Mini Nutrition Assessment, the EuroQol Five Dimensions Questionnaire, the Berg Balance Scale, the Galveston Orientation and Amnesia Test, the Rancho Los Amigos Scale, the Concise Chinese Aphasia Test, and the Mini Mental State Examination. After discharge, 96% of the patients could return to their community.Conclusion: This pilot study concluded that the program significantly promoted functional recovery for patients and could help patients with traumatic brain injury return to their communities and reduce the risk of institutionalization. Thus, patients with the potential for functional recovery could receive post-acute care in regional or community hospitals immediately after being discharged from acute wards. In the future randomized controlled trials are needed to further confirm the clinical impact of this program.Keywords: traumatic brain injury, rehabilitation, post-acute care

Wei-Ching Huang,1,* Ming-Miau Tsai,1,* Tzu-Ling Chang,1 Chung-Liang Lai1,2 1Department of Physical Medicine and Rehabilitation, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 2Department of Occupational Therapy, Asia University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Chung-Liang LaiDepartment of Physical Medicine and Rehabilitation, Taichung Hospital, Ministry of Health and Welfare, 199 San Min Road, Sec. 1, Taichung, Taiwan 403, TaiwanEmail laipeter57@yahoo.com.twBackground: Popliteal artery entrapment syndrome (PAES) is a rare disease in young adults and is thought to be under-diagnosed, and its main cause is the abnormal structure between the popliteal artery and gastrocnemius muscle. The patients experience symptoms after the blood vessels are compressed. Failure to diagnose and treat PAES can cause serious sequelae.Case: A 19-year-old male baseball pitcher with PAES type 2 suffered from left calf muscle tension and foot numbness and was mis-diagnosed for nearly a year. Finally, the lesion was detected by ultrasonography and confirmed by magnetic resonance imaging. After surgical intervention, he quickly returned to sport.Discussion/Conclusion: PAES has 6 types. Type 2 (25%) and type 3 (30%) are the most common. Patients with this syndrome suffer from aching pain, numbness, and cramping in the calf area when they exercise. It is necessary to include this disease in differential diagnosis to implement early diagnosis, and ultrasonography is a more cheap and simple method for early detection.Keywords: popliteal artery entrapment syndrome, intermittent claudication

Chung-Liang Lai,1,* Ming-Miau Tsai,1,* Jia-Yuan Luo,1 Wan-Chun Liao,1 Pi-Shan Hsu,2,3 Han-Yu Chen4 1Department of Physical Medicine and Rehabilitation, 2Department of Family Medicine, Taichung Hospital, Ministry of Health and Welfare, 3Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, 4Department of Physical Therapy, Hungkuang University, Taichung, Taiwan *These authors contributed equally to this work Background: Stroke often causes functional decline in patients. Therefore, after the acute phase, many patients require post-acute care (PAC) to maximize their functional progress, reduce disability, and make it possible for them to return to their home and community. PAC can be provided in different settings. Taiwan’s National Health Insurance (NHI) proposed a PAC pilot program, effective since 2014, for stroke patients that allowed patients with the potential for functional improvement to receive PAC rehabilitation in regional or community hospitals. The purpose of this study was to explore the initial achievements and clinical impact of this program in Taiwan. Methods: This was a retrospective cohort study that mainly analyzed basic hospitalization data and scores for function and quality of life, as recorded immediately after admission and before discharge, for stroke patients in the PAC program in a hospital in Taiwan. Results: This study collected complete data from a total of 168 patients. After an average of 43.57 days in the program, patients showed significant improvement in the Modified Rankin Scale (MRS), the Barthel Activity Daily Living Index (B-ADL), the Lawton–Brody Instrumental Activity Daily Living Scale (LB-IADL), the Functional Oral Intake Scale (FOIS), and the Mini Nutrition Assessment (MNA), in mobility, self-care, and usual activity, as well as on anxiety/depression in the EuroQol Five Dimensions Questionnaire (EQ-5D) and in the Mini Mental State Examination (MMSE). After discharge, 76.8% of the patients could return to their home and community. Conclusion: This study showed that the pilot PAC program significantly promoted recovery of function in stroke patients and helped them to return to their home and community. Patients with the potential for functional recovery should consider receiving PAC service in a hospital after discharge from acute stroke care. Keywords: post-acute care, rehabilitation, stroke

Hypophosphatemic rickets is a rare metabolic bone disease caused by renal phosphate wasting, leading to impaired bone mineralization. We present a case of a boy with fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets who did not achieve callus consolidation after six months of conventional therapy with phosphate and active vitamin D following corrective osteotomy. After one month of therapy with an FGF23 antibody (burosumab), the patient demonstrated significant improvement and no longer required a walking aid. Following six months of burosumab therapy, the bone had nearly fully healed. This report is the first to address the short-term use of burosumab therapy to promote bone healing after orthopedic surgery. Our findings further emphasize the clinical advantages and short-term applications of burosumab in FGF23-related hypophosphatemic diseases, especially for patients undergoing orthopedic surgery., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Citrin deficiency is a rare metabolic disorder prevalent in East and Southeast Asia that affects liver or neurological function throughout various life stages. While early diagnosis and dietary management can improve prognosis for infant onset disease, data on long-term neurocognitive outcomes is scarce., Purpose: This study aimed to clarify whether transient metabolic disturbances during early childhood have a lasting effect on the neurocognitive function of individuals with citrin deficiency., Methods: Thirty patients diagnosed with citrin deficiency prior to 1 year of age underwent neuropsychological assessments including attention-deficit/hyperactivity disorder (ADHD) and intelligence quotient (IQ). We compared the peak laboratory values during infancy between children who were versus were not later diagnosed with ADHD., Results: Neurocognitive assessments of 30 individuals with citrin deficiency aged 3-25 years revealed that full-scale IQ scores were normally distributed. Of this cohort, 47% (14 of 30) were diagnosed with ADHD: six, six, and two with the combined, inattentive, and hyperactive-impulsive types, respectively. This prevalence was higher than that in the general population (1.7-16%). Moreover, a one-unit increase in ammonia levels before 1 year of age was associated with a 1.023-fold increase in the likelihood of future hyperactivity-impulsivity symptoms (p = 0.038; 95% confidence interval, 1.001-1.046). Despite these findings, this long-term follow-up of individuals with citrin deficiency indicated that it had minimal impact on neurocognitive function, allowing for a generally normal life., Conclusion: Patients with a history of cholestasis caused by citrin deficiency during infancy have a greater incidence of ADHD than the general population, suggesting that metabolic disturbances during early childhood in individuals with citrin deficiency may have a long-term negative impact on their neurocognitive function.

Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E 2 (PEG 2 ) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE 2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG 2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG 2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation., Competing Interests: The authors declare no conflicts of interest.

