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Purpose: This study compared survival and metastasis occurrence between colorectal neuroendocrine neoplasms (cNEN) and colorectal adenocarcinoma with neuroendocrine differentiation (cNED) and further explored their prognostic factors and treatment indicators., Methods: Patients diagnosed as cNEN and cNED in West China Hospital from January 2009 to December 2020 were enrolled. The diagnosis and metastasis rates were calculated. Univariate and multivariate Cox analyses were conducted for progression-free survival (PFS) in cNEN surgical patients, and generalized linear regression was used for metastatic disease., Result: The study enrolled 435 patients, including 257 neuroendocrine tumors (NET), 52 neuroendocrine carcinomas (NEC), 29 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), and 97 NED patients, of whom 202 received local resection, and 233 received radical resection. Metastasis rates were higher in MiNEN and NEC groups compared to other groups (NED: 28.9%, MiNEN: 58.6%, NEC: 65.4%, NET: 8.6%, p < 0.001). The liver is the main metastatic site in cNEN, whereas cNED metastasized to various sites. For NEC and MiNEN patients, colon location (p = 0.002) and T stage > 2 (p = 0.040) were associated with disease progression separately. Independent risk factors for metastatic NET included tumor grade G2/G3 (p < 0.001), colon location (p = 0.001), size ≥ 1 cm (p = 0.005), and CK20 partial positive (p < 0.001)., Conclusion: cNEN show high metastatic capacity and are challenging to diagnose. More aggressive treatment and follow-up strategies are necessary for those patients. NET tumor grade higher than G2, size larger than 1 cm, or located in the colon should be managed with radical surgery., (© 2024. The Author(s).)

Background: Hepatobiliary and pancreatic (HBP) cancers impose a considerable burden on young populations (aged 15 to 49 years), resulting in a substantial number of new cases and fatalities each year. In young populations, the HBP cancers shows extensive variance worldwide and the updated data in China is lacking., Aim: To investigate the current status, trends, projections, and underlying risk factors of HBP cancers among young populations in China., Methods: The Global Burden of Disease Study 2019 provided data on the annual incidence, mortality, disability-adjusted life years (DALYs), age-standardized incidence rate (ASIR), mortality rate (ASMR), and DALYs rate (ASDR) of HBP cancers in young Chinese adults between 1990 and 2019. Temporal trends were assessed using estimated annual percentage change and hierarchical clustering. Sex-specific mortality and DALYs caused by various risks were analyzed across China and other regions, with future trends until 2035 projected using the Bayesian age-period-cohort model., Results: From 1990 to 2019, incident cases, deaths, DALYs, ASIR, ASMR, and ASDR for liver cancer (LC) in young Chinese individuals decreased, classified into 'significant decrease' group. Conversely, cases of gallbladder and biliary tract cancer and pancreatic cancer rose, categorized as either 'significant increase' or 'minor increase' groups. The contribution of risk factors to mortality and DALYs for HBP tumors increased to varying degrees. Healthy lifestyle behaviors, such as tobacco control, weight management, alcohol moderation, and drug avoidance, could lower HBP cancers incidence. Moreover, except for LC in females, which is likely to initially decline slightly and then rise, the forecasting model predicted that the ASIR and ASMR for all HPB cancers subtypes by gender will increase among young adults., Conclusion: HBP cancers burden among young adults in China is expected to increase until 2035, necessitating lifestyle interventions and targeted treatment strategies to mitigate the public health impact of these cancers., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p up-regulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Background: Community health centers (CHCs) are safety-net health care facilities in the United States that provide care for a substantial number of low-income, non-English speaking adults with type 2 diabetes (T2D). Whereas patient portals have been shown to be associated with significant improvements in diabetes self-management and outcomes, they remain underused in CHCs. In addition, little is known about the specific barriers to and facilitators of patient portal use in CHCs and strategies to address the barriers., Objective: The objectives of this qualitative study were to explore the barriers to and facilitators of the use of patient portals for managing diabetes in 2 CHCs from the perspective of adults with T2D and clinicians (community health workers, nurses, nurse practitioners, and physicians) and to make recommendations on strategies to enhance use., Methods: A qualitative description design was used. A total of 21 participants (n=13, 62% clinicians and n=8, 38% adults with T2D) were purposively and conveniently selected from 2 CHCs. Adults with T2D were included if they were an established patient of one of the partner CHCs, aged ≥18 years, diagnosed with T2D ≥6 months, and able to read English or Spanish. Clinicians at our partner CHCs who provided care or services for adults with T2D were eligible for this study. Semistructured interviews were conducted in either Spanish or English based on participant preference. Interviews were audio-recorded and transcribed. Spanish interviews were translated into English by a bilingual research assistant. Data were collected between October 5, 2022, and March 16, 2023. Data were analyzed using a rapid content analysis method. Standards of rigor were implemented., Results: Themes generated from interviews included perceived usefulness and challenges of the patient portal, strategies to improve patient portal use, and challenges in diabetes self-management. Participants were enthusiastic about the potential of the portal to improve access to health information and patient-clinician communication. However, challenges of health and technology literacy, maintaining engagement, and clinician burden were identified. Standardized implementation strategies were recommended to raise awareness of patient portal benefits, provide simplified training and technology support, change clinic workflow to triage messages, customize portal notification messages, minimize clinician burden, and enhance the ease with which blood glucose data can be uploaded into the portal., Conclusions: Adults with T2D and clinicians at CHCs continue to report pervasive challenges to patient portal use in CHCs. Providing training and technical support on patient portal use for patients with low health literacy at CHCs is a critical next step. Implementing standardized patient portal strategies to address the unique needs of patients receiving care at CHCs also has the potential to improve health equity and health outcomes associated with patient portal use., (©Samuel Akyirem, Julie Wagner, Helen N Chen, Joanna Lipson, Maritza Minchala, Karina Cortez, Robin Whittemore. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 16.09.2024.)

