A General Strategy for Development of Activatable NIR-II Fluorescent Probes for In Vivo High-Contrast Bioimaging.

Organic dye based NIR-II fluorescent probes, owing to their high signal-to-background ratio and deeper penetration, are highly useful for deep-tissue high-contrast imaging in vivo. However, it is still a challenge to design activatable NIR-II fluorescent probes. Here, a novel class of polymethine dyes (NIRII-RTs), with bright (quantum yield up to 2.03 %), stable, and anti-solvent quenching NIR-II emission, together with large Stokes shifts, was designed. Significantly, the novel NIR-II dyes NIRII-RT3 and NIRII-RT4, equipped with a carboxylic acid group, can serve as effective NIR-II platforms for the design of activatable bioimaging probes with high contrast. As a proof of concept, a series of target-activatable NIRII-RT probes (NIRII-RT-pH, NIRII-RT-ATP and NIRII-RT-Hg) for pH, adenosine triphosphate (ATP), and metal-ion detection, were synthesized. By applying the NIRII-RT probe, the real-time monitoring of drug-induced hepatotoxicity was realized.

Dolutegravir derivative inhibits proliferation and induces apoptosis of non-small cell lung cancer cells via calcium signaling pathway.

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. However, there has been little improvement in its cure rate in the last 30 years, due to its intricate heterogeneity and drug resistance. Accumulating evidences have demonstrated that dysregulation of calcium (Ca2+) homeostasis contributes to oncogenesis and promotes tumor development. Inhibitors of Ca2+ channels/transporters to restore intracellular Ca2+ level were found to arrest tumor cell division, induce apoptosis, and suppress tumor growth both in vitro and in vivo. Dolutegravir (DTG), which is a first-line drug for Acquired Immune Deficiency Syndrome (AIDs) treatment, has been shown to increase intracellular Ca2+ levels and Reactive oxygen species (ROS) levels in human erythrocytes, leading to suicidal erythrocyte death or eryptosis. To explore the potential of DTG as an antitumor agent, we have designed and synthesized a panel of compounds based on the principle of biologically active substructure splicing of DTG. Our data demonstrated that 7-methoxy-4-methyl-6,8-dioxo-N-(3-(1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (DTHP), a novel derivative of DTG, strongly inhibited the colony-forming ability and proliferation of NSCLC cells, but displayed no cytotoxicity to normal lung cells. DTHP treatment also induced apoptosis and upregulate intracellular Ca2+ level in NSCLC cells significantly. Inhibiting Ca2+ signaling alleviated DTHP-induced apoptosis, suggesting the perturbation of intracellular Ca2+ is responsible for DTHP-induced apoptosis. We further discovered that DTHP activates AMPK signaling pathway through binding to SERCA, a Ca2+-ATPase. On the other hand, DTHP treatment promoted mitochondrial ROS production, causing mitochondrial dysfunction and cell death. Finally, DTHP effectively inhibited tumor growth in the mouse xenograft model of lung cancer with low toxicity to normal organs. Taken together, our work identified DTHP as a superior antitumor agent, which will provide a novel strategy for the treatment of NSCLC with potential clinical application.

Investigation of Creep Behavior of HDPE Pipe Butt Fusion Welded Joints Using a Stepped Isostress Method.

The utilization of high-density polyethylene (HDPE) pipes is prevalent in water transportation due to their exceptional durability, resistance to corrosion, and ease of installation. Traditionally, butt fusion welding has been employed to connect HDPE pipes. In this study, scanning electron microscopy (SEM) was utilized to examine the microstructure of butt fusion welded joints of HDPE pipes, while the stepped isostress method (SSM) was employed to investigate their creep behavior at 100 °C in ambient air. SEM results revealed a significant presence of craze or lamellae in the base material, whereas minimal occurrences of craze or lamellae were observed in the melt zone. The results obtained from the SSM indicated that the creep life of butt fusion welded joints of HDPE pipes was not adversely affected by the welding bead, and their creep life was no less than that of the base material when ductile creep failure occurred.