Introduction: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides nutrition support for racially and ethnically diverse populations. In 2021, the monthly cash value benefit (CVB) for the purchase of fruits and vegetables increased from $9 to $35 and was later adjusted to $24. This study investigated, by racial and ethnic groups, whether CVB increases were associated with increases in CVB redemption, household food security, child fruit and vegetable intake, satisfaction with CVB amount, and likelihood of continued participation in WIC if the CVB returned to $9 per month., Methods: We conducted a longitudinal study of WIC participants (N = 1,770) in southern California at 3 time points, from April 2021 through May 2022; the CVB amount was $9 at baseline, $35 at Survey 2, and $24 at Survey 3. Racial and ethnic groups were Hispanic English-speakers, Hispanic Spanish-speakers, non-Hispanic Asian, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. We used mixed-effect and modified Poisson regressions to evaluate outcomes by group., Results: At baseline, groups differed significantly in dollars of CVB redeemed, percentage of CVB redeemed, household food security, and satisfaction with CVB amount. After the increase in CVB, we found increases in all groups in CVB redemption, household food security, and satisfaction. Non-Hispanic Black and Hispanic English-speaking groups, who had low levels of satisfaction at baseline, had larger increases in satisfaction than other groups. Reported likelihood of continued WIC participation if the monthly CVB returned to $9 also differed significantly by group, ranging from 62.5% to 90.0%., Conclusion: The increase in CVB for children receiving WIC benefited all racial and ethnic groups. Continued investment in an augmented CVB could improve health outcomes for a racially and ethnically diverse WIC population.

Introduction: The U.S. safety net, which provides critical aid to households with low income, is composed of a patchwork of separate programs, and many people with low income benefit from accessing <1 program. However, little is known about multiprogram take-up, that is, participation conditioned on eligibility. This study examined individual and multiprogram take-up patterns and sociodemographic factors associated with multiprogram take-up of U.S. safety net programs., Methods: The Assessing California Communities' Experiences with Safety Net Supports study interviewed Californians and reviewed their 2019 tax forms between August 2020 and May 2021. Take-up of safety net programs was calculated among eligible participants ( n =365), including the Earned Income Tax Credit; Supplemental Nutrition Assistance Program; the Special Supplemental Nutrition Program for Women, Infants, and Children; and Medicaid. Multivariable regressions identified sociodemographic factors associated with take-up of multiple programs., Results: Take-up was highest for Medicaid (90.6%) and lowest for Supplemental Nutrition Assistance Program (57.5%). Among people who received benefits from at least 1 other program, take-up ranged from 81.7% to 84.8% for the Earned Income Tax Credit; 54.4%-62.0% for Supplemental Nutrition Assistance Program; 74.3%-80.1% for Special Supplemental Nutrition Program for Women, Infants, and Children; and 89.7%-98.1% for Medicaid. Having a lower income and being younger were associated with concurrent take-up of Supplemental Nutrition Assistance Program and Special Supplemental Nutrition Program for Women, Infants, and Children. Among Supplemental Nutrition Assistance Program and Special Supplemental Nutrition Program for Women, Infants, and Children recipients, having higher income, being older, and being primarily English speaking were associated with Earned Income Tax Credit take-up., Conclusions: Individual and multiprogram take-up vary between programs and by sociodemographic factors. Findings suggest opportunities to increase take-up of potentially synergistic programs by improving cross-program coordination, data sharing, and targeted recruitment of underenrolled subgroups (Supplemental Nutrition Assistance Program and Special Supplemental Nutrition Program for Women, Infants, and Children)., (© 2024 The Authors.)

Matrix metalloproteinases (MMPs), which are proteolytic enzymes, promote blood-brain barrier (BBB) disruption, leading to neuronal damage and neuroinflammation. Among them, MMP-9 upregulation serves as an inflammatory biomarker in the central nervous system (CNS). Currently, the development of marine organism-derived bioactive compounds or metabolites as anti-inflammatory drugs has received considerable attention. The 9,11-secosteroid, 3β,11-dihydroxy-9,11-secogorgost-5-en-9-one (4p3f), is a novel sterol compound extracted from the soft coral Sinularia leptoclado with potential anti-inflammatory activity. However, the effect of and potential for brain protection of 4p3f on brain astrocytes remain unclear. Herein, we used rat brain astrocytes (RBAs) to investigate the effects and signaling mechanisms of 4p3f on lipopolysaccharide (LPS)-induced MMP-9 expression via zymographic, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence staining, promoter-reporter, and cell migration analyses. We first found that 4p3f blocked LPS-induced MMP-9 expression in RBAs. Next, we demonstrated that LPS induced MMP-9 expression via the activation of ERK1/2, p38 MAPK, and JNK1/2, which is linked to the STAT3-mediated NF-κB signaling pathway. Finally, 4p3f effectively inhibited LPS-induced upregulation of MMP-9-triggered RBA cell migration. These data suggest that a novel sterol from soft coral, 4p3f, may have anti-inflammatory and brain-protective effects by attenuating these signaling pathways of MMP-9-mediated events in brain astrocytes. Accordingly, the soft coral-derived sterol 4p3f may emerge as a potential candidate for drug development or as a natural compound with neuroprotective properties.

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, including the CNS. Among them, a flavonoid compound, sophoraflavanone G (SG), found in Sophora flavescens has been found to possess several medicinal properties, including anti-bacterial and anti-inflammatory effects. In this study, mouse brain microvascular endothelial cells (bMECs) were used to explore TNF-α-induced MMP-9 signaling. The effects of SG on TNF-α-induced MMP-9 expression and its mechanisms were further evaluated. Our study revealed that the expression of MMP-9 in bMECs was stimulated by TNF-α through the activation of ERK1/2, p38 MAPK, and JNK1/2 via the TNF receptor (TNFR) with a connection to the NF-κB signaling pathway. Moreover, we found that SG can interact with the TNFR. The upregulation of MMP-9 by TNF-α may lead to the disruption of zonula occludens-1 (ZO-1), which can be mitigated by SG administration. These findings provide evidence that SG may possess neuroprotective properties by inhibiting the signaling pathways associated with TNFR-mediated MMP-9 expression and the subsequent disruption of tight junctions in brain microvascular endothelial cells.

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as the μ-opioid receptor (MOR) agonists, are associated with serious intoxication and fatal overdose. Previous studies proposed that G protein biased MOR agonists are safer pain medications, while other evidence indicates that low intrinsic efficacy at MOR better explains reduced opioid side effects. Here, we characterized the in vitro functional profiles of various NSOs at MOR using adenylate cyclase inhibition and β-arrestin2 recruitment assays, in conjunction with the application of the receptor depletion approach. By fitting the concentration-response data to the operational model of agonism, we deduced the intrinsic efficacy and affinity for each opioid in the Gi protein signaling and β-arrestin2 recruitment pathways. Compared to the reference agonist DAMGO, we found that several fentanyl analogs were more efficacious at inhibiting cAMP production, whereas all fentanyl analogs were less efficacious at recruiting β-arrestin2. In contrast, the non-fentanyl 2-benzylbenzimidazole (i.e., nitazene) analogs were highly efficacious and potent in both the cAMP and β-arrestin2 assays. Our findings suggest that the high intrinsic efficacy of the NSOs in Gi protein signaling is a common property that may underlie their high risk of intoxication and overdose, highlighting the limitation of using in vitro functional bias to predict the adverse effects of opioids. Instead, our results show that, regardless of bias, opioids with sufficiently high intrinsic efficacy can be lethal, especially given the extremely high potency of many of these compounds that are now pervading the illicit drug market., Competing Interests: Declarations of Competing Interests No potential conflict of interest was reported by all authors.