Background: This study aimed to analyze the use of corticosteroids and epinephrine in neonates for the first extubation attempt and compared clinical characteristics of infants with successful and failed extubation events., Methods: This was a retrospective cohort study conducted at a single level III neonatal intensive care unit in Taiwan. The study included 215 infants born between 2020 and 2021 who had been intubated for more than 48 h before their first extubation attempt. We compared perinatal and peri-extubation characteristics and outcomes between the two groups. Successful extubation was defined as freedom from invasive ventilatory support 72 h after extubation. The relationship between corticosteroids, local epinephrine, and successful extubation was determined using multivariate logistic regression analysis., Results: In the univariate analysis, the failed extubation group received a significantly higher proportion of intravenous dexamethasone (p = 0.006) than the successful extubation group. Furthermore, the failed extubation group had a longer duration of nebulized epinephrine (p = 0.034) and more episodes of local application of epinephrine to the superior larynx (p = 0.003) than the successful extubation group. Multivariate analysis revealed that the absence of lung atelectasis, tachycardia 72 h after extubation, and lower post-extubation PCO 2 were the key factors associated with successful extubation., Conclusions: There were trends toward systemic dexamethasone, local application of epinephrine to the superior larynx, and longer duration of nebulized epinephrine in the reintubation group. However, corticosteroid or local epinephrine use was not significantly associated with successful extubation. Lung atelectasis, elevated levels of carbon dioxide, and tachycardia were identified as risk factors for extubation failure., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions and even causes mental dysfunctions such as depression and anxiety disorders. In this article, we conducted a multimodal study cross-sectionally and longitudinally, to evaluate how neuropathic pain affects the brain. Using the spared nerve injury (SNI) model which promotes long-lasting mechanical allodynia, results showed that neuropathic pain deeply modified the intrinsic organization of the brain functional network 2 weeks after injury. There are significant changes in the activity of the left thalamus (Th&#95;L) and left olfactory bulb (OB&#95;L) brain regions after SNI, as evidenced by both the blood oxygen level-dependent (BOLD) signal and c-Fos expression. Importantly, these changes were closely related to mechanical pain behavior of rats. However, it is worth noting that after morphine administration for analgesia, only the increased activity in the TH region is reversed, while the decreased activity in the OB region becomes more prominent. Functional connectivity (FC) and c-Fos correlation analysis further showed these two regions of interest (ROIs) exhibit different FC patterns with other brain regions. Our study comprehensively revealed the adaptive changes of brain neural networks induced by nerve injury in both cross-sectional and longitudinal dimensions and emphasized the abnormal activity and FC of Th&#95;L and OB&#95;L in the pathological condition. It provides reliable assistance in exploring the intricate mechanisms of diseases., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Chi et al.)

Colorectal cancer (CRC), a prevalent global malignancy, often necessitates adjuvant therapies such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy to mitigate tumor burden in advanced stages. The efficacy of these therapies is significantly influenced by reactive oxygen species (ROS). Previous research underscores the pivotal role of ROS in gut pathology, targeted therapy, and drug resistance. ROS-mediated CRC adjuvant therapies encompass a myriad of mechanisms, including cell death and proliferation, survival and cell cycle, DNA damage, metabolic reprogramming, and angiogenesis. Preliminary clinical trials have begun to unveil the potential of ROS-manipulating therapy in enhancing CRC adjuvant therapies. This review aims to provide a comprehensive synthesis of studies exploring the role of ROS in CRC adjuvant therapies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Metabolic bone disease (MBD) predominantly affects preterm infants, particularly very-low-birth-weight (VLBW) infants weighing <1500 g. However, there are limited reports on MBD and neurodevelopmental outcomes. This study aimed to analyze the risk factors for MBD and understand its impact on neurodevelopmental outcomes at 2 years of corrected age. Overall, 749 VLBW infants weighing <1350 g at birth were enrolled. Exclusion criteria were major congenital abnormalities, chromosomal abnormalities, and loss of follow-up on the Bayley Scales of Infant Development, Third Edition (BSID-III) test at 24 months of corrected age. Infants were retrospectively assessed by a trained case manager using the BSID-III test at 6, 12, and 24 months old. Infants were categorized as with or without MBD according to radiographic signs. Of those enrolled, 97 VLBW infants were diagnosed with MBD, compared to 362 VLBW infants without MBD. The proportion of infants that completed three follow-ups was 86%. At the assessment at 2 years of age, infants with MBD had lower and more significant differences in motor, language, and cognitive composites. MBD is associated with poor neurodevelopmental outcomes in cognitive, motor, and language composites for VLBW infants at 24 months of corrected age.

Background: Selenium, a natural microelement with both nutritional and toxicological properties, is intertwined with tumorigenesis and progression. However, it is not fully understood how selenium metabolism affects immune response and cancer biology., Methods: We estimated selenium metabolism by Gene Set Enrichment Analysis (GSEA) to delineate the selenium metabolism landscape using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE) and a integrated pan-cancer single-cell dataset. We systematically explored the prognostic implications of selenium metabolism and selenium-related regulatory patterns. The therapeutic value of selenium metabolism was explored through machine learning and examined in several immunotherapy cohorts. The heterogeneity and underlying mechanism of selenium metabolism were investigated by cell‒cell communication analysis at the single-cell level., Results: A GSEA analysis based on 86 genes was used to evaluate the selenium metabolism landscape. The selenium metabolism score exhibited prognostic value in predicting the lower risk of mortality, possibly due to its correlation with multiple cancer hallmarks, including a positive correlation with complement (R = 0.761, P < 0.001), inflammatory response (R = 0.663, P < 0.001), apoptosis (R = 0.626, P < 0.001), hypoxia (R = 0.587, P < 0.001), reactive oxygen species (ROS) (R = 0.558, P < 0.001), and interferon gamma response (R = 0.539, P < 0.001). We also observed heterogeneity in the relationship between selenium metabolism and immunity across different cancers. Based on selenium-related genes, we constructed a machine learning model with area under the ROC curve (AUC) of 0.82 in predicting immune checkpoint inhibitor (ICI)-based immunotherapy response. Single-cell selenium metabolism quantification revealed that adjacent and tumor tissues had higher selenium metabolism compared with normal tissues, especially in epithelial cells, fibroblasts and macrophages. The communication between high-selenium epithelium and high-selenium fibroblast was significantly higher than other cells, especially in cytokines, chemokines, collagen, Wnt, VEGF, IGF and FGF pathways., Conclusion: Our study provides a comprehensive landscape of selenium metabolism levels and diverse regulatory patterns in different cancers, deepening the understanding of selenium's roles in tumorigenesis and immunity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Distant metastasis remains a leading cause of mortality among patients with colorectal cancer (CRC). Organotropism, referring to the propensity of metastasis to target specific organs, is a well-documented phenomenon in CRC, with the liver, lungs, and peritoneum being preferred sites. Prior to establishing premetastatic niches within host organs, CRC cells secrete substances that promote metastatic organotropism. Given the pivotal role of organotropism in CRC metastasis, a comprehensive understanding of its molecular underpinnings is crucial for biomarker-based diagnosis, innovative treatment development, and ultimately, improved patient outcomes. In this review, we focus on metabolic reprogramming, tumor-derived exosomes, the immune system, and cancer cell-organ interactions to outline the molecular mechanisms of CRC organotropic metastasis. Furthermore, we consider the prospect of targeting metastatic organotropism for CRC therapy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Coral-associated organisms often exhibit a continuum of host specificities. We do not know whether the variation in host specificity is related to the settlement organs or preferential settlement behaviours of the larvae. We examined the morphology of attachment discs, the settlement and metamorphosis of coral barnacles-Pyrgoma cancellatum (lives in a single coral species), Nobia grandis (two families of corals), and Armatobalanus allium (six families of corals). Our results revealed that the attachment organ of all three species are spear-shaped with sparse villi, indicating that the morphology of the attachment organs does not vary among species with different host specificities. Larvae of P. cancellatum and N. grandis only settle on their specific hosts, suggesting that chemical cues are involved in the settlement. Cyprids of N. grandis display close searching behaviour before settlement. Cyprids of P. cancellatum settle immediately on their specific host corals, without any exploratory behaviour. The host specificity and exploratory behaviours of coral barnacle cyprids are results of adaptive evolution. We argue that there is a trade-off between exploration and energy conservation for metamorphosis processes. Coral barnacle metamorphosis is longer when compared to free-living species, likely because it involves the development of a tube-shaped base on the coral surface., (© 2023. The Author(s).)

