Cu(II) complex that synergistically potentiates cytotoxicity and an antitumor immune response by targeting cellular redox homeostasis.

Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.

Association of sleep fragmentation with general and abdominal obesity: a population-based longitudinal study.

OBJECTIVE: To evaluate the causal relationship between sleep fragmentation (SF) parameters with general and abdominal obesity in free-living conditions. METHODS: SF parameters were assessed by ActiGraph accelerometers for 7 consecutive days. Obesity was measured at baseline and 1-year follow-up with InBody S10 body composition analyzer. RESULTS: At baseline, the mean age of the study population was 18.7 years old (SD = 0.9) and 139 (35.7%) were male. Each 1-unit increase of baseline sleep fragmentation index (SFI) was associated with 0.08 kg/m2-increase of body mass index (BMI) (95% CI: 0.03, 0.14), 0.20%-increase of percentage of body fat (PBF) (95% CI: 0.07, 0.32), 0.15 kg-increase of fat mass (FM) (95% CI: 0.03, 0.27), 0.15 cm-increase of waist circumference (WC) (95% CI: 0.03, 0.26) and 0.91 cm2-increase of visceral fat area (VFA) (95% CI: 0.36, 1.46) at the 1-year follow-up. In addition, each 1-unit increase of baseline SFI was associated with 15% increased risk of general obesity (OR = 1.15, 95% CI = 1.04-1.28; p = 0.006) and 7% increased risk of abdominal obesity (OR = 1.07, 95% CI = 1.01-1.13; p = 0.021) in the following year. CONCLUSIONS: Fragmented sleep is independently associated with an increased risk of both general and abdominal obesity. The result highlights SF as a modifiable risk factor for the prevention and treatment of obesity.

Engineering an Organic Nanoplatform for Augmented Pyroeletroimmunotherapy.

Photothermal immunotherapy has shown great promise in the treatment of tumor metastasis. However, the thermal resistance of tumor cells substantially compromises the treatment effect of photothermal immunotherapy. Herein, a high-performance organic pyroelectric nanoplatform, tBu-TPAD-BF2 nanoparticles (NPs), is rationally engineered for the effective pyroelectroimmunotherapy of tumor metastasis. Biocompatible tBu-TPAD-BF2 NPs with excellent pyroelectric and photothermal conversion properties are constructed by assembling organic, low-bandgap pyroelectric molecules with amphiphilic polymers. After internalization by tumor cells, treatment with tBu-TPAD-BF2 NPs causes an apparent temperature elevation upon near-infrared (NIR) laser irradiation, inducing potent immunogenic cell death (ICD). Additionally, the temperature variations under alternating NIR laser irradiation facilitate reactive oxygen species production for pyroelectric therapy, thus promoting ICD activation and lowering thermal resistance. Importantly, in vivo assessments illustrate that tBu-TPAD-BF2 NPs in combination with NIR laser exposure notably inhibit primary and distant tumor proliferation and prominently retarded lung metastasis. RNA profiling reveals that treatment with tBu-TPAD-BF2 NPs markedly suppresses metastasis under NIR laser illumination by downregulating metastasis-related genes and upregulating immune response-associated pathways. Therefore, this study provides a strategy for designing high-performance pyroelectric nanoplatforms to effectively cure tumor metastasis, thereby overcoming the inherent shortcomings of photothermal immunotherapy.

Upf2-Mediated Nonsense-Mediated Degradation Pathway Involved in Genetic Compensation of TrpA1 Knockout Mutant Silkworm (Bombyx mori).

Genetic mutations leading to premature termination codons are known to have detrimental effects. Using the Lepidoptera model insect, the silkworm (Bombyx mori), we explored the genetic compensatory response triggered by mutations with premature termination codons. Additionally, we delved into the molecular mechanisms associated with the nonsense-mediated mRNA degradation pathway. CRISPR/Cas9 technology was utilized to generate a homozygous bivoltine silkworm line BmTrpA1-/- with a premature termination. Transcript levels were assessed for the BmTrpA paralogs, BmPyrexia and BmPainless as well as for the essential factors Upf1, Upf2, and Upf3a involved in the nonsense-mediated mRNA degradation (NMD) pathway. Upf2 was specifically knocked down via RNA interference at the embryonic stage. The results comfirmed that the BmTrpA1 transcripts with a 2-base deletion generating a premature termination codon in the BmTrpA1-/- line. From day 6 of embryonic development, the mRNA levels of BmPyrexia, BmPainless, Upf1, and Upf2 were significantly elevated in the gene-edited line. Embryonic knockdown of Upf2 resulted in the suppression of the genetic compensation response in the mutant. As a result, the offspring silkworm eggs were able to hatch normally after 10 days of incubation, displaying a non-diapause phenotype. It was observed that a genetic compensation response does exist in BmTrpA1-/-B. mori. This study presents a novel discovery of the NMD-mediated genetic compensation response in B. mori. The findings offer new insights into understanding the genetic compensation response and exploring the gene functions in lepidopteran insects, such as silkworms.

