A pH-responsive cetuximab-conjugated DMAKO-20 nano-delivery system for overcoming K-ras mutations and drug resistance in colorectal carcinoma.

Cetuximab (Cet) and oxaliplatin (OXA) are used as first-line drugs for patients with colorectal carcinoma (CRC). In fact, the heterogeneity of CRC, mainly caused by K-ras mutations and drug resistance, undermines the effectiveness of drugs. Recently, a hydrophobic prodrug, (1E,4E)-6-((S)-1-(isopentyloxy)-4-methylpent-3-en-1-yl)-5,8-dimethoxynaphthalene-1,4­dione dioxime (DMAKO-20), has been shown to undergo tumor-specific CYP1B1-catalyzed bioactivation. This process results in the production of nitric oxide and active naphthoquinone mono-oximes, which exhibit specific antitumor activity against drug-resistant CRC. In this study, a Cet-conjugated bioresponsive DMAKO-20/PCL-PEOz-targeted nanocodelivery system (DMAKO@PCL-PEOz-Cet) was constructed to address the issue of DMAKO-20 dissolution and achieve multitargeted delivery of the cargoes to different subtypes of CRC cells to overcome K-ras mutations and drug resistance in CRC. The experimental results demonstrated that DMAKO@PCL-PEOz-Cet efficiently delivered DMAKO-20 to both K-ras mutant and wild-type CRC cells by targeting the epidermal growth factor receptor (EGFR). It exhibited a higher anticancer effect than OXA in K-ras mutant cells and drug-resistant cells. Additionally, it was observed that DMAKO@PCL-PEOz-Cet reduced the expression of glutathione peroxidase 4 (GPX4) in CRC cells and significantly inhibited the growth of heterogeneous HCT-116 subcutaneous tumors and patient-derived tumor xenografts (PDX) model tumors. This work provides a new strategy for the development of safe and effective approaches for treating CRC. STATEMENT OF SIGNIFICANCE: (1) Significance: This work reports a new approach for the treatment of colorectal carcinoma (CRC) using the bioresponsible Cet-conjugated PCL-PEOz/DMAKO-20 nanodelivery system (DMAKO@PCL-PEOz-Cet) prepared with Cet and PCL-PEOz for the targeted transfer of DMAKO-20, which is an anticancer multitarget drug that can even prevent drug resistance, to wild-type and K-ras mutant CRC cells. DMAKO@PCL-PEOz-Cet, in the form of nanocrystal micelles, maintained stability in peripheral blood and efficiently transported DMAKO-20 to various subtypes of colorectal carcinoma cells, overcoming the challenges posed by K-ras mutations and drug resistance. The system's secure and effective delivery capabilities have also been confirmed in organoid and PDX models. (2) This is the first report demonstrating that this approach simultaneously overcomes the K-ras mutation and drug resistance of CRC.

Safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine (RQ3013) given as the fourth booster following three doses of inactivated vaccines: a double-blinded, randomised, controlled, phase 3b trial.