This study evaluated the association between inflammatory diets as measured by the Dietary Inflammatory index (DII), inflammation biomarkers and the development of preeclampsia among the Chinese population. We followed the reporting guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology statement for observational studies. A total of 466 preeclampsia cases aged over 18 years were recruited between March 2016 and June 2019, and 466 healthy controls were 1:1 ratio matched by age (±3 years), week of gestation (±1 week) and gestational diabetes mellitus. The energy-adjusted DII (E-DII) was computed based on dietary intake assessed using a seventy-nine item semiquantitative FFQ. Inflammatory biomarkers were analysed by ELISA kits. The mean E-DII scores were -0·65 ± 1·58 for cases and -1·19 ± 1·47 for controls ( P value < 0·001). E-DII scores positively correlated with interferon- γ ( r s = 0·194, P value = 0·001) and IL-4 ( r s = 0·135, P value = 0·021). After multivariable adjustment, E-DII scores were positively related to preeclampsia risk ( P trend < 0·001). The highest tertile of E-DII was 2·18 times the lowest tertiles (95 % CI = 1·52, 3·13). The odds of preeclampsia increased by 30 % (95 % CI = 18 %, 43 %, P value < 0·001) for each E-DII score increase. The preeclampsia risk was positively associated with IL-2 (OR = 1·07, 95 % CI = 1·03, 1·11), IL-4 (OR = 1·26, 95 % CI = 1·03, 1·54) and transforming growth factor beta (TGF- β ) (OR = 1·17, 95 % CI = 1·06, 1·29). Therefore, proinflammatory diets, corresponding to higher IL-2, IL-4 and TGF- β levels, were associated with increased preeclampsia risk.

GSK3α and GSK3β are two GSK3 isoforms with 84% overall identity and 98% identity in their catalytic domains. GSK3β plays important roles in the pathogenesis of cancer, while GSK3α has long been considered a functionally redundant protein of GSK3β. Few studies have specifically investigated the functions of GSK3α. In this study, unexpectedly, we found that the expression of GSK3α, but not GSK3β, was significantly correlated with the overall survival of colon cancer patients in 4 independent cohorts. To decipher the roles of GSK3α in colon cancer, we profiled the phosphorylation substrates of GSK3α and uncovered 156 phosphosites from 130 proteins specifically regulated by GSK3α. A number of these GSK3α-mediated phosphosites have never been reported before or have been incorrectly identified as substrates of GSK3β. Among them, the levels of HSF1 S303p , CANX S583p , MCM2 S41p , POGZ S425p , SRRM2 T983p , and PRPF4B S431p were significantly correlated with the overall survival of colon cancer patients. Further pull-down assays identified 23 proteins, such as THRAP3, BCLAF1, and STAU1, showing strong binding affinity to GSK3α. The interaction between THRAP3 and GSK3α was verified by biochemical experiments. Notably, among the 18 phosphosites of THRAP3, phosphorylation at S248, S253, and S682 is specifically mediated by GSK3α. Mutation of S248 to D (S248D), which mimics the effect of phosphorylation, obviously increased cancer cell migration and the binding affinity to proteins related to DNA damage repair. Collectively, this work not only discloses the specific function of GSK3α as a kinase but also suggests GSK3α as a promising therapeutic target for colon cancer., Competing Interests: Conflict of Interest There is no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the Wnt/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in CRC patients with APC mutations. Although previous genomics studies have investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. Based on the proteome and phosphoproteome data, we classified APC-mutant colon cancer patients and revealed genomic, proteomic, and phosphoproteomic heterogeneity in APC-mutant tumors. More importantly, we identified RAI14 as a key prognostic determinant for APC-mutant but not APC-wildtype colon cancer patients. The heterogeneity and the significance of prognostic biomarkers in APC-mutant tumors were further validated in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that colon cancer patients with high expression of RAI14 were less responsive to chemotherapy. Knockdown of RAI14 in cell lines led to reduced cell migration and changes in epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 remodeled the phosphoproteome associated with cell adhesion, which might affect EMT marker expression and promote F-actin degradation. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies RAI14 as an important prognostic determinant for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment., Competing Interests: Conflict of interest There is no competing financial interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Distant metastasis is a major contributor to cancer-related mortality. However, the role of circRNAs in this process remains unclear. Herein, we profiled the circRNA expression in a cohort of 68 colorectal carcinoma (CRC) primary tumors and their paired liver metastatic lesions. By overlapping with the TGFβ-responsive circRNAs, circNEIL3 (hsa&#95;circ&#95;0001460) was identified as a TGFβ-repressive and metastasis-related circRNA. Functionally, circNEIL3 effectively inhibited tumor metastasis in both and in vivo and in vivo models of various cancer types. Mechanistically, circNEIL3 exerts its metastasis-repressive function through its direct interaction with oncogenic protein, Y-box-binding protein 1 (YBX1), which consequently promotes the Nedd4L-mediated proteasomal degradation of YBX1. Importantly, circNEIL3 expression was negatively correlated to YBX1 protein level and metastatic tendency in CRC patient samples. Collectively, our findings indicate the YBX1-dependent antimetastatic function of circNEIL3 and highlight the potential of circNEIL3 as a biomarker and therapeutic option in cancer treatment.