The diversification of the shoot branching system: A quantitative and comparative perspective in meristem determinacy.

Reiterative shoot branching largely defines important yield components of crops and is essentially controlled by programs that direct the initiation, dormancy release, and differentiation of meristems in the axils of leaves. Here, we focus on meristem determinacy, defining the number of reiterations that shape the shoot architectures and exhibit enormous diversity in a wide range of species. The meristem determinacy per se is hierarchically complex and context-dependent for the successively emerged meristems, representing a crucial mechanism in shaping the complexity of the shoot branching. In addition, we have highlighted that two key components of axillary meristem developmental programs may have been co-opted in controlling flower/ear number of an axillary inflorescence in legumes/maize, hinting at the diversification of axillary-meristem-patterning programs in different lineages. This begs the question how axillary meristem patterning programs may have diversified during plant evolution and hence helped shape the rich variation in shoot branching systems.

FTO is Associated with Patient Prognosis and Immune Infiltrates in Gastric Cancer and Regulates TGF-ß Expression.

AIMS: This study aimed to examine the associations of FTO expression with prognosis, tumor microenvironment (TME), immune cell infiltration, immune checkpoint genes, and relevant signaling pathways in GC. Furthermore, the relationship between FTO and TGF-ß was studied in GC. METHODS: The mRNA expression and clinical survival data of GC samples were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD). TIMER2, TNM plot, and GEPIA database were used to analyze FTO expression. The associations of FTO with prognosis and clinicopathologic features were assessed using the Kaplan-Meier plotter and UALCAN database, respectively. The R software was employed to analyze its related signaling pathways and the associations with TME, immune cell infiltration, and immune checkpoint genes. GEPIA and ENCORI were used to examine the association of FTO with TGF-ß expression. The SRAMP website was utilized to predict m6A modification of TGF-ß. IHC, Western blot, and qPCR were used to analyze the expression levels of FTO and TGF-ß in clinical gastric cancer tissue samples or gastric cancer cell lines. In addition, a m6A RNA methylation assay kit was used to determine m6A levels in gastric cancer cells. RESULTS: FTO mRNA and protein levels were significantly elevated in GC compared to normal gastric tissues. Kaplan-Meier survival analysis suggested that upregulated FTO was associated with a worse prognosis in GC. Upregulated FTO was markedly correlated with differentiation degree, lymph node metastasis, and clinical TNM stage. GO and KEGG pathway analyses revealed that FTO-associated molecules were enriched in neuroactive ligand-receptor interaction, calcium signaling, PI3k-Akt signaling, cAMP signaling pathways, and TGF-ß signaling pathways, among others. The TME score was remarkably higher in the high-FTO group than in the low-FTO group. Furthermore, FTO expression had positive correlations with different types of immune cells and immune checkpoint genes. Moreover, FTO may regulate TGF-ß in an m6A RNA modification manner in GC. CONCLUSION: FTO may become an independent predictive prognostic biomarker correlating with TME, immune cell infiltration, and immune checkpoint genes in gastric cancer and might influence GC progression by regulating TGF-ß expression.