Double-nylon purse-string suture in closing postoperative wounds following endoscopic resection of large (≥ 3 cm) gastric submucosal tumors.

BACKGROUND: Endoscopic full-thickness resection (EFTR) of gastric submucosal tumors (SMTs) is safe and effective; however, postoperative wound management is equally important. Literature on suturing following EFTR for large (≥ 3 cm) SMTs is scarce and limited. AIM: To evaluate the efficacy and clinical value of double-nylon purse-string suture in closing postoperative wounds following EFTR of large (≥ 3 cm) SMTs. METHODS: We retrospectively analyzed the data of 85 patients with gastric SMTs in the fundus of the stomach or in the lesser curvature of the gastric body whose wounds were treated with double-nylon purse-string sutures after successful tumor resection at the Endoscopy Center of Renmin Hospital of Wuhan University. The operative, postoperative, and follow-up conditions of the patients were evaluated. RESULTS: All tumors were completely resected using EFTR. 36 (42.35%) patients had tumors located in the fundus of the stomach, and 49 (57.65%) had tumors located in the body of the stomach. All patients underwent suturing with double-nylon sutures after EFTR without laparoscopic assistance or further surgical treatment. Postoperative fever and stomach pain were reported in 13 (15.29%) and 14 (16.47%) patients, respectively. No serious adverse events occurred during the intraoperative or postoperative periods. A postoperative review of all patients revealed no residual or recurrent lesions. CONCLUSION: Double-nylon purse-string sutures can be used to successfully close wounds that cannot be completely closed with a single nylon suture, especially for large (≥ 3 cm) EFTR wounds in SMTs.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer.

ABSTRACT: This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Influence of blood glucose fluctuations on chemotherapy efficacy and safety in type 2 diabetes mellitus patients complicated with lung carcinoma.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have large fluctuations in blood glucose (BG), abnormal metabolic function and low immunity to varying degrees, which increases the risk of malignant tumor diseases and affects the efficacy of tumor chemotherapy. Controlling hyperglycemia may have important therapeutic implications for cancer patients. AIM: To clarify the influence of BG fluctuations on chemotherapy efficacy and safety in T2DM patients complicated with lung carcinoma (LC). METHODS: The clinical data of 60 T2DM + LC patients who presented to the First Affiliated Hospital of Ningbo University between January 2019 and January 2021 were retrospectively analyzed. All patients underwent chemotherapy and were grouped as a control group (CG; normal BG fluctuation with a mean fluctuation < 3.9 mmol/L) and an observation group (OG; high BG fluctuation with a mean fluctuation ≥ 3.9 mmol/L) based on their BG fluctuations, with 30 cases each. BG-related indices, tumor markers, serum inflammatory cytokines and adverse reactions were comparatively analyzed. Pearson correlation analysis was performed to analyze the correlation between BG fluctuations and tumor markers. RESULTS: The fasting blood glucose and 2-hour postprandial blood glucose levels in the OG were notably elevated compared with those in the CG, together with markedly higher mean amplitude of glycemic excursions (MAGE), mean of daily differences, largest amplitude of glycemic excursions and standard deviation of blood glucose (P < 0.05). In addition, the OG exhibited evidently higher levels of carbohydrate antigen 19-9, carbohydrate antigen 125, carcinoembryonic antigen, neuron-specific enolase, cytokeratin 19, tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein than the CG (P < 0.05). Pearson analysis revealed a positive association of MAGE with serum tumor markers. The incidence of adverse reactions was significantly higher in the OG than in the CG (P < 0.05). CONCLUSION: The greater the BG fluctuation in LC patients after chemotherapy, the more unfavorable the therapeutic effect of chemotherapy; the higher the level of tumor markers and inflammatory cytokines, the more adverse reactions the patient experiences.