Metastasis is considered as the major cause of cancer death. Cancer cells can be released from primary tumors into the circulation and then colonize in distant organs. How cancer cells acquire the ability to colonize in distant organs has always been the focus of tumor biology. To enable survival and growth in the new environment, metastases commonly reprogram their metabolic states and therefore display different metabolic properties and preferences compared with the primary lesions. For different microenvironments in various colonization sites, cancer cells must transfer to specific metabolic states to colonize in different distant organs, which provides the possibility of evaluating metastasis tendency by tumor metabolic states. Amino acids provide crucial precursors for many biosynthesis and play an essential role in cancer metastasis. Evidence has proved the hyperactivation of several amino acid biosynthetic pathways in metastatic cancer cells, including glutamine, serine, glycine, branched chain amino acids (BCAAs), proline, and asparagine metabolism. The reprogramming of amino acid metabolism can orchestrate energy supply, redox homeostasis, and other metabolism-associated pathways during cancer metastasis. Here, we review the role and function of amino acid metabolic reprogramming in cancer cells colonizing in common metastatic organs, including lung, liver, brain, peritoneum, and bone. In addition, we summarize the current biomarker identification and drug development of cancer metastasis under the amino acid metabolism reprogramming, and discuss the possibility and prospect of targeting organ-specific metastasis for cancer treatment., 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 Wang, Wu, Chen and Wang.)

Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI., (© 2023. The Author(s).)

Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in hepatocellular carcinoma (HCC) tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is markedly downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged nonmethylated peptide inhibits serine synthesis and restrains HCC growth in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC., (© 2023. The Author(s).)

The single-nucleotide polymorphism (SNP) of p53, in particular the codon 72 variants, has recently been implicated as a critical regulator in tumor progression. However, the underlying mechanism remains elusive. Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation. Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant (but not p53 72R ) with phosphoserine aminotransferase 1 (PSAT1). Interestingly, p53 72P -PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) that otherwise bound to p53 72P , leading to subsequent nuclear translocation of PGC-1α and activation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Depletion of PSAT1 restored p53 72P -PGC-1α interaction and impeded the OXPHOS and TCA function, resulting in mitochondrial dysfunction and metastasis suppression. Notably, pharmacological targeting the PSAT1-p53 72P interaction by aminooxyacetic acid (AOA) crippled the growth of liver cancer cells carrying the p53 72P variant in both in vitro and patient-derived xenograft models. Moreover, AOA plus regorafenib, an FDA-proved drug for hepatocellular carcinoma and colorectal cancer, achieved a better anti-tumor effect on tumors carrying the p53 72P variant. Therefore, our findings identified a gain of function of the p53 72P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53 72P -PSAT1 perturbation., (© 2022. The Author(s).)

Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F 1 F O -ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B-ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1 + tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ ., (© 2022. The Author(s).)

Various risk factors are associated with neonatal sepsis; however, its relationship to maternal postpartum fever is unknown. This study aimed to determine the relationship between maternal postpartum fever and neonatal sepsis. Full-term and late preterm stable infants born from January 2019 to June 2021 and whose mothers developed intra- or post-partum fever were included in the study. After the newborns were transferred to the nursery, laboratory assessments were performed. Based on clinical conditions and data, the newborns were divided into unlikely sepsis and probable/proven sepsis groups. Maternal fever onset, duration, and maximum body temperature were recorded. We included 1059 newborns whose mothers developed fever intra-partum (n = 192), post-partum (n = 844), and intra- and post-partum (n = 23). The newborns were grouped into those with unlikely sepsis (n = 550) and those with probable/proven sepsis (n = 509). The incidence of intrapartum fever was higher in the probable/proven sepsis group than in the unlikely sepsis group (27.9% vs. 13.3%, p < 0.001). The incidence of postpartum fever was lower in the probable/proven sepsis group than in the unlikely sepsis group (74.7% vs. 88.5%, p < 0.001). Development of maternal fever within 1.8 h postpartum and a newborn respiratory rate of >60 breaths/min were positive predictors (91.6%) for neonatal probable/proven sepsis.

Background: Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined., Methods: The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/β-catenin axis in CRC proliferation and metastasis., Results: Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N 6 -methyladenosine (m 6 A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m 6 A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe 2+ ). Increased Fe 2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and inhibited its kinase activity, thus releasing β-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression., Conclusions: Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/β-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe 2+ ), which induces the Ser 9 phosphorylation and inactivation of GSK3β, releasing β-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression., (© 2022. The Author(s).)

The effect of vitamin D (VD) on the risk of preeclampsia (PE) is uncertain. Few of previous studies focused on the relationship between dietary VD intake and PE risk. Therefore, we conducted this 1:1 matched case-control study to explore the association of dietary VD intake and serum VD concentrations with PE risk in Chinese pregnant women. A total of 440 pairs of participants were recruited during March 2016 to June 2019. Dietary information was obtained using a seventy-eight-item semi-quantitative FFQ. Serum concentrations of 25(OH)D 2 and 25(OH)D 3 were measured by liquid chromatography-tandem MS. Multivariate conditional logistic regression was used to estimate OR and 95 % CI. Restricted cubic splines (RCS) were plotted to evaluate the dose-response relationship of dietary VD intake and serum VD concentrations with PE risk. Compared with the lowest quartile, the OR of the highest quartile were 0·45 (95 % CI 0·29, 0·71, P trend = 0·001) for VD dietary intake and 0·26 (95 % CI 0·11, 0·60, P trend = 0·003) for serum levels after adjusting for confounders. In addition, the RCS analysis suggested a reverse J-shaped relationship between dietary VD intake and PE risk ( P -nonlinearity = 0·02). A similar association was also found between serum concentrations of total 25(OH)D and PE risk ( P -nonlinearity = 0·02). In conclusion, this study provides evidence that higher dietary intake and serum levels of VD are associated with the lower risk of PE in Chinese pregnant women.