Lysosomal storage diseases (LSDs) are a group of metabolic disorders resulting from a deficiency in one of the lysosomal hydrolases. Most LSDs are inherited in an autosomal or X-linked recessive manner. As LSDs are rare, their true incidence in Taiwan remains unknown. In this study, we used high-coverage whole-genome sequencing data from 1,495 Taiwanese individuals obtained from the Taiwan Biobank. We found 3826 variants in 71 genes responsible for autosomal recessive LSDs. We first excluded benign variants by allele frequency and other criteria. As a result, 270 variants were considered disease-causing. We curated these variants using published guidelines from the American College of Medical Genetics and Genomics (ACMG). Our results revealed a combined incidence rate of 13 per 100,000 (conservative estimation by pathologic and likely pathogenic variants; 95% CI 6.92-22.23) to 94 per 100,000 (extended estimation by the inclusion of variants of unknown significance; 95% CI 75.96-115.03) among 71 autosomal recessive disease-associated genes. The conservative estimations were similar to those in published clinical data. No disease-causing mutations were found for 18 other diseases; thus, these diseases are likely extremely rare in Taiwan. The study results are important for designing screening and treatment methods for LSDs in Taiwan and demonstrate the importance of mutation curation to avoid overestimating disease incidences from genomic data., (© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.)

Introduction: The life expectancy of Pompe disease patients has increased due to improved neonatal screening and enzyme replacement therapy. Nevertheless, the potential effect of frequent medical device exposure on pubertal development in these patients is not well understood, so further investigation is warranted., Methods: In this cross-sectional study, we assessed the growth and puberty of nine Pompe disease patients. In addition, to determine the effects of frequent plastic medical device exposure in these patients, we measured urinary phthalate metabolites before and one day after enzyme replacement therapy., Results: Five out of nine patients (55%) with Pompe disease on enzyme replacement therapy had precocious puberty. Patients with precocious puberty had significantly shorter predicted adult heights compared to those with normal puberty ( p = 0.014). The levels of mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) increased after enzyme replacement therapy, but the average levels of phthalate metabolites did not significantly differ between patients with normal and precocious puberty., Conclusion: Pompe disease patients on enzyme replacement therapy tend to have precocious puberty, which may reduce their adult height. There are no significant differences in urinary phthalate metabolites between normal and precocious puberty patients. Regular follow-up of growth and puberty in Pompe disease patients is important to improve their health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tsai, Chen, Chien and Tung.)

Background: Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) food packages for children ages 1 to 4 y include a cash value benefit (CVB) redeemable for fruits and vegetables (FVs) with participating vendors. The CVB value was increased beginning in June 2021., Objectives: This study evaluated associations of the augmented CVB with the amount and diversity of redeemed FVs., Methods: Price look-up codes (PLUs) in redemption data determined outcomes including any redemption (any, none), amount redeemed (United States dollars [USD]/mo), and percent of total CVB redemption (percent) in 54 FV commodity groups among a cohort of 1770 WIC-participating children in Southern California. Outcomes across all commodity groups for fresh fruits, fresh vegetables, and all FVs were evaluated including dollar amount redeemed , percentage of redemption , and diversity of produce redeemed (variety and balance among items redeemed). Comparisons were made between augmented CVB periods (35 USD/mo in June-September 2021, 24 USD/mo October 2021-June 2022) and the preaugment period (9 USD/mo in June 2020-May 2021). Associations were tested in multivariable generalized estimating equation Poisson (any redemption) and linear (amount, percent, diversity) regression models., Results: The augmented CVB was associated with higher any redemption prevalence and amount redeemed for 53 of 54 commodity groups at both 35 USD/mo and 24 USD/mo compared with 9 USD/mo. Redemption diversity increased for both fruits, vegetables, and all produce during both augment periods, and modestly greater increases in redeemed fruits relative to vegetables were observed at 35 USD/mo. The most commonly redeemed vegetables were tomatoes, onions, cucumbers, peppers, and avocados and the most commonly redeemed fruits were bananas, apples, grapes, limes, and melons., Conclusions: The augmented CVB was associated with greater redeemed FV amount and greater redeemed FV diversity. Data on FV intake diversity among WIC-participating children are needed to understand dietary impacts of the CVB increase., (© 2023 The Authors.)

The United States (US) School Breakfast Program provides Breakfast After The Bell (BATB) to alleviate hunger, provide nutrition, and ensure students have a healthy start to the day. This study aims to review the evidence regarding the impact of BATB on students' diet and academic outcomes, including participation, diet quality and consumption, body mass index (BMI) and weight status, attendance, classroom behavior, and academic performance. The articles were extracted from three electronic databases and published since the start of the literature through December 2022. Studies were peer-reviewed; quantitative research articles or government reports; and conducted in public or private elementary, middle, and high schools. Quality was assessed using the Newcastle-Ottawa Scale. Thirty-seven studies were included in this review. This review found BATB increased school breakfast participation, improved diet quality, and improved classroom behavior particularly among students from racial and ethnic minority backgrounds and students eligible for free or reduced-price meals. The impact of BATB on BMI and weight status, academic achievement and attendance was mixed. This review is particularly timely given free school meals and updated school nutrition standards are being prioritized over the next decade in the US. Thus, it is important to evaluate the nutritional and educational outcomes of BATB. (PROSPERO registration: CRD42021289719).

Liver cancer is one of the most lethal cancers in the world, mainly owing to the lack of effective means for early monitoring and treatment. Accordingly, there is considerable research interest in various clinically applicable methods for addressing these unmet needs. At present, the most commonly used biomarker for the early diagnosis of liver cancer is alpha-fetoprotein (AFP), but AFP is sensitive to interference from other factors and cannot really be used as the basis for determining liver cancer. Treatment options in addition to liver surgery (resection, transplantation) include radiation therapy, chemotherapy, and targeted therapy. However, even more expensive targeted drug therapies have a limited impact on the clinical outcome of liver cancer. One of the big reasons is the rapid emergence of drug resistance. Therefore, in addition to finding effective biomarkers for early diagnosis, an important focus of current discussions is on how to effectively adjust and select drug strategies and guidelines for the treatment of liver cancer patients. In this review, we bring this thought process to the drug resistance problem faced by different treatment strategies, approaching it from the perspective of gene expression and molecular biology and the possibility of finding effective solutions.

Background/purposes: Congenital adrenal hyperplasia attributable to 21-hydroxylase deficiency (21-OHD) is a disorder of adrenal steroidogenesis. Achievement of optimal growth by such patients is challenging. We evaluated the adult height of Taiwanese children with 21-OHD and the effect of a gonadotropin-releasing hormone analogue (GnRHa) in patients with central precocious puberty (CPP) complicating 21-OHD., Methods: Among 116 patients with 21-OHD in Taiwan, 90 who had attained adult height were subjected to an analysis of height outcomes. Nine with progressive CPP were treated with GnRHa and the effects of this therapy on adult height were further analyzed., Results: In the pre-screening era, the percentage of boys with 21-OHD was lower than expected. Although neonatal screening can prevent mortality caused by adrenal crisis, some cases may be missed. The pooled mean adult height of the 78 patients treated with conventional therapy were -1.1 SD and -0.5 SD adjusting for the genetic potential. The disease features affecting height outcomes are the genetic height potential and in boys the simple virilizing type. Nine patients with CPP were treated with GnRHa in addition to conventional therapy; the mean adult height increased from the predicted -4.1 SD to -1.0 SD after 6.0 ± 2.5 years of treatment., Conclusion: Patients with 21-OHD had poorer mean adult height. A high caregiver's index of suspicion is required for the early diagnosis of patients with 21-OHD missed on neonatal screening. Adjuvant therapy with GnRHa can improve the adult height of patients with CPP complicating 21-OHD., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022. Published by Elsevier B.V.)