Bu zhong Yiqi Decoction ameliorates mild cognitive impairment by improving mitochondrial oxidative stress damage via the SIRT3/MnSOD/OGG1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Bu-Zhong-Yi-Qi Decoction(BZYQD) is a traditional formula commonly used in China, known for its effects in tonifying Qi and raising Yang. It can relieve symptoms of cognitive impairment such as forgetfulness and lack of concentration caused by qi deficiency, which is common in aging and debilitating. However, much of the current research on BZYQD has been focused on its impact on the digestive system, leaving its molecular mechanisms in improving cognitive function largely unexplored. AIM OF THE STUDY: Cognitive decline in the aging central nervous system is intrinsically linked to oxidative damage. This study aims to investigate the therapeutic mechanism of BZYQD in treating mild cognitive impairment caused by qi deficiency, particularly through repair of mitochondrial oxidative damage. MATERIALS AND METHODS: A rat model of mild cognitive impairment (MCI) was established by administering reserpine subcutaneously for two weeks, followed by a two-week treatment with BZYQD/GBE. In vitro experiments were conducted to assess the effects of BZYQD on neuronal cells using a H2O2-induced oxidative damage model in PC12 cells. The open field test and the Morris water maze test evaluated the cognitive and learning memory abilities of the rats. HE staining and TEM were employed to observe morphological changes in the hippocampus and its mitochondria. Mitochondrial activity, ATP levels, and cellular viability were measured using assay kits. Protein expression in the SIRT3/MnSOD/OGG1 pathway was analyzed in tissues and cells through western blotting. Levels of 8-OH-dG in mitochondria extracted from tissues and cells were quantified using ELISA. Mitochondrial morphology in PC12 cells was visualized using Mito Red, and mitochondrial membrane potential was assessed using the JC-1 kit. RESULTS: BZYQD treatment significantly improved cognitive decline caused by reserpine in rats, as well as enhanced mitochondrial morphology and function in the hippocampus. Our findings indicate that BZYQD mitigates mtDNA oxidative damage in rats by modulating the SIRT3/MnSOD/OGG1 pathway. In PC12 cells, BZYQD reduced oxidative damage to mitochondria and mtDNA in H2O2-induced conditions and was associated with changes in the SIRT3/MnSOD/OGG1 pathway. CONCLUSION: BZYQD effectively counteracts reserpine-induced mild cognitive impairment and ameliorates mitochondrial oxidative stress damage through the SIRT3/MnSOD/OGG1 pathway.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

[Change and Prediction of Water Purification Function in the South Bank of Hangzhou Bay in the Past 20 Years].

The investigation of regional water purification functionality and its influencing factors holds significant pragmatic implications in understanding the potential of regional water purification, guiding context-specific regional comprehensive planning schemes, and environmental conservation measures. The study site, situated along the southern coast of Hangzhou Bay, represents a prototypical region characterized by intricate land-sea interactions that bear substantial economic and ecological functions. By assimilating a meticulously collected topographical and land-use dataset, in conjunction with site-specific meteorological records, the water purification model embedded within the integrated valuation of ecosystem services and trade-offs (InVEST) framework was employed to scrutinize the spatiotemporal dynamics of nitrogen (N) and phosphorus (P) loads, discharges, and removals within the southern coast of Hangzhou Bay. The prime objective of this study was to unravel the differentials in water purification functionality under diverse developmental scenarios. The investigation unearthed distinct temporal discrepancies in N and P discharges and removals over two temporal dimensions. Relative to the benchmark year 2000, the total N load experienced a reduction of 276.72 t, whereas the N discharge and removals decreased by 140.86 and 137.86 t, respectively, in the year 2020. In contrast, the total P load observed an increase of 93.65 t, accompanied by a surge in P discharge and removals by 28.91 and 64.74 t, respectively. Spatially, the distribution pattern of N and P discharges exhibited a general inclination of elevated values in the northern region and subdued values in the southern region, with certain pockets in the southern region exhibiting pronounced peaks, intimately associated with land-use typologies. Simulation analyses conducted under distinct scenarios unveiled that under the natural development priority scenario, the N and P discharges within the study area amounted to 1 682.36 and 115.50 t, respectively. Conversely, under the scenario emphasizing economic development, the regional N and P discharges showed an approximate escalation of 83.02% and 79.93%, correspondingly. In contrast, under the scenario emphasizing environmental conservation, the regional N and P discharges exhibited a notable decline of approximately 79.96% and 56.44%, respectively. Hence, the scenario prioritizing the amalgamation of environmental conservation and development effectively reduced the N and P discharges within the region, bolstering the water purification functionality. The results derived from this study furnish a solid theoretical foundation for effectuating region-specific planning schemes fostering coordinated economic and ecological advancement within the study area.