Objectives: To investigate the survival rate of hydrops fetalis after fetal interventions and neonatal intensive care., Methods: We reviewed the medical records of patients diagnosed with hydrops fetalis from January 2009 to December 2019 at Changhua Christian Children's Hospital. All cases had abnormal fluid accumulation in at least two body compartments during pre- and postnatal examination. The primary outcome measure was the mortality rate. We also collected information regarding disease etiology, duration of hospital stay, Apgar score, gestational age at birth, initial hydrops fetalis diagnosis, fetal intervention, first albumin and pH levels, and maternal history., Results: Of the 42 cases enrolled, 30 survived and 12 died; the mortality rate was 28.6%. Furthermore, 22 cases received fetal intervention, while 20 cases did not; there was no significant difference in their survival rates (75% and 68%, respectively). Survival rate was associated with gestational age at birth, initial diagnosis time, birthweight, Apgar score, initial albumin and pH levels, and gestational hypertension. Only one case was immune-mediated. Among the nonimmune-mediated cases, the three most common etiologies were lymphatic dysplasia (12/42), idiopathic disorders (10/42), and cardiovascular disorders (5/42)., Conclusions: Overall, hydrops fetalis was diagnosed early, and fetal intervention was performed in a timely manner. Preterm births were more frequent, and birthweight was lower in the cases that underwent fetal intervention than in those that did not, but there was no significant between-group difference in mortality. The initial diagnosis time, gestational age at birth, birthweight, Apgar score, and first albumin and pH levels were independently associated with mortality.

Entering a drug-tolerant persister (DTP) state of cancer cells is a transient self-adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug-resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA-seq revealed that these cells partially prevented chemotherapy-triggered oxidative stress by promoting NPC1L1-regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the -205 to -215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple-combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti-tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

We report on experimental evidence of non-conversional pairing in In and Sn nanoparticle assemblies. Spontaneous magnetizations are observed, through extremely weak-field magnetization and neutron-diffraction measurements, to develop when the nanoparticles enter the superconducting state. The superconducting transition temperature T C shifts to a noticeably higher temperature when an external magnetic field or magnetic Ni nanoparticles are introduced into the vicinity of the superconducting In or Sn nanoparticles. There is a critical magnetic field and a critical Ni composition that must be reached before the magnetic environment will suppress the superconductivity. The observations may be understood when assuming development of spin-parallel superconducting pairs on the surfaces and spin-antiparallel superconducting pairs in the core of the nanoparticles., (© 2022. The Author(s).)

Background & Aims: Latent metastasis of colorectal cancer (CRC) frequently develops months or years after primary surgery, followed by adjuvant therapies, and may progress rapidly even with targeted therapy administered, but the underlying mechanism remains unclear. Here, we aim to explore the molecular basis for the aggressive behavior of latent metastasis in CRC., Methods: Transcriptional profiling and pathway enrichment analysis of paired primary and metastatic tumor samples were performed. The underlying mechanisms of pleckstrin homology-like domain, family B, member 2 (PHLDB2) in CRC were investigated by RNA immunoprecipitation assay, immunohistochemistry, mass spectrometry analysis, and Duolink in situ proximity ligation assay (Sigma-Aldrich, Shanghai, China). The efficacy of targeting PHLDB2 in cetuximab treatment was elucidated in CRC cell lines and mouse models., Results: Based on the transcriptional profile of paired primary and metastatic tumor samples, we identified PHLDB2 as a potential regulator in latent liver metastasis. A detailed mechanistic study showed that chemotherapeutic agent-induced oxidative stress promotes methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine modification of PHLDB2 messenger RNA, facilitating its protein expression. Up-regulated PHLDB2 stabilizes epidermal growth factor receptor (EGFR) and promotes its nuclear translocation, which in turn results in EGFR signaling activation and consequent cetuximab resistance. Moreover, Arg1163 (R1163) of PHLDB2 is crucial for interaction with EGFR, and the R1163A mutation abrogates its regulatory function in EGFR signaling., Conclusions: PHLDB2 plays a crucial role in cetuximab resistance and is proposed to be a potential target for the treatment of CRC., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer cells utilize rapidly elevated cellular antioxidant programs to accommodate chemotherapy-induced oxidative stress; however, the underlying mechanism remains largely unexplored. Here we screen redox-sensitive effectors as potential therapeutic targets for colorectal cancer (CRC) treatment and find that cyclophilin A (CypA) is a compelling candidate. Our results show that CypA forms an intramolecular disulfide bond between Cys115 and Cys161 upon oxidative stress and the oxidized cysteines in CypA are recycled to a reduced state by peroxiredoxin-2 (PRDX2). Furthermore, CypA reduces cellular reactive oxygen species levels and increases CRC cell survival under insults of H 2 O 2 and chemotherapeutics through a CypA-PRDX2-mediated antioxidant apparatus. Notably, CypA is upregulated in chemoresistant CRC samples, which predicts poor prognosis. Moreover, targeting CypA by cyclosporine A exhibits promising efficacy against chemoresistant CRC when combined with chemotherapeutics. Collectively, our findings highlight CypA as a component of cellular noncanonical antioxidant defense and as a potential druggable therapeutic target to ameliorate CRC chemoresistance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Blood glucose and serum sodium abnormalities in very low birth weight infants may cause increased morbidity and mortality, but data regarding the long-term outcomes are limited. This study aimed to investigate the association between the peak and nadir blood glucose and serum sodium levels and neurodevelopmental outcomes in very low birth weight infants., Methods: A single-center retrospective medical record of 284 infants with birth weight<1500 g born between February 1, 2011 and January 31, 2015 was reviewed. We analyzed the correlation between peak and nadir blood glucose and serum sodium levels during hospitalization and Bayley Scales of Infant and Toddler Development, third edition at 6, 12, and 24 months of corrected age., Results: A total of 284 very low birth weight premature infants were eligible, and 223, 208, and 188 patients were assessed at 6, 12, and 24 months of corrected age, respectively. Multiple linear regression analysis with generalized estimating equations showed that the BSID-III cognitive scores were significantly lower in the peak serum sodium group when sodium was ≧150 mmol/L (95% confidence interval -11.681 to -0.822) than when sodium did not exceed 150 mmol/L., Conclusion: A peak serum sodium of ≧150 mmol/L is associated with poor cognitive outcomes in very low birth weight infants. Further studies are necessary to determine if this association is causal or an expression of disease severity., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier B.V.)

Aim: To develop nomograms for predicting cancer-specific survival (CSS) and overall survival (OS) in patients with invasive extramammary Paget's disease (iEMPD). Patients & methods: Retrospective data of 1955 patients with iEMPD were collected from the Surveillance, Epidemiology, and End Results database. Nomograms for predicting CSS and OS were established using competing risk regression and Cox regression, respectively, and were internally validated. Results: Five (age, surgery, tumor location, stage and concurrent malignancy) and eight (gender, age, race, marital status, surgery, tumor location, stage and lymph node metastasis) clinicopathological factors were utilized to construct nomograms for predicting CSS and OS, respectively. The concordance indices of the nomograms for predicting CSS and OS were 0.78 and 0.73, respectively. The validation of the nomograms showed good calibration and discrimination. The decision curve analyses confirmed the clinical utility of these nomograms. Conclusion: The nomograms can be a reliable tool for treatment design and prognostic evaluation of iEMPD.