Tanshinone IIA induces ER stress and JNK activation to inhibit tumor growth and enhance anti-PD-1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains at the forefront of new cancer cases, and there is an urgent need to find new treatments or improve the efficacy of existing therapies. In addition to the application in the field of cerebrovascular diseases, recent studies have revealed that tanshinone IIA (Tan IIA) has anticancer activity in a variety of cancers. PURPOSE: To investigate the potential anticancer mechanism of Tan IIA and its impact on immunotherapy in NSCLC. METHODS: Cytotoxicity and colony formation assays were used to detect the Tan IIA inhibitory effect on NSCLC cells. This research clarified the mechanisms of Tan IIA in anti-tumor and programmed death-ligand 1 (PD-L1) regulation by using flow cytometry, transient transfection, western blotting and immunohistochemistry (IHC) methods. Besides, IHC was also used to analyze the nuclear factor of activated T cells 1 (NFAT2) expression in NSCLC clinical samples. Two animal models including xenograft mouse model and Lewis lung cancer model were used for evaluating tumor suppressive efficacy of Tan IIA. We also tested the efficacy of Tan IIA combined with programmed cell death protein 1 (PD-1) inhibitors in Lewis lung cancer model. RESULTS: Tan IIA exhibited good NSCLC inhibitory effect which was accompanied by endoplasmic reticulum (ER) stress response and increasing Ca2+ levels. Moreover, Tan IIA could suppress the NFAT2/ Myc proto oncogene protein (c-Myc) signaling, and it also was able to control the Jun Proto-Oncogene(c-Jun)/PD-L1 axis in NSCLC cells through the c-Jun N-terminal kinase (JNK) pathway. High NFAT2 levels were potential factors for poor prognosis in NSCLC patients. Finally, animal experiments data showed a stronger immune activation phenotype, when we performed treatment of Tan IIA combined with PD-1 monoclonal antibody. CONCLUSION: The findings of our research suggested a novel mechanism for Tan IIA to inhibit NSCLC, which could exert anti-cancer effects through the JNK/NFAT2/c-Myc pathway. Furthermore, Tan IIA could regulate tumor PD-L1 levels and has the potential to improve the efficacy of PD-1 inhibitors.

Clinical Features and Vaccination Effects among Children with Post-Acute Sequelae of COVID-19 in Taiwan.

BACKGROUND: Post-acute sequelae of SARS-CoV-2 infection (PASC) affects patients after recovering from acute coronavirus disease 2019 (COVID-19). This study investigates the impact of SARS-CoV-2 vaccination on PASC symptoms in children in Taiwan during the Omicron pandemic. METHODS: We enrolled children under 18 years with PASC symptoms persisting for more than 4 weeks. Data collected included demographics, clinical information, vaccination status, and symptom persistence. We used logistic regression models to compare symptoms in the acute and post-COVID-19 phases and to assess the association between vaccination and these symptoms. RESULTS: Among 500 PASC children, 292 (58.4%) were vaccinated, 282 (52.8%) were male, and the mean (SD) age was 7.6 (4.6) years. Vaccinated individuals exhibited higher odds of experiencing symptoms in the previous acute phase, such as cough (adjusted odds ratio [AOR] = 1.57; 95% confidence interval [CI]: 1.02-2.42), rhinorrhea/nasal congestion (AOR = 1.74; 95% CI: 1.13-2.67), sneezing (AOR = 1.68; 95% CI: 1.02-2.76), sputum production (AOR = 1.91; 95% CI: 1.15-3.19), headache/dizziness (AOR = 1.73; 95% CI: 1.04-2.87), and muscle soreness (AOR = 2.33; 95% CI: 1.13-4.80). In contrast, there were lower odds of experiencing abdominal pain (AOR = 0.49; 95% CI: 0.25-0.94) and diarrhea (AOR = 0.37; 95% CI: 0.17-0.78) in children who had received vaccination during the post-COVID-19 phase. CONCLUSIONS: This study revealed clinical features and vaccination effects in PASC children in Taiwan. Vaccination may reduce some gastrointestinal symptoms in the post-COVID-19 phase.

Synergistic phototherapy of NIR wavelength xanthene-quinoline salt-based heavy-atom-free photosensitizers for tumor therapy.

We propose a practical strategy to design a series of heavy-atom-free synergistic phototherapy agents (CSQs) with both photodynamic therapy (PDT) and photothermal therapy (PTT) under NIR wavelength excitation by simply replacing the indole salt of xanthene Changsha (CS) with quinoline salt.

Bacterial coinfections in hospitalized children with COVID-19 during the SARS-CoV-2 Omicron BA.2 variant pandemic in Taiwan.