An integrated data analysis reveals distribution, hosts, and pathogen diversity of Haemaphysalis concinna.

BACKGROUND: Haemaphysalis concinna, carrying multiple pathogens, has attracted increasing attention because of its expanded geographical range and significant role in disease transmission. This study aimed to identify the potential public health risks posed by H. concinna and H. concinna-associated pathogens. METHODS: A comprehensive database integrating a field survey, literature review, reference book, and relevant websites was developed. The geographical distribution of H. concinna and its associated pathogens was illustrated using ArcGIS. Meta-analysis was performed to estimate the prevalence of H. concinna-associated microbes. Phylogenetic and geographical methods were used to investigate the role of birds in the transmission of H. concinna-associated microbes. The potential global distribution of H. concinna was predicted by ecological niche modeling. RESULTS: Haemaphysalis concinna was distributed in 34 countries across the Eurasian continent, predominantly in China, Russia, and Central Europe. The tick species carried at least 40 human pathogens, including six species in the Anaplasmataceae family, five species of Babesia, four genospecies in the complex Borrelia burgdorferi sensu lato, ten species of spotted fever group rickettsiae, ten species of viruses, as well as Francisella, Coxiella, and other bacteria. Haemaphysalis concinna could parasitize 119 host species, with nearly half of them being birds, which played a crucial role in the long-distance transmission of tick-borne microbes. Our predictive modeling suggested that H. concinna could potentially survive in regions where the tick has never been previously recorded such as central North America, southern South America, southeast Oceania, and southern Africa. CONCLUSIONS: Our study revealed the wide distribution, broad host range, and pathogen diversity of H. concinna. Authorities, healthcare professionals, and the entire community should address the growing threat of H. concinna and associated pathogens. Tick monitoring and control, pathogen identification, diagnostic tools, and continuous research should be enhanced.

Treatment With Selumetinib for Café-au-Lait Macules and Plexiform Neurofibroma in Pediatric Patients With Neurofibromatosis Type 1.

This case report describes 4 patients with a rare autosomal dominant multisystem disorder resulting from NF1 variants that leads to café-au-lait macules and neurofibromas.

Immunomodulation of cuproptosis and ferroptosis in liver cancer.

According to statistics, the incidence of liver cancer is increasing yearly, and effective treatment of liver cancer is imminent. For early liver cancer, resection surgery is currently the most effective treatment. However, resection does not treat the disease in advanced patients, so finding a method with a better prognosis is necessary. In recent years, ferroptosis and cuproptosis have been gradually defined, and related studies have proved that they show excellent results in the therapy of liver cancer. Cuproptosis is a new form of cell death, and the use of cuproptosis combined with ferroptosis to inhibit the production of hepatocellular carcinoma cells has good development prospects and is worthy of in-depth discussion by researchers. In this review, we summarize the research progress on cuproptosis combined with ferroptosis in treating liver cancer, analyze the value of cuproptosis and ferroptosis in the immune of liver cancer, and propose potential pathways in oncotherapy with the combination of cuproptosis and ferroptosis, which can provide background knowledge for subsequent related research.

Investigating the pathogens associated with Dermacentor nuttalli and its global distribution: A study integrating metagenomic sequencing, meta-analysis and niche modeling.

Dermacentor nuttalli, a member of family Ixodidae and genus Dermacentor, is predominantly found in North Asia. It transmits various pathogens of human and animal diseases, such as Lymphocytic choriomeningitis mammarenavirus and Brucella ovis, leading to severe symptoms in patients and posing serious hazards to livestock husbandry. To profile pathogen abundances of wild D. nuttalli, metagenomic sequencing was performed of four field-collected tick samples, revealing that Rickettsia, Streptomyces, and Pseudomonas were the most abundant bacterial genera in D. nuttalli. Specifically, four nearly complete Rickettsia genomes were assembled, closely relative to Rickettsia conorii subsp. raoultii. Then, a comprehensive meta-analysis was performed to evaluate its potential threats based on detected pathogens and geographical distribution positions reported in literature, reference books, related websites, and field surveys. At least 48 pathogens were identified, including 20 species of bacteria, seven species of eukaryota, and 21 species of virus. Notably, Rickettsia conorii subsp. raoultii, Coxiella burnetii, and Brucella ovis displayed remarkably high positivity rates, which were known to cause infectious diseases in both humans and livestock. Currently, the primary distribution of D. nuttalli spans China, Mongolia, and Russia. However, an additional 14 countries in Asia and America that may also be affected by D. nuttalli were identified in our niche model, despite no previous reports of its presence in these areas. This study provides comprehensive data and analysis on the pathogens carried by D. nuttalli, along with documented and potential distribution, suggesting an emerging threat to public health and animal husbandry. Therefore, there is a need for heightened surveillance and thorough investigation of D. nuttalli.