Understanding satisfaction of nutrition education and other services provided in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) is needed to ensure the program is responsive to the needs of diverse populations. This study examined the variation of WIC participants’ perceptions and satisfaction with WIC nutrition education and services by race, ethnicity, and language preference. Phone surveys were conducted in 2019 with California WIC families with children aged 1−4 years. While most participants (86%) preferred one-on-one nutrition education, online/mobile apps were also favored (69%). The majority (89%) found nutrition education equally important to receiving the WIC food package. Racial/ethnic groups differed in which WIC service they primarily valued as 20% of non-Hispanic White people rated the food package as more important than nutrition education compared to 5% of Spanish- and 6% of English-speaking Hispanic people, respectively. More Spanish (91%) and English-speaking Hispanic people (87%) than non-Hispanic white (79%) or Black people (74%) changed a behavior because of something they learned at WIC (p < 0.001). Spanish-speaking Hispanic people (90%) had the highest satisfaction with WIC nutrition education. Preferential differences among participants suggest that providing flexible options may improve program satisfaction and emphasizes the need for future studies to examine WIC services by race and ethnicity.

Hoyeraal-Hreidarsson syndrome (HHS) is the most severe form of dyskeratosis congenita (DC) and is caused by mutations in genes involved in telomere maintenance. Here, we identified male siblings from a family with HHS carrying a hemizygous mutation (c.1345C > G, p.R449G), located in the C-terminal nuclear localization signal (NLS) of the DKC1 gene. These patients exhibit progressive cerebellar hypoplasia, recurrent infections, pancytopenia due to bone marrow failure, and short leukocyte telomere lengths. Single-cell RNA sequencing analysis suggested defects in the NLRP3 inflammasome in monocytes and the activation and maturation of NK cells and B cells. In experiments using induced pluripotent stem cells (iPSCs) from patients, DKC1&#95;R449G iPSCs had short telomere lengths due to reduced levels of human telomerase RNA (hTR) and increased cytosolic proportions of DKC1. Treatment with dihydroquinolizinone RG7834 and 3'deoxyanosine cordycepin rescued telomere length in patient-derived iPSCs. Together, our findings not only provide new insights into immunodeficiency in DC patients but also provide treatment options for telomerase insufficiency disorders., (© 2022. The Author(s).)

The United States Department of Agriculture approved an increase to the Cash Value Benefit (CVB) for the purchase of fruits and vegetables issued to participants receiving an eligible Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) food package. In order to understand satisfaction, perceptions, and the overall impact of additional benefits for fruits and vegetables at the household level, a qualitative study consisting of structured phone interviews was conducted with families served by WIC in Southern California from November to December 2021 (n = 30). Families were selected from a large longitudinal study sample (N = 2784); the sample was restricted by benefit redemption and stratified by language and race. WIC participants were highly satisfied with the CVB increase, reporting increased purchasing and consumption of a variety of fruits and vegetables. Respondents noted the improved quality and variety of fruits and vegetables purchased due to the increased amount. Findings are expected to inform policy makers to adjust the CVB offered in the WIC food package with the potential to improve participant satisfaction and increase participation and retention of eligible families with benefits from healthy diets supported by WIC.

In the central nervous system (CNS), the matrix metalloproteinase-9 (MMP-9) is induced by several factors and contributes to CNS disorders, including inflammation and neurodegeneration. Thus, the upregulation of MMP-9 has been considered to be an indicator of inflammation. Interleukin-1β (IL-1β) is an important proinflammatory cytokine which can induce various inflammatory factors, such as MMP-9, in many inflammatory disorders. Several phytochemicals are believed to reduce the risk of several inflammatory disorders, including the CNS diseases. Among them, the resveratrol, a principal phenolic compound of the grape, blueberry, and mulberry peels and Cassia plants, has been shown to possess several medicinal properties, including antioxidative, anti-inflammatory, and antitumor function. Herein, we used mouse-brain microvascular endothelial cells (bMECs) to demonstrate the signaling mechanisms of IL-1β-induced MMP-9 expression via zymographic, RT-PCR, Western blot, reactive oxygen species (ROS) detection, immunofluorescence stain, and promoter reporter analyses. Then we evaluated the effects of resveratrol on IL-1β-induced MMP-9 expression in bMECs and its mechanism of action. We first demonstrated that IL-1β induced MMP-9 expression in bMECs. Subsequently, IL-1β induced MMP-9 expression via ROS-mediated c-Src-dependent transactivation of EGFR, and then activation of the ERK1/2, p38 MAPK, JNK1/2, and NF-κB signaling pathway. Finally, we determined that IL-1β-induced upregulation of MMP-9 may cause the disruption of the arranged integrity of zonula occludens-1 (ZO-1), but this could be inhibited by resveratrol. These data indicated that resveratrol may have antioxidative and brain-protective activities by reducing these related pathways of ROS-mediated MMP-9 expression and tight junction disruption in brain microvascular endothelial cells.