Background: Bacterial coinfections have been widely recognized in adults with coronavirus disease 2019 (COVID-19). However, bacterial coinfections in hospitalized children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been sufficiently researched. This study aimed to determine the clinical presentations and risk factors for bacterial coinfections of pediatric inpatients during the SARS-CoV-2 Omicron BA.2 variant pandemic. Methods: This retrospective, observational study included patients younger than 18 years of age who were hospitalized for COVID-19 confirmed by polymerase chain reaction (PCR) or antigen rapid tests during the SARS-CoV-2 Omicron BA.2 variant pandemic. Data and outcomes of these patients with or without bacterial coinfections were compared. Results: During this study period, 161 children with confirmed COVID-19 were hospitalized. Twenty-four had bacterial coinfections. The most frequently reported concurrent diagnosis was bacterial enteritis, followed by lower respiratory tract infections. Children with bacterial coinfections had higher white blood cell (WBC) counts and PCR cycle threshold values. The bacterial coinfection group comprised a relatively greater proportion of patients who required high-flow nasal cannula oxygen and remdesivir. The length of stay in the hospital and that in the intensive care unit were longer for children with COVID-19 with bacterial coinfections. Mortality was not observed in either group. Abdominal pain, diarrhea, and comorbidity with neurologic illnesses were risk factors for bacterial coinfections with COVID-19. Conclusion: This study provides clinicians with reference points for the detection of COVID-19 in children and its possible association with bacterial infections. Children with COVID-19 and neurologic diseases who present with abdominal pain or diarrhea are at risk of bacterial coinfections. Prolonged fever duration and higher PCR test cycle threshold values, WBC levels, and high-sensitivity C-reactive protein (hsCRP) levels may indicate bacterial coinfections in children with COVID-19.

Microstructure and Mechanical Properties of Co32Cr28Ni32.94Al4.06Ti3 High-Entropy Alloy.

High-entropy alloys have good application prospects in nuclear power plants due to their excellent mechanical properties and radiation resistance. In this paper, the microstructure of the Co32Cr28Ni32.94Al4.06Ti3 high-entropy alloy was researched using metallurgical microscopy, X-ray diffraction, and scanning electron microscopy. The mechanical properties were tested using a Vickers microhardness tester and a tensile testing machine, respectively. The results showed that Co32Cr28Ni32.94Al4.06Ti3 had a single-phase, disordered, face-centered, cubic solid-solution structure and was strengthened by solid solution. The alloy lattice parameter and density were estimated as 0.304 nm and 7.89 g/cm3, respectively. The test results indicated that the alloy had satisfactory mechanical properties with yield stress and tensile strength of about 530 MPa and 985 MPa, respectively.

An Immune-Related Prognostic Signature Predicts Overall Survival in Stomach Adenocarcinomas.

This study aimed to explore an immune response-related gene signature to predict the clinical prognosis and tumor immunity of stomach adenocarcinomas (STAD). Based on the expression and clinical data of STAD in the TCGA database, the immune cell infiltration status was evaluated using CIBERSORT and ESTIMATE methods. Samples were grouped into "hot" and "cold" tumors based on immune cell infiltration status and consensus clustering. The infiltration abundance of activated memory CD4 T cells and CD8 T cells had a significant effect on the overall survival of STAD patients. Among the three clusters, cluster 2 had a higher immune score and a significantly higher abundance of CD8 T cells and activated memory CD4 T cells were assigned as a hot tumor, while cluster 1 and 3 were assigned as a cold tumor. DEGs between hot and cold tumors were mainly enriched in immune-related biological processes and pathways. Total of 13 DEGs were related to the overall survival (OS). After the univariate and multivariable Cox regression analysis, three signature genes (PEG10, DKK1, and RGS1) was identified to establish a prognostic model. Patients with the high-risk score were associated with worse survival, and the risk score had an independent prognostic value. Based on TIMER online tool, the infiltration levels of six immune cell types showed significant differences among different copy number statuses of PEG10, DKK1, and RGS1. In this study, an immune-related prognostic model containing three genes was established to predict survival for STAD patients.