Background: Heterologous vaccine schedules have been recommended to provide superior immunity and protection against emergent SARS-CoV-2 variants of concern. We aimed to evaluate the safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine RQ3013 compared with adenoviral vectored vaccine Ad5-nCoV and protein subunit vaccine ZF2001 as the fourth dose in adults primed with three doses of inactivated vaccines in China. Methods: We conducted a double-blinded, randomised, controlled, phase 3b trial among healthy Chinese adults at Lancang County, Yunnan, China. Adults who had received three doses of inactivated COVID-19 vaccines at least 6 months prior were randomly allocated (3:1:1) to receive heterologous boosters with RQ3013, Ad5-nCoV, or ZF2001. We assessed safety within 28 days post boost and the serum geometric mean titres (GMTs) of neutralising antibodies (NAbs) against the live SARS-CoV-2 omicron variant BA.5 on day 14 post-boost. We used Poisson regression to assess the vaccine efficacy against the first episode of virologically confirmed symptomatic COVID-19 occurring at least 7 days post boost. Subgroup analyses categorized by age and sex were also performed for safety and immunogenicity outcomes. This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2200065281) and is now complete. Findings: Between December 12 and December 18, 2022, a total of 1382 adults were screened, and 1250 were enrolled and randomly assigned to receive one dose of RQ3013 (n = 750), Ad5-nCoV (n = 250), or ZF2001 (n = 250). Although solicited adverse reactions within 28 days post boost were more frequent in the RQ3013 group (175 [23.3%]) compared to the control groups (24 [9.6%] in both the Ad5-nCOV and ZF2001 groups, P < 0.05), incidences of Grade 3 events were low (9 [0.7%]) and comparable across three groups (P > 0.05). On day 14 post-boost, RQ3013 (GMT 69.14, 95% CI 47.90-99.81) elicited 4.8-fold and 5.6-fold higher concentrations of NAbs against BA.5 than did Ad5-nCoV (14.37, 7.78-26.56) and ZF2001 (12.21, 5.13-29.06), respectively. On day 28 post-boost, RQ3013 demonstrated a relative efficacy of 62.2% (95% CI 13.7-83.1, P = 0.02) compared to Ad5-nCoV, and of 69.0% (33.5-85.7, P = 0.002) compared to ZF2001. Interpretation: The administrations of all the three heterologous boosters were well tolerated. The heterologous prime-boost regimen with RQ3013 elicited superior immune responses and demonstrated better protection against symptomatic SARS-CoV-2 infections compared with Ad5-nCoV or ZF2001, supporting the use of RQ3013 as a booster vaccination in adults. Funding: Yunnan Province Science and Technology Department (grant no.202302AA310047).

Polyphosphazene-derived carbon modified nanowires for high-performance electrochemical energy storage.

Two one-dimensional nanowires, Fe3O4and MnO2nanowires, were modified with polyphosphazene-derived carbon (PZSC) usingin situpolymerization and high-temperature calcination methods. PZSC coated with MnO2nanowire (MnO2/PZSCNW) was designed as the positive electrode, while PZSC coated with Fe3O4nanowire (Fe3O4/PZSCNW) was designed as the negative electrode. Both MnO2/PZSCNW (+) and Fe3O4/PZSCNW (-) exhibit much larger specific capacities than the corresponding MnO2and Fe3O4nanowires, reaching 75.5 mAh g-1and 75.9 mAh g-1, respectively. The maximum specific capacity, power and energy density of MnO2/PZSCNW (+)//Fe3O4/PZSCNW (-) in alkaline electrolyte are up to 63.2 mAh g-1, 429.6 W kg-1and 53.7 Wh kg-1, respectively. After 10 000 cycles, the cell maintains 100% capacity. The experimental results indicate that the polyphosphazene-derived carbon coating can significantly improve the electrochemical performance, providing a feasible solution for constructing high-performance supercapacitors.

Precision Therapy of Recurrent Breast Cancer through Targeting Different Malignant Tumor Cells with a HER2/CD44-Targeted Hydrogel Nanobot.

Heterogeneity and drug resistance of tumor cells are the leading causes of incurability and poor survival for patients with recurrent breast cancer. In order to accurately deliver the biological anticancer drugs to different subtypes of malignant tumor cells for omnidirectional targeted treatment of recurrent breast cancer, a distinct design is demonstrated by embedding liposome-based nanocomplexes containing pro-apoptotic peptide and survivin siRNA drugs (LPR) into Herceptin/hyaluronic acid cross-linked nanohydrogels (Herceptin-HA) to fabricate a HER2/CD44-targeted hydrogel nanobot (named as ALPR). ALPR delivered cargoes to the cells overexpressing CD44 and HER2, followed by Herceptin-HA biodegradation, subsequently, the exposed lipid component containing DOPE fused with the endosomal membrane and released peptide and siRNA into the cytoplasm. These experiments indicated that ALPR can specifically deliver Herceptin, peptide, and siRNA drugs to HER2-positive SKBR-3, triple-negative MDA-MB-231, and HER2-negative drug-resistant MCF-7 human breast cancer cells. ALPR completely inhibited the growth of heterogeneous breast tumors via multichannel synergistic effects: disrupting mitochondria, downregulating the survivin gene, and blocking HER2 receptors on the surface of HER2-positive cells. The present design overcomes the chemical drug resistance and opens a feasible route for the combinative treatment of recurrent breast cancer, even other solid tumors, utilizing different kinds of biological drugs.