Granulocytes encompass diverse roles, from fighting off pathogens to regulating inflammatory processes in allergies. These roles are represented by distinct cellular phenotypes that we captured with mass cytometry (CyTOF). Our protocol enables simultaneous evaluation of human basophils, eosinophils, and neutrophils under homeostasis and upon immune activation by anti-Immunoglobulin E (anti-IgE) or interleukin-3 (IL-3). Granulocyte integrity and detection of protein markers were optimized so that rare granulocyte populations could be deeply characterized by single cell mass cytometry. For complete details on the use and execution of this protocol, please refer to Vivanco Gonzalez et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Short stature and intellectual disability are two of the major components of many dysmorphic syndromes. Jansen-de Vries syndrome (JDVS) is a rare syndromic disorder that was discovered recently using next-generation sequencing. It is characterized by hypotonia, developmental delay, a dysmorphic face, short stature, and high pain threshold and is caused by the variants of the protein phosphatase magnesium-dependent 1D (PPM1D) gene. Here, we report the first two cases of PPM1D mutations in Taiwan; both had de novo variants in exon 6. Both presented with short stature, developmental delay, and dysmorphic faces. In addition to the characteristics listed above, syndactyly was noted in one. Genetic studies should be considered when approaching a patient with growth retardation, intellectual disability, and other major or minor dysmorphisms., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Gastric injury is the most common digestive system disease worldwide and involves inflammation, which can lead to gastric ulcer or gastric cancer (GC). Matrix metallopeptidase-9 [MMP-9 (gelatinase-B)] plays an important role in inflammation and GC progression. Quercetin and quercetin-rich diets represent potential food supplements and a source of medications for treating gastric injury given their anti-inflammatory activities. However, the effects and mechanisms of action of quercetin on human chronic gastritis and whether quercetin can relieve symptoms remain unclear., Aim: To assess whether tumor necrosis factor-α (TNF-α)-induced MMP-9 expression mediates the anti-inflammatory effects of quercetin in normal human gastric mucosal epithelial cells., Methods: The normal human gastric mucosa epithelial cell line GES-1 was used to establish a normal human gastric epithelial cell model of TNF-α-induced MMP-9 protein overexpression to evaluate the anti-inflammatory effects of quercetin. The cell counting Kit-8 assay was used to evaluate the effects of varying quercetin doses on cell viability in the normal GES-1 cell line. Cell migration was measured using Transwell assay. The expression of proto-oncogene tyrosine-protein kinase Src (c-Src), phospho (p)-c-Src, extracellular-signal-regulated kinase 2 (ERK2), p-ERK1/2, c-Fos, p-c-Fos, nuclear factor kappa B (NF-κB/p65), and p-p65 and the effects of their inhibitors were examined using Western blot analysis and measurement of luciferase activity. p65 expression was detected by immunofluorescence. MMP-9 mRNA and protein levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and gelatin zymography, respectively., Results: qRT-PCR and gelatin zymography showed that TNF-α induced MMP-9 mRNA and protein expression in a dose- and time-dependent manner. These effects were reduced by the pretreatment of GES-1 cells with quercetin or a TNF-α antagonist (TNFR inhibitor) in a dose- and time-dependent manner. Quercetin and TNF-α antagonists decreased the TNF-α-induced phosphorylation of c-Src, ERK1/2, c-Fos, and p65 in a dose- and time-dependent manner. Quercetin, TNF-α antagonist, PP1, U0126, and tanshinone IIA (TSIIA) reduced TNF-α-induced c-Fos phosphorylation and AP-1-Luciferase (Luc) activity in a dose- and time-dependent manner. Pretreatment with quercetin, TNF-α antagonist, PP1, U0126, or Bay 11-7082 reduced TNF-α-induced p65 phosphorylation and translocation and p65-Luc activity in a dose- and time-dependent manner. TNF-α significantly increased GES-1 cell migration, and these results were reduced by pretreatment with quercetin or a TNF-α antagonist., Conclusion: Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src-ERK1/2 and c-Fos or NF-κB pathways., Competing Interests: Conflict-of-interest statement: All authors have nothing to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: In 2019, California and Wilmington, Delaware' implemented policies requiring healthier default beverages with restaurant kids' meals. The current study assessed restaurant beverage offerings and manager perceptions., Design: Pre-post menu observations were conducted in California and Wilmington. Observations of cashiers/servers during orders were conducted pre-post implementation in California and post-implementation in Wilmington. Changes in California were compared using multilevel logistic regression and paired t tests. Post-implementation, managers were interviewed., Setting: Inside and drive-through ordering venues in a sample of quick-service restaurants in low-income California communities and all restaurants in Wilmington subject to the policy, the month before and 7-12 months after policy implementation., Participants: Restaurant observations (California n 110; Wilmington n 14); managers (California n 75; Wilmington n 15)., Results: Pre-implementation, the most common kids' meal beverages on California menus were unflavoured milk and water (78·8 %, 52·0 %); in Wilmington, juice, milk and sugar-sweetened beverages were most common (81·8 %, 66·7 % and 46·2 %). Post-implementation, menus including only policy-consistent beverages significantly increased in California (9·7 % to 66·1 %, P < 0·0001), but remained constant in Wilmington (30·8 %). During orders, cashiers/servers offering only policy-consistent beverages significantly decreased post-implementation in California (5·0 % to 1·0 %, P = 0·002). Few managers (California 29·3 %; Wilmington 0 %) reported policy knowledge, although most expressed support. Most managers wanted additional information for customers and staff., Conclusions: While the proportion of menus offering only policy-consistent kids' meal default beverages increased in California, offerings did not change in Wilmington. In both jurisdictions, managers lacked policy knowledge, and few cashiers/servers offered only policy-consistent beverages. Additional efforts are needed to strengthen implementation of kids' meal beverage policies.

Objective: To examine associations between household food insecurity and children's physical activity and sedentary behaviours., Design: Secondary analysis was conducted on the Healthy Communities Study, an observational study from 2013 to 2015. Household food insecurity was assessed by two items from the US Department of Agriculture's 18-item US Household Food Security Survey Module. Physical activity was measured using the 7-d Physical Activity Behaviour Recall instrument. Data were analysed using multilevel statistical modelling., Setting: A total of 130 communities in the USA., Participants: In sum, 5138 US children aged 4-15 years., Results: No associations were found for the relationship between household food insecurity and child physical activity. A significant interaction between household food insecurity and child sex for sedentary behaviours was observed (P = 0·03)., Conclusions: Additional research capturing a more detailed assessment of children's experiences of food insecurity in relation to physical activity is warranted. Future studies may consider adopting qualitative study designs or utilising food insecurity measures that specifically target child-level food insecurity. Subsequent research may also seek to further explore sub-group analyses by sex.

Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial-mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment., Competing Interests: Conflict-of-interest statement: The author has no conflict of interest to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Gastric cancer (GC) is the second most prevalent cancer worldwide and the eighth most common cause of tumor-related death in Taiwan. Helminthostachys zeylanica , a flavonoid compound, has anti-inflammatory, immunomodulatory, and anticancer effects. We examined whether an extract of H. zeylanica (E1 and E2) has potential as a treatment for GC. Methods: We investigated the effects (pro-apoptosis, pro-autophagy, and antiproliferation ability) of H. zeylanica -E2 on cell viability in healthy gastric epithelial (GES-1) and GC cells (AGS and BGC823). H. zeylanica -E2 was toxic to GC cells but had little or no toxicity to normal cells. Results: In this study, H. zeylanica -E2 induced apoptosis through caspase 3/7, Bcl-2, Bax, cyclooxygenase-2 (COX-2), and cleaved poly (ADP-ribose) polymerase pathways in GC cells. In addition, it increased autophagy by stimulating autophagy-related protein (ATG)5, ATG7, LC3-I/LC3-II, and inhibiting COX-2 activity in GC cells. We also found that H. zeylanica -E2 exhibited antiproliferation ability through cell cycle arrest in G0/G1 and G2/M and suppressed the migration of GC cells. The anticancer effects of H. zeylanica -E2 in GC cells might be mediated partly through inhibition of tumor necrosis factor-α (TNF-α)-activated proinflammatory cytosolic phospholipase A2 (cPLA2)-COX-2-prostaglandin E 2 (PGE 2 ) pathway. Conclusions: Our results suggest that H. zeylanica -E2 has potential as a novel adjunctive agent for the treatment of GC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Kinins are endogenous, biologically active peptides released into the plasma and tissues via the kallikrein-kinin system in several pathophysiological events. Among kinins, bradykinin (BK) is widely distributed in the periphery and brain. Several studies on the neuro-modulatory actions of BK by the B 2 BK receptor (B 2 BKR) indicate that this neuropeptide also functions during neural fate determination. Previously, BK has been shown to induce differentiation of nerve-related stem cells into neuron cells, but the response in mature brain astrocytes is unknown. Herein, we used rat brain astrocyte (RBA) to investigate the effect of BK on cell transdifferentiation into a neuron-like cell morphology. Moreover, the signaling mechanisms were explored by zymographic, RT-PCR, Western blot, and immunofluorescence staining analyses. We first observed that BK induced RBA transdifferentiation into neuron-like cells. Subsequently, we demonstrated that BK-induced RBA transdifferentiation is mediated through B 2 BKR, PKC-δ, ERK1/2, and MMP-9. Finally, we found that BK downregulated the astrocytic marker glial fibrillary acidic protein (GFAP) and upregulated the neuronal marker neuron-specific enolase (NSE) via the B 2 BKR/PKC-δ/ERK pathway in the event. Therefore, BK may be a reprogramming factor promoting brain astrocytic transdifferentiation into a neuron-like cell, including downregulation of GFAP and upregulation of NSE and MMP-9 via the B 2 BKR/PKC-δ/ERK cascade. Here, we also confirmed the transdifferentiative event by observing the upregulated neuronal nuclear protein (NeuN). However, the electrophysiological properties of the cells after BK treatment should be investigated in the future to confirm their phenotype.