Nanoparticle-Delivered Transforming Growth Factor-ß1 siRNA Induces PD-1 against Gastric Cancer by Transforming the Phenotype of the Tumor Immune Microenvironment.

Immune checkpoint blockade (ICB) is currently considered to be an important therapeutic method, which obtained FDA approval for clinical use in gastric cancer in 2017. As a new mechanism, it was found that the effect of αPDL1 could be improved by blocking the TGF-ß1 signaling pathway, which converts the tumor immune microenvironment from the "immune-excluded phenotype" to the "immune-inflamed phenotype". Based on this phenomenon, this project was designed to prepare TGF-ß1-siRNA-loaded PEG-PCL nanoparticles conjugated to αPDL1 (siTGF-ß1-αPDL1-PEG-PCL) since we have linked similar antibodies to PEG-PCL previously. Therefore, MFC tumor-engrafted mice were established to simulate the biological characteristics of converting the phenotype of the immune microenvironment, and to study the anti-tumor effect and possible molecular mechanism. In this study, αPDL1 antibody conjugates markedly increased the cell uptake of NPs. The produced αPDL1-PEG-PCL NPs efficiently reduced the amounts of TGF-ß1 mRNA in MFC cells, converting the immune microenvironment of MFC tumors engrafted mice from the "immune-excluded phenotype" to the "immune-inflamed phenotype". PDL1-harboring gastric cancer had increased susceptibility to αPDL1. The value of this drug-controlled release system targeting the tumor microenvironment in immune checkpoint therapy of gastric cancer would provide a scientific basis for clinically applying nucleic acid drugs.

Bacillus Calmette-Guérin (BCG) osteomyelitis among children: Experience in a single tertiary center in central Taiwan.

BACKGROUND: The insidious nature of BCG-osteomyelitis makes it challenging for clinicians to detect it early on. METHODS: This 12-year retrospective analysis was conducted at a single tertiary hospital in central Taiwan. Electronic medical records of pediatric patients treated for BCG-osteomyelitis were reviewed. Demographics, clinical features, and laboratory findings were compared with patients diagnosed with culture-proven pyogenic osteomyelitis. RESULTS: In total, eight patients fulfilled our inclusion criteria. Their median age was 16 months, and no obvious gender prevalence was found. Six of the eight patients had lesions involving the lower extremities. When compared with the pyogenic osteomyelitis group, age of disease onset was found to be significantly younger in the BCG osteomyelitis group (p=0.038). Absence of fever and pain in the BCG osteomyelitis group was found to be statistically significant when compared with the pyogenic group (p=0.002 and p=0.026 respectively). CRP and ESR were found to be significantly higher in the pyogenic osteomyelitis group (p=0.000 and p=0.004 respectively). CONCLUSION: BCG-related osteomyelitis must be considered when evaluating an afebrile child presenting with an unexplainable swelling or limp, and especially when the lesion is located on a lower limb. Laboratory studies may reveal normal WBC and CRP, with a normal to modest elevation of ESR. Imaging studies, including plain radiographs, magnetic resonance imaging (MRI), or computed tomography (CT) should be employed to rule out BCG-related osteomyelitis. Early diagnosis help minimize inappropriate antibiotics use, and may lead to a better outcome.

Detection of respiratory pathogens by application of multiplex PCR panel during early period of COVID-19 pandemic in a tertiary hospital in Central Taiwan.