Characterization of Global Research Trends and Prospects on Moyamoya Disease: Bibliometric Analysis.

BACKGROUND: Moyamoya disease (MMD) is a rare cerebrovascular disease in neurology. This study investigates the literature related to MMD from its discovery to the present and identifies research levels, achievements, and trends. METHODS: All publications on MMD from its discovery to present were downloaded from the Web of Science Core Collection on September 15, 2022 and bibliometric analyses were visualized by HistCite Pro, VOSviewer, Scimago Graphica, CiteSpace, and R language. RESULTS: There were 3414 articles in 680 journals by 10,522 authors in 2441 institutions and 74 countries/regions worldwise are included in the analyses. Since the discovery of MMD, output of publications has shown an upward trend. Japan, the United States, China, and South Korea are 4 major countries in MMD. The United States has the strongest cooperation with other countries. China's Capital Medical University is the output-leading institution worldwide, followed by Seoul National University and Tohoku University. The 3 authors with the most published articles are Kiyohiro Houkin, Dong Zhang, and Satoshi Kuroda. World Neurosurgery, Neurosurgery, and Stroke are the most recognized journals for researchers. Hemorrhagic moyamoya disease, susceptibility gene, and arterial spin are the primary focus areas of MMD research. "Rnf213,""vascular disorder," and "progress" are the top keywords. CONCLUSIONS: We analyzed publications of global scientific research on MMD systematically by bibliometric methods. This study can provide one of the most comprehensive and accurate analyses for MMD scholars worldwide.

Generation characteristics and spreading risk of VOCs released from a biological fermentation pharmaceutical factory.

Pharmaceutical factories produce a large amount of volatile organic compounds (VOCs), which may pose a potential health threat to the environment, workers, and nearby residents. Sampling points were set up in the tylosin biological fermentation workshop (FW) and sewage treatment station (STS) of a pharmaceutical factory in a central city in northern China to collect VOCs and study their generation characteristics and diffusion. The results indicated that with the increase in fermentation time, VOC production decreased gradually, and the decline was rapid. The main VOCs produced by the FW are oxygen-containing organics and nitrogen-containing organics including 1-heptyladehyde (8.86 × 102 mg m-3), 1-methyl-2-pyrrolidone (6.36 × 102 mg m-3) and benzene (5.85 × 102 mg m-3). The STS mainly produces nitrogen-containing organics and oxygen-containing organics including 1-methyl-2-pyrrolidone (3.38 × 103 mg m-3), diethyl amine (9.60 × 102 mg m-3) and methyl ethyl ketone (2.98 × 102 mg m-3). VOCs produced by biopharmaceutical factories can diffuse for a long distance in the atmosphere. The highest concentration of chlorinated organic compounds can spread to 11.43 kilometers in the horizontal direction and 3 kilometers in the vertical direction. Acetaldehyde, butyraldehyde, diethylamine, butyl acetate and methyl ethyl ketone are odorous gases detected in the FW and STS, respectively. Benzene, carbon tetrachloride and acetaldehyde are the main carcinogenic VOCs produced in the fermentation process of tylosin. The research elucidated production characteristics, diffusion and health risks of VOCs in the FW, which provided a reference for the control of VOCs.

Characteristics, non-carcinogenic risk assessment and prediction by HYSPLIT of bioaerosol released from Hospital and Municipal Sewage, China.