Background: Although it has been recommended that schools be the hub of efforts to improve child nutrition, research describing school nutrition environments in US public schools and their associations with child health is limited., Objective: This study aimed to evaluate the applicability of factor analysis methods to characterize school nutrition environments by identifying underlying factors, or dimensions, in the observed data and to examine the relation between school nutrition environment dimensions and child anthropometric and dietary outcomes., Methods: This study examined a cross-sectional sample of 4635 US children aged 4-15 y from 386 US elementary and middle schools from the Healthy Communities Study (2013-2015). Data collected from schools were used to create 34 variables that assessed the school nutrition environment. To identify dimensions of school nutrition environments, exploratory factor analysis was conducted with orthogonal rotation, and factor scores were derived using methods to account for sporadic missing data. Mixed-effects regression models adjusted for child- and community-level variables and clustered by community and school examined the associations of school nutrition environment dimensions with child anthropometric and dietary outcomes., Results: Six dimensions of school nutrition environments were derived: nutrition education, food options, wellness policies, dining environment, unhealthy food restriction, and nutrition programs. The unhealthy food restriction dimension was negatively associated with added sugar intake (β = -1.13, P < 0.0001), and the wellness policies dimension was positively associated with waist circumference (β = 0.57, P = 0.01)., Conclusions: This study demonstrates how factor analysis can reduce multiple measures of complex school nutrition environments into conceptually cohesive dimensions for purposes of assessing the relation of these dimensions to student health-related outcomes. Findings were mixed and indicate that the restriction of unhealthy foods in school is associated with lower added sugar intake. Additional, longitudinal studies are needed to substantiate the utility of this method for identifying promising school nutrition environments., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: The matrix metalloproteinase-9 (MMP-9) is up-regulated by several proinflammatory mediators in the central nervous system (CNS) diseases. Increasing reports show that MMP-9 expression is an inflammatory biomarker of several CNS disorders, including the CNS inflammation and neurodegeneration. Bradykinin (BK) is a common proinflammatory mediator and elevated in several brain injury and inflammatory disorders. The raised BK may be detrimental effects on the CNS that may aggravate brain inflammation through MMP-9 up-regulation or cyclooxygenase-2 (COX-2)-derived prostaglandin E 2 (PGE 2 ) production in brain astrocytes. However, the relationship between BK-induced MMP-9 expression and COX-2-derived PGE 2 release in brain astrocytes remains unclear., Methods: Herein we used rat brain astrocytes (RBA) to investigate the role of the COX-2/PGE 2 system in BK-induced MMP-9 expression. We used zymographic, RT-PCR, EIA, and Western blotting analyses to confirm that BK induces MMP-9 expression via a COX-2/PGE 2 -dependent pathway., Results: Our results show activation of native COX-2 by BK led to PGE 2 production and release. Subsequently, PGE 2 induced MMP-9 expression via PGE 2 receptor (EP)-mediated c-Src, Jak2, ERK1/2, and then activated signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, up-regulation of MMP-9 by BK via the pathway may promote astrocytic migration., Conclusion: These results demonstrated that a novel autocrine pathway for BK-induced MMP-9 protein expression is mediated through activation of STAT3 by native COX-2/PGE 2 -mediated c-Src/Jak2/ERK cascades in brain astrocytes. Video Abstract.

Basophils, the rarest granulocyte, play critical roles in parasite- and allergen-induced inflammation. We applied mass cytometry (CyTOF) to simultaneously asses 44 proteins to phenotype and functionally characterize neutrophils, eosinophils, and basophils from 19 healthy donors. There was minimal heterogeneity seen in eosinophils and neutrophils, but data-driven analyses revealed four unique subpopulations within phenotypically basophilic granulocytes (PBG; CD45 + HLA-DR - CD123 + ). Through CyTOF and fluorescence-activated cell sorting (FACS), we classified these four PBG subpopulations as (I) CD16 low FcεRI high CD244 high (88.5 ± 1.2%), (II) CD16 high FcεRI high CD244 high (9.1 ± 0.4%), (III) CD16 low FcεRI low CD244 low (2.3 ± 1.3), and (IV) CD16 high FcεRI low CD244 low (0.4 ± 0.1%). Prospective isolation confirmed basophilic-morphology of PBG I-III, but neutrophilic-morphology of PBG IV. Functional interrogation via IgE-crosslinking or IL-3 stimulation demonstrated that PBG I-II had significant increases in CD203c expression, whereas PBG III-IV remained unchanged compared with media-alone conditions. Thus, PBG III-IV could serve roles in non-IgE-mediated immunity. Our findings offer new perspectives in human basophil heterogeneity and the varying functional potential of these new subsets in health and disease., Competing Interests: The authors do not have conflicts of interest to declare., (© 2020 The Authors.)

Background: Upregulation of matrix metalloproteinase-9 (MMP-9) has been indicated as one of the inflammatory biomarkers. In the central nervous system (CNS), the MMP-9 is induced by several proinflammatory mediators and participates in the CNS disorders, including inflammation and neurodegeneration. In addition, protein kinase Cs (PKCs) has been shown to be involved in regulation of various inflammatory factors like MMP-9 by several stimuli in many cell types. Several phytochemicals are believed to reduce the risk of several inflammatory disorders including the CNS diseases. The rottlerin, a principal phenolic compound of the Kamala plant Mallotus philippinensis, has been shown to possess an array of medicinal properties, including anti-PKC-δ, antitumor, anti-oxidative, and anti-inflammatory activities., Methods: Herein, we used rat brain astrocytes (RBA) to demonstrate the signaling mechanisms of phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression by zymographic, RT-PCR, subcellular isolation, Western blot, ROS detection, and promoter reporter analyses. Then, we evaluate the effects of rottlerin on PMA-induced MMP-9 expression in RBA and its influencing mechanism., Results: We first demonstrated that PMA stimulated activation of various types of PKC, including PKC-δ in RBA. Subsequently, PMA induced MMP-9 expression via PKCδ-mediated reactive oxygen species (ROS) generation, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, and then induced c-Fos/AP-1 signaling pathway. Finally, upregulation of MMP-9 by PMA via the pathway may promote astrocytic migration, and the event could be attenuated by rottlerin., Conclusions: These data indicated that rottlerin may have anti-inflammatory activity by reducing these related pathways of PKC-δ-dependent ROS-mediated MMP-9 expression in brain astrocytes.

Gastric cancer (GC) is the second most widespread cause of cancer-related mortality worldwide. The discovery of novel biomarkers of oncoproteins can facilitate the development of therapeutic strategies for GC treatment. In this study, we identified novel biomarkers by integrating isobaric tags for relative and absolute quantitation (iTRAQ), a human plasma proteome database, and public Oncomine datasets to search for aberrantly expressed oncogene-associated proteins in GC tissues and plasma. One of the most significantly upregulated biomarkers, DEK, was selected and its expression validated. Our immunohistochemistry (IHC) ( n = 92) and quantitative real-time polymerase chain reaction (qRT-PCR) ( n = 72) analyses disclosed a marked increase in DEK expression in tumor tissue, compared with paired nontumor mucosa. Importantly, significantly higher preoperative plasma DEK levels were detected in GC patients than in healthy controls via enzyme-linked immunosorbent assay (ELISA). In clinicopathological analysis, higher expression of DEK in both tissue and plasma was significantly associated with advanced stage and poorer survival outcomes of GC patients. Data from receiver operating characteristic (ROC) curve analysis disclosed a better diagnostic accuracy of plasma DEK than carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), and C-reactive protein (CRP), highlighting its potential as an effective plasma biomarker for GC. Plasma DEK is also more sensitive in tumor detection than the other three biomarkers. Knockdown of DEK resulted in inhibition of GC cell migration via a mechanism involving modulation of matrix metalloproteinase MMP-2/MMP-9 level and vice versa. Our results collectively support plasma DEK as a useful biomarker for making diagnosis and prognosis of GC patients.

Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare.

Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis., Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., Competing Interests: QW, CL, HR, LR, MT, HW, Ev, NL, MB, NH, EE, FO, LP, NG, SG, CC, JS, YF, SG, WR No competing interests declared, LS Virginia Commonwealth University collects royalties for the tryptase assay licensed to Thermofisher and for tryptase antibodies licensed to Millipore and Santa Cruz, which are shared with Lawrence B Schwartz, who also is a paid consultant for Genentech., (© 2019, Wang et al.)

The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer.Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues.Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed.

Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase ( QPRT ) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism-related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome., Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT - KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain., Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome level, genes linked to neurodevelopmental processes and synaptic structures were affected. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala., Conclusions: In this study, QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells and affected the regulation of genes and gene networks previously implicated in ASD. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers., Competing Interests: All study participants have given written informed consent, and the genetic study has been positively reviewed by the ethic’s committee Frankfurt (No 267/09).All authors agree to publish the presented work.All authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Radiotherapy is a well-established regimen for nearly half the cancer patients worldwide. However, not all cancer patients respond to irradiation treatment, and radioresistance is highly associated with poor prognosis and risk of recurrence. Elucidation of the biological characteristics of radioresistance and development of effective prognostic markers to guide clinical decision making clearly remain an urgent medical requirement. In tumorigenic and radioresistant cancer cell populations, phenotypic switch is observed during the course of irradiation treatment, which is associated with both stable genetic and epigenetic changes. While the importance of epigenetic changes is widely accepted, the irradiation-triggered specific epigenetic alterations at the molecular level are incompletely defined. The present review provides a summary of current studies on the molecular functions of DNA and RNA m⁶A methylation, the key epigenetic mechanisms involved in regulating the expression of genetic information, in resistance to irradiation and cancer progression. We additionally discuss the effects of DNA methylation and RNA N ⁶-methyladenosine (m⁶A) of specific genes in cancer progression, recurrence, and radioresistance. As epigenetic alterations could be reversed by drug treatment or inhibition of specific genes, they are also considered potential targets for anticancer therapy and/or radiotherapy sensitizers. The mechanisms of irradiation-induced alterations in DNA and RNA m⁶A methylation, and ways in which this understanding can be applied clinically, including utilization of methylation patterns as prognostic markers for cancer radiotherapy and their manipulation for anticancer therapy or use as radiotherapy sensitizers, have been further discussed., Competing Interests: The authors declare no conflict of interest.

Infection by hepatitis B virus (HBV) accounts for 50-80% of hepatocellular carcinoma (HCC) development worldwide, in which the HBV-encoded X protein (HBx) has critical role in the induction of carcinogenesis. Several studies have shown that thyroid hormone (TH) suppresses HCC development and protects hepatocytes from HBx-induced damage, thus it is of interest to examine whether TH can protect hepatocytes from HBx-induced carcinogenesis. By treating HBx- transgenic mice with or without TH, we confirmed the protective effects of TH on HBx-induced hepatocarcinogenesis, which was achieved via reduction of reactive oxygen species (ROS) inflicted DNA damage. We further found that TH induced biogenesis of mitochondria (MITO) and autophagy of HBx-targeted MITO simultaneously, consequently leading to suppression of HBx-promoted ROS and carcinogenesis. Using microarray data analysis, this protective effect of TH was found to be mediated via activation of PTEN-induced kinase 1 (PINK1) in hepatocytes. PINK1, in turn, activated and recruited Parkin, an E3 ligase, to ubiquitinate MITO-associated HBx protein and trigger selective mitophagy. The pathological significance of the TH/PINK1 pathway in liver protection was confirmed by the concomitant decrease in expression of both TR and PINK1 in matched HCC tumor tissues and negatively correlated with aggressive progression of cancer and poor prognosis. Our data indicate that TH/PINK1/Parkin pathway has a critical role in protecting hepatocytes from HBx-induced carcinogenesis. Notably, several liver-targeting therapeutic derivatives of TH facilitating prevention or therapy of steatosis have been identified. Furthermore, our proof-of-concept experiments suggest that application of T 3 constitutes an effective novel therapeutic or preventive option for HCC. Thus, the utilization of the agonists of TRs could be the meaningful strategy in liver relative diseases, ranging from simple hepatic steatosis to HCC.

Radiotherapy is a well-established therapeutic regimen applied to treat at least half of all cancer patients worldwide. Radioresistance of cancers or failure to treat certain tumor types with radiation is associated with enhanced local invasion, metastasis and poor prognosis. Elucidation of the biological characteristics underlying radioresistance is therefore critical to ensure the development of effective strategies to resolve this issue, which remains an urgent medical problem. Cancer stem cells (CSCs) comprise a small population of tumor cells that constitute the origin of most cancer cell types. CSCs are virtually resistant to radiotherapy, and consequently contribute to recurrence and disease progression. Metastasis is an increasing problem in resistance to cancer radiotherapy and closely associated with the morbidity and mortality rates of several cancer types. Accumulating evidence has demonstrated that radiation induces epithelial-mesenchymal transition (EMT) accompanied by increased cancer recurrence, metastasis and CSC generation. CSCs are believed to serve as the basis of metastasis. Previous studies indicate that CSCs contribute to the generation of metastasis, either in a direct or indirect manner. Moreover, the heterogeneity of CSCs may be responsible for organ specificity and considerable complexity of metastases. Long noncoding RNAs (lncRNAs) are a class of noncoding molecules over 200 nucleotides in length involved in the initiation and progression of several cancer types. Recently, lncRNAs have attracted considerable attention as novel critical regulators of cancer progression and metastasis. In the current review, we have discussed lncRNA-mediated regulation of CSCs following radiotherapy, their association with tumor metastasis and significance in radioresistance of cancer., Competing Interests: The authors declare no conflict of interest.

Amino acid sequence differences in the variable region of immunoglobulin (Ig) cause wide variations in secretion outputs. To address how a primary sequence difference comes to modulate Ig secretion, we investigated the biosynthetic process of 2 human IgG2κ monoclonal antibodies (mAbs) that differ only by one amino acid in the light chain complementarity-determining region 1 while showing ∼20-fold variance in secretion titer. Although poorly secreted, the lower-secreting mAb of the 2 was by no means defective in terms of its folding stability, antigen binding, and in vitro biologic activity. However, upon overexpression in HEK293 cells, the low-secreting mAb revealed a high propensity to aggregate into enlarged globular structures called Russell bodies (RBs) in the endoplasmic reticulum. While Golgi morphology was affected by the formation of RBs, secretory pathway membrane traffic remained operational in those cells. Importantly, cellular protein synthesis was severely suppressed in RB-positive cells through the phosphorylation of eIF2α. PERK-dependent signaling was implicated in this event, given the upregulation and nuclear accumulation of downstream effectors such as ATF4 and CHOP. These findings illustrated that the underlining process of poor Ig secretion in RB-positive cells was due to downregulation of Ig synthesis instead of a disruption or blockade of secretory pathway trafficking. Therefore, RB formation signifies an end of active Ig production at the protein translation level. Consequently, depending on how soon and how severely an antibody-expressing cell develops the RB phenotype, the productive window of Ig secretion can vary widely among the cells expressing different mAbs.