BACKGROUND: Respiratory tract infections (RTIs) represent a major cause of clinical visits worldwide. Viral epidemiology of RTIs in adults has been less studied compared to children. FilmArray respiratory panel (FA-RP), a multiplex, real time polymerase chain reaction method can simultaneously detect the nucleic acids of multiple pathogens. The purpose of this study is to analyze the epidemiology and clinical presentations of an RTI cohort. METHODS: This retrospective cohort study was conducted at China Medical University Hospital (CMUH) and China Medical University Children's Hospital (CMUCH), from January 2020 to June 2020. The FA-RP results were collected and analyzed according to upper versus lower RTIs. RESULTS: Among 253 respiratory samples tested, 135 (53.4%) were from adults and 118 (46.6%) from children. A total positive rate of 33.9% (86/253) was found, with 21.48% (29/135) in adults and 48.31% (57/118) in children. Human rhinovirus/Enterovirus (HRV/EV) was detected in most of the age groups and was more common in URIs. HRV/EV was found as a frequent co-detection virus. Among children, HRV/EV was the most detected pathogen of URIs, while the most predominant pathogen in LRIs was Mycoplasma pneumoniae. CONCLUSIONS: FA-RP has the potential to improve the detection rate of respiratory pathogens. The positive rate of FA-RP was higher in children compared to adults, which likely corresponds to the higher incidence of viral RTIs in children. Different pathogens may lead to different types of respiratory infections.

Clinical characteristics and prediction analysis of pediatric urinary tract infections caused by gram-positive bacteria.

Gram-positive (GP) pathogens are less accounted for in pediatric urinary tract infection (UTI), and their clinical impact is underrecognized. This study aimed to identify predictors of GP uropathogens in pediatric UTI. In this 14-year retrospective cohort of pediatric patients with UTI, we classified first-time UTIs cases into those caused by GP or Gram-negative (GN) bacteria. We constructed a multivariable logistic regression model to predict GP UTI. We evaluated model performance through calibration and discrimination plots. We developed a nomogram to predict GP UTI that is clinically feasible. Of 3783 children with first-time UTI, 166 (4.4%) were infected by GP and 3617 (95.6%) by GN bacteria. Among children with GP UTI, the most common uropathogens were vancomycin-resistant Enterococcus faecalis (VRE) (27.1%), Staphylococcus saprophyticus (26.5%), and coagulase-negative Staphylococci (12.7%). Eight independent risk factors were associated with GP UTI: Age ≥ 24 months (odds ratio [OR]: 3.21), no prior antibiotic use (OR: 3.13), serum white blood cell (WBC) count < 14.4 × 103/µL (OR: 2.19), high sensitivity C-reactive protein (hsCRP) < 3.4 mg/dL (OR: 2.18), hemoglobin ≥ 11.3 g/dL (OR: 1.90), negative urine leukocyte esterase (OR: 3.19), negative urine nitrite (OR: 4.13), and urine WBC < 420/µL (OR: 2.37). The model exhibited good discrimination (C-statistic 0.879; 95% CI 0.845-0.913) and calibration performance. VR E. faecalis, the leading GP uropathogen causing pediatric UTI, requires early detection for infection control. Our model for predicting GP UTI can help clinicians detect GP uropathogens and administer antibiotic regimen early.

Association between urine pH and common uropathogens in children with urinary tract infections.

BACKGROUND/PURPOSE: Urinary tract infections (UTIs) are one of the most common pediatric infections. Our objective in this study is to investigate the association between urine pH and uropathogens in pediatric patients. METHODS: The source population comprised 26 066 paired urinalysis (UA) and urine culture (UC) samples obtained from pediatric patients. We classified the paired UA-UC samples into UTI positive (N = 6348) and UTI negative (N = 19 718) according to the colony forming units corresponding to the sampling source. We included UTI positive patients with infection caused by a single species of pathogen (N = 5201) and frequency matched them with UTI negative patients (N = 4729) by age, sex, sampling source, and visit type. RESULTS: This study included 5201 pediatric patients with UTIs and found that urine with Proteus mirabilis or Pseudomonas aeruginosa demonstrated the least acidic pH (mean pH = 6.72 and 6.62, respectively), whereas urine with Escherichia coli or Klebsiella pneumoniae exhibited the most acidic pH (pH = 6.21 and 6.18). After stratifying the UTI samples by their pH range (<6, 6-6.9, 7-7.9, and ≥8). The prevalence of P. mirabilis increased significantly across increasing pH categories. CONCLUSION: This research is the first epidemiological study that linked urine pH to specific uropathogens in a pediatric population. Both urine pH and age are associated with certain causative uropathogens. Urine that grew P. mirabilis or P. aeruginosa had the least acidic pH. Additional studies should validate the role of urine pH in predicting uropathogens and UTI.