L-Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide, which has shown broad-spectrum anticancer activity. But the anticancer mechanisms and regulators remain unknown. In this study, we investigated the effects of carnosine on human glioma U87 and U251 cell lines under normoxia (21% O 2 ) and hypoxia (1% O 2 ). We showed that carnosine (25-75 mM) dose-dependently inhibited the proliferation of the glioma cells; carnosine (50 mM) inhibited their colony formation, migration, and invasion capacity. But there was no significant difference in the inhibitory effects of carnosine under normoxia and hypoxia. Treatment with carnosine (50 mM) significantly decreased the expression of glutamine synthetase (GS) at the translation level rather than the transcription level in U87 and U251 cells, both under normoxia and hypoxia. Furthermore, the silencing of GS gene with shRNA and glutamine (Gln) deprivation significantly suppressed the growth, migratory, and invasive potential of the glioma cells. The inhibitory effect of carnosine on U87 and U251 cells was partly achieved by inhibiting the Gln metabolism pathway. Carnosine reduced the expression of GS in U87 and U251 cells by promoting the degradation of GS through the proteasome pathway, shortening the protein half-life, and reducing its stability. Given that targeting tumor metabolism is a proven efficient therapeutic tactic, our results may present new treatment strategies and drugs for improving the prognosis of gliomas.

Objective: Preterm infants receive long-term parenteral nutrition (PN) for gastrointestinal immaturity. This study aimed to determine if mixed lipid emulsions containing fish oil decrease the incidence of PN-associated cholestasis by reducing oxidative stress and providing an anti-inflammatory effect., Methods: This retrospective cohort study enrolled 399 very low birth weight premature infants (gestational age ≤32 weeks) between January 2009 and November 2017 at a single neonatal intensive care unit. Preterm infants received total PN with either mixed lipid emulsion including fish oil (SMOFlipid®, n = 195) or soybean oil-based lipid emulsion (Lipovenoes®, n = 204) for at least 7 days. We compared the outcomes of PN-associated cholestasis, comorbidities, and mortality between the groups., Results: The incidence of PN-associated cholestasis was significantly lower in the SMOFlipid group than in the Lipovenoes group. The duration to full feeding days was significantly shorter in the SMOFlipid group compared with the Lipovenoes group. Relevant complications, such as severe retinopathy of prematurity and bronchopulmonary dysplasia, were also significantly reduced in the SMOFlipid group compared with the Lipovenoes group., Conclusion: In premature infants, PN with fish oil-based lipid emulsions is associated with a lower incidence of PN-associated cholestasis compared with soybean oil-based lipid emulsions.

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial-mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal-epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade., 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 © 2021 Liu, Luo, Huang, Chen and Zhou.)

Although epithelial cell adhesion molecule (EpCAM) has previously been shown to promote tumor progression, the underlying mechanisms remain largely unknown. Here, we report that the EGF-like domain I within the extracellular domain of EpCAM (EpEX) binds EGFR, activating both AKT and MAPK signaling to inhibit forkhead transcription factor O3a (FOXO3a) function and stabilize PD-L1 protein, respectively. Treatment with the EpCAM neutralizing antibody, EpAb2-6, inhibited AKT and FOXO3a phosphorylation, increased FOXO3a nuclear translocation, and upregulated high temperature requirement A2 (HtrA2) expression to promote apoptosis while decreasing PD-L1 protein levels to enhance the cytotoxic activity of CD8 + T cells. In vivo , EpAb2-6 markedly extended survival in mouse metastasis and orthotopic models of human colorectal cancer. The combination of EpAb2-6 with atezolizumab, an anti-PD-L1 antibody, almost completely eliminated tumors. Moreover, the number of CD8 + T cells in combination-treated tumors was increased compared with atezolizumab alone. Our findings suggest a new combination strategy for cancer immunotherapy in patients with EpCAM-expressing tumors. SIGNIFICANCE: This study shows that treatment with an EpCAM neutralizing antibody promotes apoptosis while decreasing PD-L1 protein to enhance cytotoxic activity of CD8 + T cells., (©2020 American Association for Cancer Research.)

Background: The concept of parental nutritional care for premature infants has been applied and advanced over the past decade. This study compared the clinical outcomes before and after nutrition practice (NP) implementation and evaluated the effects of implementation on growth velocity and weight gain in premature infants., Methods: Descriptive data of premature infants (gestational age < 30 weeks; body weight ≤ 1250 g) born 4 years before and after NP implementation were retrospectively reviewed in a neonatal intensive care unit at a hospital in Taiwan. Nutrient intake, growth velocity, weight gain, and nutrition-related biochemical markers were compared at weeks 1, 2, and 4 after delivery., Results: A total of 77 premature infants were enrolled before NP implementation (non-NP group), whereas 89 were enrolled after implementation (NP group). The non-NP group consumed less fat and energy in week 1, and less protein, fat, and energy in weeks 2 and 4 compared with the NP group. Growth velocity was slower in the non-NP group. Fat intake was significantly positively correlated with body weight at week 4 in the non-NP group. However, protein and fat intake were significantly associated with body weight at week 1, fat and energy intakes were significantly associated with body weight at week 2, and fat intake was significantly associated with body weight at week 4 in the NP group., Conclusion: These findings indicate that the NP implemented in this study is relatively safe and can improve growth velocity and body weight gain in premature infants., (Copyright © 2020. Published by Elsevier B.V.)

Background : To provide a better quality of death for patients at the end of life who choose to die at home and their families, the hospice care team at Taipei Veterans General Hospital has promoted an personalized discharged end-of-life care plan since the initial of 2018. Methods : This study is a retrospective analysis of administrative data. All incoming calls of the 24-hour specialist palliative care emergency telephone advice service records were analyzed. Personal information of any callers or consultants was not registered in the content. Results : A total of 728 telephone consultations was registered during the study period. The content of the consultation of different callers was significantly different ( p < 0.001). The decrease in the number of calls from the patients who were discharged from the hospice ward had the largest reduction in proportion, from 80 (19.0%) to 32 (10.5%), There was a significant difference in the identity of the callers between 2017 and 2018 ( p = 0.025). The proportion of consultation calls for the management of near-death symptoms significantly reduced from 15.6% to 10.5% ( p = 0.027). Conclusions : Though the evidence from this study is not enough to support that the personalized discharged end-of-life care plan might reduce the frequency of dialing 24-hour hotlines by the family members of discharged terminally ill patients. For patients who choose to die at home and their families, the hotlines provide a 24-hour humane support. Thus, we need to conduct relevant research to determine whether the service of this dedicated line meets the needs of patients and their families in the terminal stage.