Epidemiological behaviour and interventions of malaria in Niger, 2010-2019: a time-series analysis of national surveillance data.

BACKGROUND: Malaria remains a significant public health concern in Niger, with the number of cases increasing from 592,334 in 2000 to 3,138,696 in 2010. In response, a concerted campaign against the disease has been initiated. However, the implementation of these malaria interventions and their association with epidemiological behaviour remains unclear. METHODS: A time-series study was conducted in Niger from 2010 to 2019. Multiple data sources concerning malaria were integrated, encompassing national surveillance data, Statistic Yearbook, targeted malaria control interventions, and meteorological data. Incidence rate, mortality rate, and case fatality ratio (CFR) by different regions and age groups were analysed. Joinpoint regression models were used to estimate annual changes in malaria. The changes in coverage of malaria interventions were evaluated. RESULTS: Between 2010 to 2019, the incidence rate of malaria decreased from 249.43 to 187.00 cases per 1,000 population in Niger. Niamey had a high annual mean incidence rate and the lowest CFR, while Agadez was on the contrary. Joinpoint regression analysis revealed a declining trend in malaria incidence for all age groups except the 10-24 years group, and the mortality rate and the CFR initially decreased followed by an increase in all age groups. Niger has implemented a series of malaria interventions, with the major ones being scaled up to larger populations during the study period. CONCLUSIONS: The scale-up of multi-interventions in Niger has significantly reduced malaria incidence, but the rise in mortality rate and CFR addresses the challenges in malaria control and elimination. Malaria endemic countries should enhance surveillance of malaria cases and drug resistance in Plasmodium, improve diagnosis and treatment, expand the population coverage of insecticide-treated bed nets and seasonal malaria chemoprevention, and strengthen the management of severe malaria cases.

Comorbidity increases the risk of pulmonary tuberculosis: a nested case-control study using multi-source big data.

BACKGROUND: Some medical conditions may increase the risk of developing pulmonary tuberculosis (PTB); however, no systematic study on PTB-associated comorbidities and comorbidity clusters has been undertaken. METHODS: A nested case-control study was conducted from 2013 to 2017 using multi-source big data. We defined cases as patients with incident PTB, and we matched each case with four event-free controls using propensity score matching (PSM). Comorbidities diagnosed prior to PTB were defined with the International Classification of Diseases-10 (ICD-10). The longitudinal relationships between multimorbidity burden and PTB were analyzed using a generalized estimating equation. The associations between PTB and 30 comorbidities were examined using conditional logistic regression, and the comorbidity clusters were identified using network analysis. RESULTS: A total of 4265 cases and 17,060 controls were enrolled during the study period. A total of 849 (19.91%) cases and 1141 (6.69%) controls were multimorbid before the index date. Having 1, 2, and ≥ 3 comorbidities was associated with an increased risk of PTB (aOR 2.85-5.16). Fourteen out of thirty comorbidities were significantly associated with PTB (aOR 1.28-7.27), and the associations differed by sex and age. Network analysis identified three major clusters, mainly in the respiratory, circulatory, and endocrine/metabolic systems, in PTB cases. CONCLUSIONS: Certain comorbidities involving multiple systems may significantly increase the risk of PTB. Enhanced awareness and surveillance of comorbidity are warranted to ensure early prevention and timely control of PTB.

Genomic epidemiology of hypervirulent carbapenem-resistant Klebsiella pneumoniae at Jinshan local hospital, Shanghai, during 2014-2018.