Roles of Ion Fluxes, Metabolism, and Redox Balance in Cancer Therapy.

Recent Advances: The 2019 Nobel Prize awarded to the mechanisms for oxygen sensing and adaptation according to oxygen availability, highlighting the fundamental importance of gaseous molecules. Gaseous molecules, including reactive oxygen species (ROS), can interact with different cations generated during metabolic and redox dysregulation in cancer cells. Cross talk between calcium signaling and metabolic/redox pathways leads to network-based dyregulation in cancer. Significance: Recent discovery on using small molecules targeting the ion channels, redox signaling, and protein modification on metabolic enzymes can effectively inhibit cancer growth. Several FDA-approved drugs and clinical trials are ongoing to target the calcium channels, such as TRPV6 and TRPM8. Multiple small molecules from natural products target metablic and redox enzymes to exert an anticancer effect. Critical Issues: Small molecules targeting key ion channels, metabolic enzymes that control key aspects of metabolism, and redox proteins are promising, but their action mechanisms of the target are needed to be elucidated with advanced-omic technologies, which can give network-based and highly dimensioal data. In addition, small molecules that can directly modify the protein residues have emerged as a novel anticancer strategy. Future Directions: Advanced technology accelerates the detection of ions and metabolic and redox changes in clinical samples for diagnosis and informs the decision of cancer treatment. The improvement of ROS detection, ROS target identification, and computational-aid drug discovery also improves clincal outcome.Overall, network-based or holistic regulations of cancer via ion therapy and metabolic and redox intervention are promising as new anticancer strategies. Antioxid. Redox Signal. 34, 1108-1127.

Clinical characteristics and outcomes of culture-negative versus culture-positive osteomyelitis in children treated at a tertiary hospital in central Taiwan.

BACKGROUND: The causative pathogen of pediatric osteomyelitis is often unidentified despite culturing attempts. This study evaluated and compared the clinical characteristics, therapeutic approach, and outcomes of osteomyelitis caused by unknown pathogens and identified microorganisms. METHOD: This 17-year retrospective study was conducted at a tertiary hospital in central Taiwan. Medical records of children aged less than 18 years with a diagnosis of osteomyelitis between 2003 and 2019 were reviewed. RESULT: In total, 70 patients (median age = 6.4 years; male = 65.7%) fulfilled the inclusion criteria, of whom 33 (47.1%) were culture negative. Staphylococcus aureus was the main pathogen (67.6% of identified bacteria). The proportion of methicillin-resistant S. aureus (MRSA) was 44% and 54.5% of the MRSA isolates exhibited clindamycin resistance. Compared to children with culture-positive osteomyelitis, those with culture-negative osteomyelitis had a lower rate of concomitant septic arthritis (40.5% vs. 15.2%, p = 0.019) and leukocytosis on presentation (45.9% vs. 21.2%, p = 0.030); they also required fewer surgical interventions (56.8% vs. 24.2%, p = 0.006) and received a shorter course of total antibiotic therapy (49.0 vs. 43.0 days, p = 0.045). In the culture-negative group, the MRSA coverage rate was 18.8% during initial empirical therapy and increased to 59.4% during further adjusted therapy. The overall complication rate was 18.6% and was lower in the culture-negative group (32.4% vs. 3.0%, p = 0.002). CONCLUSION: In areas where community-associated MRSA and clindamycin resistance strains are a concern, empirical glycopeptide-based therapy is suggested in pediatric osteomyelitis, particularly in those with culture-negative infections.