Anaplastic large-cell lymphoma (ALCL) is a rare type of highly malignant, non-Hodgkin lymphoma (NHL). Currently, only studies on the chimeric oncogene NPM-ALK have reported a link to ALCL progression. However, the specific molecular mechanisms underlying the invasion of ALCL are still unclear. Here, we sought to investigate differentially expressed, long non-coding RNAs (lncRNAs) in ALCL and their potential biological function. Our microarray analyses revealed that LINC01013, a novel non-coding RNA gene, was highly expressed in clinical specimens of ALCL and was significantly upregulated in invasive ALCL cell lines. Knockdown of LINC01013 suppressed tumor cell invasion; conversely, its overexpression enhanced tumor cell invasion. LINC01013-induced invasion was mediated by activation of the epithelial-to-mesenchymal transition (EMT)-associated proteins, snail and fibronectin. Specifically, LINC01013 induced snail, resulting in activation of fibronectin and enhanced ALCL cell invasion. Collectively, these findings support a potential role for LINC01013 in cancer cell invasion through the snail-fibronectin activation cascade and suggest that LINC01013 could potentially be utilized as a metastasis marker in ALCL.

Stathmin (STMN1), a recognized oncoprotein upregulated in various solid tumors, promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms underlying the genetic regulation of STMN1 have yet to be elucidated. In the current study, we report that thyroid hormone receptor (THR) expression is negatively correlated with STMN1 expression in a subset of clinical hepatocellular carcinoma (HCC) specimens. We further identified the STMN1 gene as a target of thyroid hormone (T 3 ) in the HepG2 hepatoma cell line. An analysis of STMN1 expression profile and mechanism of transcriptional regulation revealed that T 3 significantly suppressed STMN1 mRNA and protein expression, and further showed that THR directly targeted the STMN1 upstream element to regulate STMN1 transcriptional activity. Specific knockdown of STMN1 suppressed cell proliferation and xenograft tumor growth in mice. In addition, T 3 regulation of cell growth arrest and cell cycle distribution were attenuated by overexpression of STMN1. Our results suggest that the oncogene STMN1 is transcriptionally downregulated by T 3 in the liver. This T 3 -mediated suppression of STMN1 supports the theory that T 3 plays an inhibitory role in HCC tumor growth, and suggests that the lack of normal THR function leads to elevated STMN1 expression and malignant growth.

Recent studies have demonstrated a critical association between disruption of cellular thyroid hormone (TH) signaling and the incidence of hepatocellular carcinoma (HCC), but the underlying mechanisms remain largely elusive. Here, we showed that disruption of TH production results in a marked increase in progression of diethylnitrosamine (DEN)-induced HCC in a murine model, and conversely, TH administration suppresses the carcinogenic process via activation of autophagy. Inhibition of autophagy via treatment with chloroquine (CQ) or knockdown of ATG7 (autophagy-related 7) via adeno-associated virus (AAV) vectors, suppressed the protective effects of TH against DEN-induced hepatic damage and development of HCC. The involvement of autophagy in TH-mediated protection was further supported by data showing transcriptional activation of DAPK2 (death-associated protein kinase 2; a serine/threonine protein kinase), which enhanced the phosphorylation of SQSTM1/p62 (sequestosome 1) to promote selective autophagic clearance of protein aggregates. Ectopic expression of DAPK2 further attenuated DEN-induced hepatoxicity and DNA damage though enhanced autophagy, whereas, knockdown of DAPK2 displayed the opposite effect. The pathological significance of the TH-mediated hepatoprotective effect by DAPK2 was confirmed by the concomitant decrease in the expression of THRs and DAPK2 in matched HCC tumor tissues. Taken together, these findings indicate that TH promotes selective autophagy via induction of DAPK2-SQSTM1 cascade, which in turn protects hepatocytes from DEN-induced hepatotoxicity or carcinogenesis.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells.

MicroRNAs (miRNA) play an important role in carcinogenesis. Previously, we identified miR-26b as a significantly downregulated miRNA in gastric cancer (GC) tissues (n = 106) based on differential quantitative RT-PCR (RT-qPCR) miRNA expression profiles. In the current study, we aimed to clarify the potential role of miR-26b and related target genes in GC progression. Downregulation of miR-26b was associated with advanced tumor-node-metastasis stage (TNM stage) and poor 5-year survival rate. Forced expression of miR-26b led to inhibition of GC cell migration and invasion in vitro and lung metastasis formation in vivo. Conversely, depletion of miR-26b had stimulatory effects. Additionally, miR-26b affected GC cell behavior through negative regulation of the metastasis promoter, karyopherin alpha 2 (KPNA2). Ectopic expression of miR-26b induced a reduction in KPNA2 protein levels, confirmed by luciferase assay data showing that miR-26b directly binds to the 3' untranslated regions (UTR) of KPNA2 mRNA. Furthermore, miR-26b and KPNA2 mRNA/protein expression patterns were inversely correlated in GC tissues. Cag A of Helicobacter pylori (Hp) enhanced miR-26b levels through regulation of the KPNA2/c-jun pathway. Taken together, our data indicate that miR-26b plays an anti-metastatic role and is downregulated in GC tissues via the KPNA2/c-jun pathway. Based on the study findings, we propose that miR-26b overexpression or KPNA2/c-jun suppression may have therapeutic potential in inhibiting GC metastasis., Competing Interests: The authors declare no conflicting financial interests.

Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.

The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers.

Background: The thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3), has been shown to modulate cellular processes via interactions with thyroid hormone receptors (TRs), but the secretory proteins that are regulated to exert these effects remain to be characterized. Brain-specific serine protease 4 (BSSP4), a member of the human serine protease family, participates in extracellular matrix remodeling. However, the physiological role and underlying mechanism of T3-mediated regulation of BSSP4 in hepatocellular carcinogenesis are yet to be established., Methods: The thyroid hormone response element was identified by reporter and chromatin immunoprecipitation assays. The cell motility was analyzed via transwell and SCID mice. The BSSP4 expression in clinical specimens was examined by Western blot and quantitative reverse transcription polymerase chain reaction., Results: Upregulation of BSSP4 at mRNA and protein levels after T3 stimulation is a time- and dose-dependent manner in hepatoma cell lines. Additionally, the regulatory region of the BSSP4 promoter stimulated by T3 was identified at positions -609/-594. BSSP4 overexpression enhanced tumor cell migration and invasion, both in vitro and in vivo. Subsequently, BSSP4-induced migration occurs through the ERK 1/2-C/EBPβ-VEGF cascade, similar to that observed in HepG2-TRα1 and J7-TRα1 cells. BSSP4 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively associated with TRα1 and VEGF to a significant extent. Importantly, a mild association between BSSP4 expression and distant metastasis was observed., Conclusions: Our findings collectively support a potential role of T3 in cancer cell progression through regulation of the BSSP4 protease via the ERK 1/2-C/EBPβ-VEGF cascade. BSSP4 may thus be effectively utilized as a novel marker and anti-cancer therapeutic target in HCC.