Novel coumarin-iminophosphorane (IPP) fluorophores that have stable resonance contributions from aza-ylides were formed by using the nonhydrolysis Staudinger reaction. The N═P formation reaction kinetics obey the conventional Staudinger reaction. The absorption and emission profiles of the coumarin-IPP derivatives can be fine-tuned: an electron-donating group at PPh 3 enhances absorption and fluorescence, whereas an electron-withdrawing group at C-3 drives absorption and emission peaks toward blue-light wavelengths. Two-photon adsorption, accompanied by anti-Stokes fluorescence, is achieved under near-infrared femtosecond laser excitation.

Background: The aim of the study was to assess the impact of different types of parenteral emulsions on retinopathy of prematurity (ROP) in very low birth weight (VLBW, birth body weight < 1500 g) infants by comparing fish oil-containing and soy-based parenteral emulsions., Methods: Data of preterm infants with body weights below 1500 gm at birth and receiving total parenteral nutrition (TPN) for a minimum of 7 days during the period between January 2009 and November 2017 were analyzed in this retrospective study. We compared clinical outcomes in two epochs using different lipid emulsions: epoch 1 (soybean-based lipid emulsions, January 2009-February 2014) versus epoch 2 (fish oil-containing lipid emulsions, January 2015-November 2017). The primary outcomes measured were the incidence of ROP and the number of ROP cases requiring bevacizumab therapy., Results: A total of 396 infants were enrolled in this study (203 in epoch 1 and 193 in epoch 2). A lower incidence of any stage ROP (24.1 vs. 11.4%, p < 0.001) and lower requirement of bevacizumab therapy (12.8 vs. 5.2%, p = 0.001) were observed in epoch 2. Gestational age, glutamic-pyruvic transaminase, total bilirubin, and alkaline phosphatase levels, and type of lipid emulsion in TPN were associated with higher ROP incidence. Multivariate logistic regression analysis revealed that parenteral nutrition in the form of lipid emulsions containing fish oil was associated with a lower risk of development of ROP [Odds Ratio: 0.178, 95% confidence interval (CI): 0.095-0.330, p < 0.001]., Conclusions: Compared with soybean-based lipid solutions, the use of fish oil-containing lipid solutions may be associated with a lower incidence of ROP and decreased need for bevacizumab treatment in preterm infants., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2019. Published by Elsevier B.V.)

Drug resistance presents serious difficulties for cancer treatment. A combination of paclitaxel (PTX) and lapatinib (LAPA) shows potentials in multiple drug resistant cancers in the clinic, but it is almost impossible to deliver these two drugs to the tumor at the same time with the best proportion by simple co-administration of the respective current formualtions for their different pharmacokinetic profiles. Here composite nanocrystals of PTX and LAPA (cNC) were designed with a ratio of 2:1 ( w / w ), which was their intracellular ratio at the best synergistic efficacy on a drug-resistant cancer cell line (MCF-7/ADR). Such cNC were prepared using a bottom-up method to achieve a nearly spherical appearance and a narrow size distribution of 95.1 ± 2.1 nm. For nanocrystal stabilization, Polyethylene glycol (PEG) coating was introduced into the cNC via polydopamine (PDA) coating in order to get a PEGylated composite nanocrystal (cNC@PDA-PEG) with nanoscale size (170.5 ± 1.4 nm), considerable drug loading (PTX: 21.33 ± 1.48%, LAPA: 10.95 ± 1.24%) and good stability for at least 4 days in plasma-containing buffers. Differential scanning calorimeter (DSC) and XRD data both indicated the different crystalline states of the cNC as well as the cNC@PDA-PEG in comparison with bulk drugs. In vitro release data showed that PTX and LAPA were gradually and completely released from cNC@PDA-PEG in 3 days, while drug release from bulk drugs or cNC was only 30%. cNC@PDA-PEG also showed negligible hemolysis in vitro. Cellular uptake experiments in the MCF-7/ADR cell line showed that the nanocrystals entered the cells in a complete form through endocytosis and then released the drug in the cell. cNC@PDA-PEG inhibits the growth of this drug-resistant cell more effectively than the unmodified version (cNC). In summary, PEGylated PTX and LAPA composite nanocrystals showed the potential for treament of drug-resistant tumors by simultaneously delivering two drugs to tumor cells with the best proportion., Competing Interests: The authors declare no conflict of interest.

Rationale : The sustained and severe endoplasmic reticulum (ER) stress in cancer cells may contribute to apoptotic cell death, thus representing a potential target for cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods : ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo . A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results : Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo , supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion : The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

BACKGROUND The aim of this study was to identify gene signals for lower-grade glioma (LGG) and to assess their potential as recurrence biomarkers. MATERIAL AND METHODS An LGG-related mRNA sequencing dataset was downloaded from The Cancer Genome Atlas (TCGA) Informix. Multiple bioinformatics analysis methods were used to identify key genes and potential molecular mechanisms in recurrence of LGG. RESULTS A total of 326 differentially-expressed genes (DEGs), were identified from 511 primary LGG tumor and 18 recurrent samples. Gene ontology (GO) analysis revealed that the DEGs were implicated in cell differentiation, neuron differentiation, negative regulation of neuron differentiation, and cell proliferation in the forebrain. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database suggests that DEGs are associated with proteoglycans in cancer, the Wnt signaling pathway, ECM-receptor interaction, the PI3K-Akt signaling pathway, transcriptional deregulation in cancer, and the Hippo signaling pathway. The hub DEGs in the protein-protein interaction network are apolipoprotein A2 (APOA2), collagen type III alpha 1 chain (COL3A1), collagen type I alpha 1 chain (COL1A1), tyrosinase (TYR), collagen type I alpha 2 chain (COL1A2), neurotensin (NTS), collagen type V alpha 1 chain (COL5A1), poly(A) polymerase beta (PAPOLB), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and anomalous homeobox (ANHX). GSEA revealed that the following biological processes may associated with LGG recurrence: cell cycle, DNA replication and repair, regulation of apoptosis, neuronal differentiation, and Wnt signaling pathway. CONCLUSIONS Our study demonstrated that hub DEGs may assist in the molecular understanding of LGG recurrence. These findings still need further molecular studies to identify the assignment of DEGs in LGG.