BACKGROUND: Hypervirulent carbapenem-resistant Klebsiella pneumoniae (Hv-CRKP) triggered a significant public health challenge. This study explored the prevalence trends and key genetic characteristics of Hv-CRKP in one Shanghai suburbs hospital during 2014-2018. METHODS: During five years, Hv-CRKP strains identified from 2579 CRKP by specific PCR, were subjected to performed short- and long-read sequencing technology; epidemiological characteristics, antimicrobial-resistance genes (ARGs), virulence determinants, detailed plasmid profiles and conjugation efficiency were comprehensively investigated. RESULTS: 155 Hv-CRKP and 31 non-Hv-CRKP strains were sequenced. Hv-CRKP strains exhibited significant resistance to six common antibiotic classes (>92%). ST11 steadily increased and became the most prevalent ST (85.2%), followed by ST15 (8.5%), ST65 (2.6%), ST23 (1.9%), and ST86 (0.6%). ST11-KL64 (65.2%) rapidly increased from 0 in 2014 to 93.9% in 2018. blaKPC-2 was the primary carbapenemase gene (97.4%). Other ARGs switched from aac(3)-IId to aadA2 in aminoglycoside and from sul1 to sul2 in sulfanilamide. The time-dated phylogenetic tree was divided into four independent evolutionary clades. Clade 1 and 3 strains were mostly limited in the ICU, whereas Clade 2 strains were distributed among multiple departments. Compared to ybt14 in ICEKp12 in Clade 1, Clade 3 strains harbored ybt9 in ICEKp3 and blaCTX-M-65. Hv-CRKP infected more wards than non-Hv-CRKP and showed greater transmission capacity. Three plasmids containing crucial carbapenemase genes demonstrated their early transmission across China. CONCLUSION: The Hv-CRKP ST11-KL64 has rapidly replaced ST11-KL47 and emerged as the predominant epidemic subtype in various hospital wards, highlighting the importance of conducting comprehensive early surveillance for Hv-CRKP, especially in respiratory infections.

Fatal hemophagocytic lymphohistiocytosis-induced multiorgan dysfunction secondary to Burkholderia pseudomallei sepsis: A case report.

BACKGROUND: Burkholderia pseudomallei (B. pseudomallei) is a short, straight, medium-sized Gram-negative bacterium that mostly exists alone, without a capsule or spores, has more than three flagella at one end, and actively moves. B. pseudomallei confers high morbidity and mortality, with frequent granulocytopenia in B. pseudomallei sepsis-related deaths. However, mortality may be related to hemophagocytic lymphohistiocytosis (HLH) secondary to B. pseudomallei infection. CASE SUMMARY: A 12-year-old female was referred from a local hospital to the pediatric intensive care unit with suspected septic shock and fever, cough, dyspnea, and malaise. After admission, supportive symptomatic treatments including fluid resuscitation, anti-infective therapy, mechanical ventilation, and a vasoactive drug maintenance cycle were carefully initiated. The patient became unconscious, her blood pressure could not be maintained even under the exposure of vasoactive drugs, and she experienced cardiorespiratory arrest. The patient died due to ineffective high-quality in-hospital cardiopulmonary resuscitation. A subsequent bone marrow smear examination revealed extensive phagocytosis, and the blood culture was positive for B. pseudomallei. Family history revealed a sibling death from B. pseudomallei sepsis 5 years earlier. CONCLUSION: The higher mortality rate in patients with B. pseudomallei sepsis may be related to secondary HLH after infection, wherein multiorgan dysfunction syndrome may be directly related to infection or immune damage caused by secondary HLH. Patients with B. pseudomallei can be asymptomatic and can become an infective source.

[Corrigendum] Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, for the scratch wound assay experiments shown in Fig. 1 on p. 2413, the panels showing the '0 h' experiments for the respective incubations with VEGF or BC001 were apparently identical. The authors were able to re­examine their original data files, and realized that this figure had been inadverently assembled incorrectly. The revised version of Fig. 1, containing the correct data for the '0 h / BC001' panel, is shown below. Note that the revisions made to this figure do not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [International Journal of Oncology 45: 2411­2420, 2014; DOI: 10.3892/ijo.2014.2690].

Formal (4+2) cycloaddition of azoalkenes with trifluoromethylimidoyl sulfoxonium ylides: synthesis of trifluoromethyl pyridazine derivatives.

CF3-substituted imidoyl sulfoxonium ylides (TFISYs) are extraordinarily versatile and powerful synthons for use in cyclization chemistry that affords diverse CF3-substituted N-heterocycles. We first reacted TFISYs as a two-atom synthon with readily available azoalkenes and then subjected the products to metal-free formal (4+2) cycloaddition chemistry. This protocol features mild conditions and broad substrate scope, is simple to operate, and provides highly functionalized trifluoromethylpyridazines that are widely found in bioactive molecules.