Bioaerosol is a new type of pollutant, which is related to the spread of many diseases. In particular, the bioaerosol produced in the hospital sewage treatment process contains many pathogenic bacteria, which will impact patients and surrounding residents. In this study, the biochemical tank (BRT) of the hospital sewage treatment station (HSTS) and municipal wastewater treatment plant (MWTP) were used as sampling points. The results showed that the concentration of bacteria (1843 CFU/m3) in bioaerosol produced by BRT of HSTS was higher than that in the air at BRT of MWTP (1278 CFU/m3). The proportion of small-size bacteria (<3.3 µm) in the air of HSTS and MWTP was similar. However, the abundance of small-size pathogenic bacteria in HSTS was higher than that in MWTP, such as Acinetobacter and Arcobacter. The dominant bacteria in HSTS and MWTP were different under different particle sizes. The dominant bacterial genera of bioaerosol in HSTS under different particle sizes were similar (Acinetobacter, Arcobacter, Comamonas); There were significant differences in the dominant bacterial genera of bioaerosol in MWTP under different particle sizes. The dominant strains with particle sizes ranging from 0 ∼ 0.43 µm were Acinetobacter (23.22%). Kocuria (15.13%) accounted for a relatively high proportion in the aerosol of 0.43 µm ∼ 0.65 µm. The dominant strains with particle sizes of 0.65 µm ∼ 1.1 µm and 1.1 µm ∼ 2.1 µm were relatively single, and Exiguobacterium and Paenibacillus accounted for 51.51% and 60.15%, respectively. Source tracker showed that most of the pathogenic bacteria in bioaerosols came from sewage. One hour later, the concentration of particulate matter in the place 200 m away from BRT of HSTS (1 × 10-10 mg/m3) was higher than that in MWTP (1 × 10-11 mg/m3). The hazard quotient (HQ) of people around HSTS (HQmale: 1.70 × 10-1; HQfemale: 1.36 × 10-1) was higher than that of MWTP (HQmale: 1.18 × 10-1; HQfemale: 9.40 × 10-2). Pathogenic bacteria (Acinetobacter, Arcobacter) were detected in HSTS and MWTP and the BugBase phenotype prediction results showed potential pathogenicity. More attention should be paid to the protection of the people. It is suggested to strengthen the air sterilization treatment near HSTS according to the diffusion trajectory of bioaerosol, and the surrounding personnel should wear N95 and other protective masks.

The generation characteristics, pattern, and exposure risk of bioaerosol emitted in an A²O process wastewater treatment plant.

Bioaerosols can be generated in wastewater treatment plants (WWTPs), they may contain pathogenic bacteria, cause disease transmission, and attract the public's attention. In this study, bioaerosols were collected from seven different stages of an A²O process WWTP. The component characteristics were analyzed by bacterial culture and high-throughput sequencing. The correlations in different processes were analyzed, and the health risks of bioaerosols produced were evaluated. The results showed that the concentration range of bacteria aerosol in the WWTP was 75 CFU/m³-706 CFU/m³. The concentration range of total suspended particles was 111.13 µg/m³-211.67 µg/m³, the primary water-soluble ions were Ca²âº and Cl⁻. In the air of each stage, the main bacteria were Cetobacterium, Bacteroides, Romboutsia, and the fungi were Fusarium, Alternaria, and Aspergillus. The dominant bacteria in the wastewater were Cetobacterium, Romboutsia, Stenotrophobacter, and the fungi were Fusarium, Aspergillus, and Mortierella. The total bacterial concentration and ion concentration in the aerobic section of the biochemical tank were the highest. The results of species composition and principal component analysis showed that the bacterial composition in the air at different processes was similar, while the bacteria in wastewater differed significantly. Among them, the wastewater bacteria in the aerobic section of the biochemical tank were closer to that in the air. Fungal results were similar to bacteria but not prominent. The bioaerosol exposure risk results show that the risk in each stage was acceptable (5.15 ×10⁻4-6.47 ×10⁻³). However, the exposure risk of bioaerosol was calculated by the total bacterial concentration. In fact, some pathogenic microorganisms such as Escherichia coli and Aspergillus flavus were detected in bioaerosols, which may cause hemorrhagic colitis, cancer and other diseases by swallowing and inhalation. Therefore, the risk might be underestimated and should be a cause of concern.

Which is the real oxidant in competitive ligand self-hydroxylation and substrate oxidation-a biomimetic iron(II)-hydroperoxo species or an oxo-iron(IV)-hydroxy one?