Self-organized thermo-responsive poly (lactic-co-glycolic acid)-graft-pullulan nanoparticles for synergistic thermo-chemotherapy of tumor.

Poly (lactic-co-glycolic acid)-graft-pullulan (PPLGA) based self-organized nanoparticles hold immense potential for synergistic thermo-chemotherapy of tumor. Herein, the biocompatible and biodegradable PPLGA were synthesized by a novel microwave-assisted solution polymerization. The polymers showed thermo-responsive properties, which was attributed to the change of polymer-water hydrogen bonding in controlling the macromolecular contraction, chain collapse as a result of changes in micro-rigidity of core. The curcumin loaded PPLGA nanoparticles (CUR-PPLGA-N), with impressively high drug loading (10.85 ± 0.27 %), exhibited temperature dependence in drug release kinetics. The results of both MTT and antitumor efficiency elucidated that the CUR-PPLGA-N under high temperature facilitated on-demand drug release from the nano-assembly and had a synergistic therapeutic effect for cancer. Thus the developed thermo-responsive PPLGA addressed concerns related to the low drug loading and inefficient drug release at target sites, and might be considered as a powerful nanoplatform for synergistic thermo-chemotherapy of tumor.

Evodiamine suppresses non-small cell lung cancer by elevating CD8+ T cells and downregulating the MUC1-C/PD-L1 axis.

BACKGROUND: Accumulating evidence showed that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Programmed Death Ligand 1 (PD-L1) is expressed in many cancer cell types, while its binding partner Programmed Death 1 (PD1) is expressed in activated T cells and antigen-presenting cells. Whereas, its dysregulation in the microenvironment is poorly understood. In the present study, we confirmed that evodiamine downregulates MUC1-C, resulting in modulating PD-L1 expression in non-small cell lung cancer (NSCLC). METHODS: Cell viability was measured by MTT assays. Apoptosis, cell cycle and surface PD-L1 expression on NSCLC cells were analyzed by flow cytometry. The expression of MUC1-C and PD-L1 mRNA was measured by real time RT-PCR methods. Protein expression was examined in evodiamine-treated NSCLC cells using immunoblotting or immunofluorescence assays. The effects of evodiamine treatment on NSCLC sensitivity towards T cells were investigated using human peripheral blood mononuclear cells and Jurkat, apoptosis and IL-2 secretion assays. Female H1975 xenograft nude mice were used to assess the effect of evodiamine on tumorigenesis in vivo. Lewis lung carcinoma model was used to investigate the therapeutic effects of combination evodiamine and anti-PD-1 treatment. RESULTS: We showed that evodiamine significantly inhibited growth, induced apoptosis and cell cycle arrest at G2 phase of NSCLC cells. Evodiamine suppressed IFN-γ-induced PD-L1 expression in H1975 and H1650. MUC1-C mRNA and protein expression were decreased by evodiamine in NSCLC cells as well. Evodiamine could downregulate the PD-L1 expression and diminish the apoptosis of T cells. It inhibited MUC1-C expression and potentiated CD8+ T cell effector function. Meanwhile, evodiamine showed good anti-tumor activity in H1975 tumor xenograft, which reduced tumor size. Evodiamine exhibited anti-tumor activity by elevation of CD8+ T cells in vivo in Lewis lung carcinoma model. Combination evodiamine and anti-PD-1 mAb treatment enhanced tumor growth control and survival of mice. CONCLUSIONS: Evodiamine can suppress NSCLC by elevating of CD8+ T cells and downregulating of the MUC1-C/PD-L1 axis. Our findings uncover a novel mechanism of action of evodiamine and indicate that evodiamine represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat NSCLC cancer patients. MUC1-C overexpression is common in female, non-smoker, patients with advanced-stage adenocarcinoma.