Ketoconazole is a broad-spectrum antifungal agent, which has recently been characterized as a potential anticancer agent in several cancer types. However, the molecular mechanism underlying the anticancer effect of ketoconazole is not clearly defined. Our recent findings demonstrate that ketoconazole suppresses the growth of hepatocellular carcinoma (HCC) cells by exacerbating mitophagy in vitro and in vivo. Mechanistically, PINK1-PRKN-mediated mitophagy are led by ketoconazole-induced suppression of PTGS2 (prostaglandin-endoperoxide synthase 2), which in turn results in mitochondrial dysfunction and consequent apoptosis. These data link PTGS2 to mitophagy machinery and implicate ketoconazole as a potential therapeutic option for HCC treatment.

Perivascular adipose tissue (PVAT), a special type of adipose tissue, closely surrounds vascular adventitia and produces numerous bioactive substances to maintain vascular homeostasis. PVAT dysfunction has a crucial role in regulating vascular remodeling, but the exact mechanisms remain unclear. In this study, we investigated whether and how obesity-induced PVAT dysfunction affected adventitia remodeling in early vascular injury stages. Mini pigs were fed a high sugar and fat diet for 6 months to induce metabolic syndrome and obesity. In the mini pigs, left carotid vascular injury was then generated using balloon dilation. Compared with normal mini pigs, obese mini pigs displayed significantly enhanced vascular injury-induced adventitial responses, evidenced by adventitia fibroblast (AF) proliferation and differentiation, and adventitia fibrosis, as well as exacerbated PVAT dysfunction characterized by increased accumulation of resident macrophages, particularly the M1 pro-inflammatory phenotype, increased expression of leptin and decreased expression of adiponectin, and production of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Primary AFs cultured in PVAT-conditioned medium from obese mini pigs also showed significantly increased proliferation and differentiation. We further revealed that activated nod-like receptor protein 3 (NLRP3) inflammasome and its downstream products, i.e., IL-1 family members such as IL-1β and IL-18 were upregulated in the PVAT of obese mini pigs; PVAT dysfunction was also demonstrated in preadipocytes treated with palmitic acid. Finally, we showed that pretreatment with IL-1 receptor (IL-1R) antagonist or IL-1R knockdown blocked AF proliferation and differentiation in AFs cultured in PVAT-conditioned medium. These results demonstrate that obesity-induced PVAT dysfunction aggravates adventitial remodeling after early vascular injury with elevated AF proliferation and differentiation via activating the NLRP3/IL-1 signaling pathway.

Introductions: Pneumothorax is the most frequent severe acupuncture-related adverse event occurring at the GB 21 acupoint. This study used ultrasonography (US) to measure the depth of the GB 21 acupoint in adults and assessed its applicability for ensuring safe acupuncture practices., Materials and Methods: A US probe was used to measure the vertical depth from the skin to the pleural line of the apex of the lungs at the right and left GB 21 acupoints. The sex, age, body weight, height, and body mass index of each person were recorded. Student t test and generalized estimating equations were used for statistical analysis., Results: Sixty women and 41 men with a median age of 29 years were included in this study. The depth of GB 21 increased with body weight, height, and body mass index (p < 0.001). The mean depth of GB 21 in men (17.4 mm) was greater than that in women (14.6 mm; p < 0.001). The depth difference between the right and left shoulders was significant in men (p < 0.001) but not in women., Conclusions: US can be used to measure GB 21 acupoint depth. Further control studies on its use to ensure safe clinical practices, including preventing acupuncture-related pneumothorax, are warranted., (Copyright © 2018. Published by Elsevier B.V.)

Antibody drug conjugates are a rapidly growing form of targeted chemotherapeutics. As companies and researchers move to develop new antibody-drug conjugate (ADC) candidates, high-throughput methods will become increasingly common. Here we use advanced characterization techniques to assess two trastuzumab-DM1 (T-DM1) ADCs; one produced using Protein A immobilization and the other produced in solution. Following determination of payload site and distribution with liquid chromatography-mass spectrometry (LC/MS), thermal stability, heat-induced aggregation, tertiary structure, and binding affinity were characterized using differential scanning calorimetry (DSC), dynamic light scattering (DLS), Raman spectroscopy, and isothermal titration calorimetry (ITC), respectively. Small differences in the thermal stability of the C H 2 domain of the antibody as well as aggregation onset temperatures were observed from DSC and DLS, respectively. However, no significant differences in secondary and tertiary structure were observed with Raman spectroscopy, or binding affinity as measured by ITC. Lysine-based ADC conjugation produces an innately heterogeneous population that can generate significant variability in the results of sensitive characterization techniques. Characterization of these ADCs indicated nominal differences in thermal stability but not in tertiary structure or binding affinity. Our results lead us to conclude that lysine-based ADCs synthesized following Protein A immobilization, common in small-scale conjugations, are highly similar to equivalent ADCs produced in larger scale, solution-based methods., Competing Interests: The authors declare no conflict of interest.

Background: Most of infantile hemangiomas involute into fibrofatty tissue in childhood, which indicates adipogenesis during this period. Mesenchymal stem cells (MSCs) contribute to the adipogenesis in IH. In this study, we investigated the effects of overexpression of PPAR-γ2 gene on the adipogenic differentiation of Hemangioma-derived MSCs (Hem-MSCs), and discussed the possibility of targeted therapy via PPAR-γ pathway., Methods: MSCs were isolated from proliferating hemangioma by their selective adhesion to plastic culture dishes. Recombinant lentivirus with PPAR-γ2 gene were prepared, and used to transfect Hem-MSCs. Transfected cells were cultured in adipogenic medium to observe the differentiation in vitro . And the cells were mixed with Matrigel, then subcutaneously injected into the back of nude mice to observe the differentiation in vivo ., Results: In the in vitro tests, Hem-MSCs with overexpression of PPAR-γ2 gene showed enhanced adipogenic differentiation with increased expression of adipogenic-related genes, including PPAR-γ2, ADD1, LPL, and CEBPA genes. In the in vivo tests, Hem-MSCs/Matrigel plugs with overexpression of PPAR-γ2 gene also showed accelerated adipogenesis and time-phased changes of above genes., Conclusions: Overexpression of PPAR-γ2 gene enhances and accelerates the adipogenic differentiation of Hem-MSCs in vitro and in vivo . The results may provide the preliminary evidences for the targeted therapy of IH via PPAR-γ signal pathway., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.