Synthetically Lethal Biomimetic Nutri-hijacker Hitchhikes and Reprograms KRAS Mutation-Driven Metabolic Addictions for Pancreatic Ductal Adenocarcinoma Treatment.

Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic "Nutri-hijacker" with "Trojan horse" design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.

Evaluating the impact of a virtual outpatient care programme in preventing hospitalizations, emergency department visits and mortality for patients with COVID-19: a matched cohort study.

OBJECTIVES: To evaluate the impact of virtual care in preventing unnecessary healthcare visits for patients with SARS-CoV-2. METHODS: We conducted a retrospective matched cohort study, evaluating the COVID-19 Expansion to Outpatients (COVIDEO) programme involving virtual assessments for all positive patients in the Sunnybrook assessment centre from January 2020 to June 2021, followed by risk-stratified routine follow-up, couriering of oxygen saturation devices, and 24 hour/day direct-to-physician pager for urgent questions. We linked COVIDEO data to province-wide datasets, matching each eligible COVIDEO patient to ≤10 other Ontario SARS-CoV-2 patients on age, sex, neighbourhood, and date. The primary outcome was emergency department (ED) visit, hospitalization or death within 30 days. Multivariable regression accounted for comorbidities, vaccination, and pre-pandemic healthcare utilization. RESULTS: Among 6508 eligible COVIDEO patients, 4763 (73.1%) were matched to ≥1 non-COVIDEO patient. COVIDEO care was protective against the primary composite outcome (adjusted odds ratio [aOR] 0.91, 95% CI, 0.82-1.02), with a reduction in ED visits (7.8% vs. 9.6%; aOR 0.79, 95% CI, 0.70-0.89), but increase in hospitalizations (3.8% vs. 2.7%, aOR 1.37, 95% CI, 1.14-1.63) reflecting more direct-to-ward admissions (1.3% vs. 0.2%, p < 0.0001). Results were similar when matched comparators were limited to patients who had not received virtual care elsewhere with a decrease in ED visits (7.8 vs. 8.6%, aOR 0.86, 95% CI, 0.75-0.99) and an increase in hospitalizations (3.7 vs. 2.4%, aOR 1.45, 95% CI, 1.17-1.80). DISCUSSION: An intensive remote care programme can prevent unnecessary ED visits and facilitate direct-to-ward hospitalizations and thereby mitigate the impact of COVID-19 on the healthcare system.

Reprogramming systemic and local immune function to empower immunotherapy against glioblastoma.

The limited benefits of immunotherapy against glioblastoma (GBM) is closely related to the paucity of T cells in brain tumor bed. Both systemic and local immunosuppression contribute to the deficiency of tumor-infiltrating T cells. However, the current studies focus heavily on the local immunosuppressive tumor microenvironment but not on the co-existence of systemic immunosuppression. Here, we develop a nanostructure named Nano-reshaper to co-encapsulate lymphopenia alleviating agent cannabidiol and lymphocyte recruiting cytokine LIGHT. The results show that Nano-reshaper increases the number of systemic T cells and improves local T-cell recruitment condition, thus greatly increasing T-cell infiltration. When combined with immune checkpoint inhibitor, this therapeutic modality achieves 83.3% long-term survivors without recurrence in GBM models in male mice. Collectively, this work unveils that simultaneous reprogramming of systemic and local immune function is critical for T-cell based immunotherapy and provides a clinically translatable option for combating brain tumors.

Vitality-Enhanced Dual-Modal Tracking System Reveals the Dynamic Fate of Mesenchymal Stem Cells for Stroke Therapy.

Mesenchymal stem cell (MSC) therapy via intravenous transplantation exhibits great potential for brain tissue regeneration, but still faces thorny clinical translation challenges as the unknown dynamic fate leads to the contentious therapeutic mechanism and the poor MSC viability in harsh lesions limits therapeutic efficiency. Here, a vitality-enhanced dual-modal tracking system is designed to improve engraftment efficiency and is utilized to noninvasively explore the fate of intravenous transplanted human umbilical cord-derived MSCs during long-term treatment of ischemic stroke. Such a system is obtained by bioorthogonally conjugating magnetic resonance imaging (MRI) contrast and near-infrared fluorescence (NIRF) imaging nanoparticles to metabolic glycoengineered MSCs with a lipoic acid-containing extracellular antioxidative protective layer. The dynamic fates of MSCs in multi-dimensional space-time evolution are digitally detailed for up to 28 days using MRI and NIRF imaging equipment, and the protective layer greatly shields MSCs from reactive oxygen spices (ROS) degradation, enhances MSC survival, and engraftment efficiency. Additionally, it is observed that the bioengineered MSCs exhibit dynamic intelligent responses corresponding to microenvironment remodeling and exert enhanced therapeutic effects. This dual-modal tracking system enables long-term tracking of MSCs while improving their viability at the lesion sites, which may serve as a valuable tool for expediting the clinical translation of MSC therapy.

Promotion and implementation effectiveness of World Health Organization's Caregiver Skills Training program in Taiwan.

The World Health Organization (WHO) developed the Caregiver Skills Training for Families of Children with Developmental Delays and Disabilities (CST) with support from Autism Speaks to address the resource gaps and worldwide needs for interventions for children with developmental disorders or delays, especially those with autism spectrum disorder (ASD), and their families. Evidence has indicated that parent-mediated interventions benefit both caregivers and children by strengthening caregivers' knowledge and confidence and children's social communication skills and behavioral regulation. The CST-Taiwan team began the prepilot field trial in 2017 and developed the project to serve families in various locations. This study (1) delineated the adaptations and promotion of CST-Taiwan; (2) determined the program's effectiveness in the promotional stage, in terms of caregiver and child outcomes, and (3) examined the maintenance of its effects. The materials, delivery, and facilitator training procedure of the original CST were adapted to Taiwan. The quantitative data indicated that CST-Taiwan is a promising program, it positively affected caregiver knowledge and confidence and reduced the severity of the children's autistic symptoms. The 3-month follow-up results suggested that the effects persisted. Thus, CST-Taiwan, and its promotional strategies are feasible and effective.