Nonheme iron(II)-hydroperoxo species (FeII-(η2-OOH)) 1 and the concomitant oxo-iron(IV)-hydroxyl one 2 are proposed as the key intermediates of a large class of 2-oxoglutarate dependent dioxygenases (e.g., isopenicillin N synthase). Extensive biomimetic experiments have been exerted to identify which one is the real oxidant and to reveal the structure-function relationship of them, whereas the mechanistic picture is still elusive. To this end, density functional theory (DFT) calculations were performed to systematically study the mechanistic details of ligand self-hydroxylation and competitive substrate oxidation by these two species supported by a tridentate ligand Fe(TpPh2)(benzilate) (TpPh2 = hydrotris(3,5-diphenylpyrazole-1-yl)borate). The calculated results revealed that the structure and the conversion of the FeII-(η2-OOH) complex 1 are obviously different from the ferric FeIII-OOH one. The orientation of the Fe-OOH moiety of 1 is side-on, while that of the ferric FeIII-OOH species is end-on. The conversion of 1 to the high-valent iron-oxo species is exothermic, while the conversion of the ferric FeIII-OOH species to the high-valent species is endothermic. Thus, the sluggish 1 does not act as the oxidant and readily decays to the robust 2. The activation energy of intramolecular ligand self-hydroxylation in 2 is 14.8 kcal mol-1 and intermolecular substrate oxidations (e.g., thioanisole sulfoxidation) with a lower barrier show a strong inhibiting ability toward ligand self-hydroxylation, while those with a higher barrier (e.g., cyclohexane hydroxylation) have no effect. Our theoretical results fit nicely with the experimental observations and will enrich the knowledge of the metal-oxygen intermediate and play a positive role in the rational design of new biomimetic catalysts.

China Factor: Exploring the Byproduct and Host Metal Dynamics for Gallium-Aluminum in a Global Green Transition.

The potential constraints of critical material supply for the global green transition have raised increasing concerns in recent years. As an important "green minor metal", gallium faces such a potential supply risk for two reasons: it is a byproduct of aluminum production, and the forthcoming end of primary aluminum production boom in China, currently the main global aluminum producer, may bring substantial impacts on the global gallium supply. Here, we investigated this byproduct and host metal linkage using a system dynamics based integrated model and characterized the gallium-aluminum dynamics in a green transition up to 2050 across five world regions (i.e., China, the United States, the European Union, Japan, and the rest of the world). Our results reveal varying patterns of gallium demand and supply in different world regions and the significant role of "the China factor" in ensuring a sustainable gallium supply globally. However, the concerns on the gallium supply risk in China for a common green future could be relieved from the coordination of mitigation strategies from both supply (primary and secondary) and demand (e.g., process efficiency improvement and material intensity reduction) sides among all world regions. Our methodological integration of system dynamics, industrial ecology, and economic geology can be extended to other materials.

BRAF V600E mutation as a novel mechanism of acquired resistance to ALK inhibition in ALK-rearranged lung adenocarcinoma: A case report.

RATIONALE: Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance. PATIENT CONCERNS: A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again. DIAGNOSIS: The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma. INTERVENTIONS: Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again. OUTCOMES: Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient's resistance to lorlatinib. LESSONS: We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.

Glioma cells are resistant to inflammation­induced alterations of mitochondrial dynamics.

Accumulating evidence suggests that inflammation is present in solid tumors. However, it is poorly understood whether inflammation exists in glioma and how it affects the metabolic signature of glioma. By analyzing immunohistochemical data and gene expression data downloaded from bioinformatic datasets, the present study revealed an accumulation of inflammatory cells in glioma, activation of microglia, upregulation of proinflammatory factors (including IL­6, IL­8, hypoxia­inducible factor­1α, STAT3, NF­κB1 and NF­κB2), destruction of mitochondrial structure and altered expression levels of electron transfer chain complexes and metabolic enzymes. By monitoring glioma cells following proinflammatory stimulation, the current study observed a remodeling of their mitochondrial network via mitochondrial fission. More than half of the mitochondria presented ring­shaped or spherical morphologies. Transmission electron microscopic analyses revealed mitochondrial swelling with partial or total cristolysis. Furthermore, proinflammatory stimuli resulted in increased generation of reactive oxygen species, decreased mitochondrial membrane potential and reprogrammed metabolism. The defective mitochondria were not eliminated via mitophagy. However, cell viability was not affected, and apoptosis was decreased in glioma cells after proinflammatory stimuli. Overall, the present findings suggested that inflammation may be present in glioma and that glioma cells may be resistant to inflammation­induced mitochondrial dysfunction.

Effect of high-fat diet on the pharmacokinetics and safety of flumatinib in healthy Chinese subjects.

PURPOSE: To evaluate the effect of a high-fat diet on the pharmacokinetics and safety of flumatinib mesylate tablets in healthy Chinese subjects. METHODS: This study was a randomized, open-label, single-dose, two-period crossover trial in which subjects were randomly assigned to take 400 mg of flumatinib mesylate after a high-fat diet or a fasted state. After a 14-day washout period, the two groups were administered flumatinib mesylate under opposite conditions. Blood samples were collected at baseline 0 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h, respectively. Plasma concentrations of flumatinib and its metabolites (M1 and M3) were analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using the non-compartmental module of the Phoenix WinNonlin Version 7.0 software. BE module of WinNonLin was used for statistical analysis of AUC0-t, AUC0-∞ and Cmax in plasma. RESULTS: Twelve healthy subjects, half male and half female, were enrolled. One subject withdrew due to a treatment-emergent adverse event. Eleven subjects were administered drugs on fasting and 12 were administered drugs after a high-fat diet. On high-fat diet/fasting, the least square geometric mean (LSGM) ratios of flumatinib, M1, M3, and their 90% confidence interval (CI) were as follows: for flumatinib, Cmax, AUC0-t and AUC0-∞ were 281.65% (225.80-351.31%), 167.43% (143.92-194.79%), and 166.87% (143.47-194.09%); for M1, Cmax, AUC0-t, and AUC0-∞ were 188.59% (145.29-244.79), 163.94% (149.11-180.24%), and 164.48% (150.36-179.94%); for M3, Cmax, AUC0-t, and AUC0-∞ were 63.47% (54.02-74.57%), 85.23% (74.72-97.22%), and 96.73% (86.63-108.02%). CONCLUSION: Among the subjects, oral administration of 400 mg of flumatinib was safe and well tolerated. High-fat diet significantly increases the exposure to flumatinib, therefore, fasting may be recommended. CLINICAL TRIAL REGISTRATION: The study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.

Downregulation of reelin predicts poor prognosis for glioma.

Aim: In the present study, we studied the relationship between RELN and prognosis in glioma. Materials & methods: Expression profiles and methylation data of RELN were obtained from bioinformatic datasets. Correlations between RELN and clinicopathological features and overall survival were respectively assessed using chi-square test and Kaplan-Meier analysis. Results:RELN was downregulated in glioma, and its downregulation correlated well with glioma malignancy and overall survival. Meanwhile, hypermethylation of RELN was significantly correlated with low RELN expression. Additionally, gene set enrichment analysis demonstrated that low expression of RELN correlated with many key cancer pathways, possibly highlighting the importance of RELN in carcinogenesis of brain. Conclusion:RELN may serve as a potential prognostic marker and promising target molecule for new therapy of glioma.

Clinical Application of Iodine-125 Seed Brachytherapy Combined with Anti-PD-1 Antibodies in the Treatment of Lung Cancer.

PURPOSE: The purpose of this case report was to investigate the clinical efficacy and tolerability of anti-programmed cell death protein (PD)-1 antibody combined with iodine (I)-125 seed brachytherapy in lung cancer treatment. METHODS: Three patients with advanced PD-L1-positive non-small-cell lung cancer were treated first with I-125 seed brachytherapy and then with anti-PD-1 antibody. Clinical efficacy was evaluated with Response Evaluation Criteria in Solid Tumors. FINDINGS: All 3 patients had complete response or partial response. None of the 3 patients had reported obvious adverse events. IMPLICATIONS: Encouraging preliminary results provide important support for further clinical treatment of lung cancer using anti-PD-1 antibody combined with I-125 seed brachytherapy.

The association between high mobility group box 1 chromatin protein and mitotic chromosomes in glioma cells.

High mobility group box 1 (HMGB1) is an abundant non-histone nuclear protein that functions as a structural protein of chromatin, regulating genome replication and recombination, mRNA transcription and DNA repair. HMGB1 has been implicated in the tumorigenesis of various cancer types, and the upregulation of HMGB1 has been demonstrated in glioma cells. However, the association between HMGB1 and the mitotic chromosomes in glioma remains uncharacterized. In the present study, the sub-cellular localization of HMGB1 in glioma tissues and cells was investigated. In addition, enhanced green fluorescent protein (EGFP)-tagging of the human HMGB1 protein and chromosome spreading were used to investigate the combination of HMGB1 with mitotic chromosomes. The results of the current study indicated that HMGB1 was localized to the nucleus and the cytoplasm, and it was determined to combine with the condensed chromosomes of proliferating cells in paraformaldehyde (PFA)-fixed glioma tissues. However, HMGB1 was also associated with interphase (but not mitotic chromosomes) when fixed with chilled methanol and 5% (v/v) acetic acid or PFA in vitro. Data from live cell imaging and chromosome spreading indicated the association of HMGB1 with mitotic chromosomes in glioma cells. The present results suggest that HMGB1 combines with mitotic chromosomes in glioma cells, and that the use of fixatives may result in the dissociation of the HMGB1-DNA interaction. Therefore, in live specimens and chromosome spreads, EGFP fusion proteins may represent an accurate indicator for the determination of the correct localization and interaction of HMGB1 in glioma cells.

Overexpression of high mobility group box 1 (HMGB1) has no correlation with the prognosis in glioma.

Aim: We aimed to characterize the role of HMGB1 overexpression in glioma and to evaluate its use as a biomarker. Materials & methods: We used the gene expression datasets and tissue microarray to assess the expression levels of HMGB1 among gliomas of all grades; We then assessed its correlation with the malignancy and outcome of glioma. Results: The increase in HMGB1 mRNA and protein levels was found in glioma, but there was no correlation between HMGB1 expression and glioma malignancy, and overall survival and vital status of glioma patients. Conclusion: Overexpression of HMGB1 is not associated with the malignancy and outcome in glioma. And it is not the valuable biomarker for the early diagnosis of glioma.

Anthraquinone derivative exerted hormetic effect on the apoptosis in oxygen-glucose deprivation-induced PC12 cells via ERK and Akt activated Nrf2/HO-1 signaling pathway.

There were accumulated evidences that agents may attenuate neurological disorders through a hormetic effect. This study was designed to investigate hormetic effect of BME on the oxygen-glucose deprivation (OGD)-induced mitochondrial apoptosis in NGF-differentiated PC12 cells. The effect of BME on the intracellular reactive oxygen species (iROS) formation and pro-survival signals mediated by ERK and Akt as well as transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathways was also determined. The present results showed that, at low concentrations, pretreatment with BME triggered stress response by causing ROS production, then, activated survival-promoting signals via ERK and Akt activated Nrf2/HO-1 signaling pathway, resulting in decrease in cytotoxicity induced by the OGD. It may be accepted that mild pretreatment with BME stimulated transient and moderate ROS production, but activated hormetic signals and induced stress responsive genes. In contrast, high concentrations of BME displayed toxic action due to massive ROS production. These results suggested that the effect of BME on the OGD-induced PC12 cells may be hormetic mechanism including induction of oxidative stress and subsequent activation of stress response gene expression.

The prevalence of glucose metabolism disturbances in Chinese Muslims and possible risk factors: a study from northwest China.

OBJECTIVE: To survey the prevalence of diabetes mellitus (DM) and pre-diabetes mellitus (PDM) in the Muslim population in northwest China, and discuss the risk factor. MATERIALS AND METHODS: According to the income and the population, we randomly selected 3 villages with stratified and cluster sampling. The subjects were residents ≥ 20 years of age, and were from families which have been local for > 3 generations. The questionnaire and oral glucose tolerance test (OGTT) were completed and analyzed for 660 subjects. RESULTS: The prevalence of DM and PDM between the Han and Muslim populations were different (P = 0.041). And the prevalence were also different with respect to age in the Han (P < 0.001) and Muslim population (P < 0.001) respectively. Except for the 20-year-old age group the prevalence of DM and PDM within the Muslim population was higher than the Han (P = 0.013), we did not find any significant difference for other age groups (P > 0.05). The intake of salt (P < 0.001) and edible oil (P < 0.001) in the Muslim population was higher than the Han, while cigarette smoking (P < 0.001) and alcohol consumption (P < 0.001) was lower. BMI (P < 0.001), age (P = 0.025), and smoking cigarettes (P = 0.011) were risk factors for DM and PDM, but alcohol consumption (P < 0.001) was a protective factor. CONCLUSIONS: In northwest China, the prevalence of DM was higher in the Muslim population, and it was special higher on the 20-year-old age compared to the Han. This might be explained by the potential genetic differences and poor dietary habits.

The prevalence of glucose metabolism disturbances in Chinese Muslims and possible risk factors: a study from northwest China / Prevalência e possíveis fatores de risco de distúrbios no metabolismo da glicose em chineses muçulmanos: um estudo no noroeste da China

Objective To survey the prevalence of diabetes mellitus (DM) and pre-diabetes mellitus (PDM) in the Muslim population in northwest China, and discuss the risk factor. Materials and methods According to the income and the population, we randomly selected 3 villages with stratified and cluster sampling. The subjects were residents ≥ 20 years of age, and were from families which have been local for > 3 generations. The questionnaire and oral glucose tolerance test (OGTT) were completed and analyzed for 660 subjects. Results The prevalence of DM and PDM between the Han and Muslim populations were different (P = 0.041). And the prevalence were also different with respect to age in the Han (P < 0.001) and Muslim population (P < 0.001) respectively. Except for the 20-year-old age group the prevalence of DM and PDM within the Muslim population was higher than the Han (P = 0.013), we did not find any significant difference for other age groups (P > 0.05). The intake of salt (P < 0.001) and edible oil (P < 0.001) in the Muslim population was higher than the Han, while cigarette smoking (P < 0.001) and alcohol consumption (P < 0.001) was lower. BMI (P < 0.001), age (P = 0.025), and smoking cigarettes (P = 0.011) were risk factors for DM and PDM, but alcohol consumption (P < 0.001) was a protective factor. Conclusions In northwest China, the prevalence of DM was higher in the Muslim population, and it was special higher on the 20-year-old age compared to the Han. This might be explained by the potential genetic differences and poor dietary habits. .

Objetivo Avaliar a prevalência de diabetes melito (DM) e pré-diabetes melito (PDM) na população muçulmana no noroeste da China e discutir os fatores de risco. Materiais e métodos Selecionamos três vilarejos de acordo com a renda e a população, usando uma amostra estratificada e por cluster. Os sujeitos eram residentes com ≥ 20 anos de idade e de famílias que estavam no local há mais de três gerações. Foram feitos e analisados um questionário e o teste de tolerância oral à glicose (TTOG) para 660 sujeitos. Resultados A prevalência do DM e PDM entre as populações Han e muçulmana foi diferente (P = 0,041), e as prevalências também foram diferentes com relação à idade na população Han (P < 0,001) e muçulmana (P < 0,001), respectivamente. Exceto pela faixa etária de 20 anos de idade, a prevalência do DM e PDM na população muçulmana foi maior do que na população Han (P = 0,013), não havendo diferenças significativas para as outras faixas etárias (P > 0,05). A ingestão de sal (P < 0,001) e óleos comestíveis (P < 0,001) na população muçulmana foi mais alta do que na população Han, enquanto o tabagismo (P < 0,001) e consumo de álcool (P < 0,001) foram mais baixos. O IMC (P < 0,001), a idade (P = 0,025) e o tabagismo (P = 0,011) foram fatores de risco para o DM e PDM, mas o consumo de álcool (P < 0,001) foi um fator protetor. Conclusões No noroeste da China, a prevalência de DM é maior na população muçulmana e é especialmente mais alta na faixa etária de 20 anos de idade, quando comparada com a população Han. Isso pode ser explicado por diferenças genéticas potenciais e hábitos alimentares ruins. .