Metformin and histone deacetylase inhibitor based anti-inflammatory nanoplatform for epithelial-mesenchymal transition suppression and metastatic tumor treatment.

Epithelial-mesenchymal transition (EMT), a differentiation process with aberrant changes of tumor cells, is identified as an initial and vital procedure for metastatic processes. Inflammation is a significant inducer of EMT and provides an indispensable target for blocking EMT, however, an anti-inflammatory therapeutic with highlighted safety and efficacy is deficient. Metformin is a promising anti-inflammatory agent with low side effects, but tumor monotherapy with an anti-inflammation drug could generate therapy resistance, cell adaptation or even promote tumor development. Combination therapies with various anti-inflammatory mechanisms can be favorable options improving therapeutic effects of metformin, here we develop a tumor targeting hybrid micelle based on metformin and a histone deacetylase inhibitor propofol-docosahexaenoic acid for efficient therapeutic efficacies of anti-inflammatory drugs. Triptolide is further encapsulated in hybrid micelles for orthotopic tumor therapies. The final multifunctional nanoplatforms (HAOPTs) with hyaluronic acid (HA) modification can target tumor efficiently, inhibit tumor cell EMT processes, repress metastasis establishment and suppress metastatic tumor development in a synergistic manner. Collectively, the results afford proof of concept that the tumor targeting anti-inflammatory nanoplatform can provide a potent, safe and clinical translational approach for EMT inhibition and metastatic tumor therapy.

Neutrophil-Biomimetic "Nanobuffer" for Remodeling the Microenvironment in the Infarct Core and Protecting Neurons in the Penumbra via Neutralization of Detrimental Factors to Treat Ischemic Stroke.

High level of detrimental factors including reactive oxygen species (ROS) and inflammatory cytokines accumulated in the infarct core and their erosion to salvageable penumbra are key pathological cascades of ischemia-reperfusion injury in stroke. Few neuroprotectants can remodel the hostile microenvironment of the infarct core for the failure to interfere with dead or biofunctionally inactive dying cells. Even ischemia-reperfusion injury is temporarily attenuated in the penumbra by medications; insults of detrimental factors from the core still erode the penumbra continuously along with drug metabolism and clearance. Herein, a strategy named "nanobuffer" is proposed to neutralize detrimental factors and buffer destructive erosion to the penumbra. Inspired by neutrophils' tropism to the infarct core and affinity to inflammatory cytokines, poly(lactic-co-glycolic acid) (PLGA) nanoparticles are coated with neutrophil membrane to target the infarct core and absorb inflammatory cytokines; α-lipoic acid is decorated on the surface and cannabidiol is loaded for ROS scavenging and neuroprotection, respectively, to construct the basic unit of the nanobuffer. Such a nanobuffer exerts a comprehensive effect on the infarct area via detrimental factor neutralization and cannabidiol-induced neuroprotection. Besides, the nanobuffer can possibly be enhanced by dynamic ROP (ring-opening-polymerization)-induced membrane cross-fusion among closely adjacent units in vivo. Systematic evaluations show significant decrease of detrimental factors in the core and the penumbra, reduced infarct volume, and improved neurological recovery compared to the untreated group of stroke rats.

Psychopathologies mediate the link between autism spectrum disorder and bullying involvement: A follow-up study.

BACKGROUND/PURPOSE: Youths with autism spectrum disorder (ASD) are at a high risk of involvement in school bully. The study investigated whether comorbid psychopathologies mediated the link between ASD and bullying involvement. METHODS: We assessed 353 youths (mean age, 11.8 ± 3.1 years), including 121 youths with ASD and 232 typically developing (TD) controls, using semi-structured diagnostic interviews on ASD and other psychiatric conditions. Follow-up assessments took place 2-5 years (37.6 ± 15 months) later. Meanwhile, their parents reported on the Social Adjustment Inventory for Children and Adolescents about bullying involvement statuses. We identified significant mediators by simple mediation models, followed by multiple mediation models to scrutinize the mediation effects of selected mediators. RESULTS: The results showed a sevenfold increased risk of bullying involvement among youths with ASD compared with TD controls at follow-up. In general, psychopathologies mediated the link between ASD and bullying involvement, even independent of age and sex. Specifically, we found mediating effects of social problems on victimization-only and aggressive behaviors on victimization-perpetration. CONCLUSION: Our findings strongly suggest the link between ASD and later bullying involvement is mediated by pre-existing comorbid psychiatric conditions, besides the direct effect of ASD on bullying victimization. Hence, early identification and intervention of these psychopathologies are highly suggested.

Systemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy.

Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.

Risk of COVID-19 infection in MS and neuromyelitis optica spectrum disorders.

OBJECTIVE: Disease-modifying drugs (DMDs) may alter the immune status and thus increase the susceptibility to coronavirus disease 2019 (COVID-19) in patients with MS or neuromyelitis optica spectrum disorders (NMOSD). However, evidence supporting this notion is currently lacking. In this study, we conducted a survey on the risk of COVID-19 in patients with MS and NMOSD. METHODS: The survey was conducted through the Chinese Medical Network for Neuroinflammation. Patients in 10 MS centers from 8 cities including Wuhan were included. Information about MS and NMOSD disease duration and the usage of DMDs were collected. Data of suspected cases of COVID-19 were obtained from hospital visits, questionnaires, and patient self-reporting. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was confirmed through clinical evaluation by a panel of experts in conjunction with chest CT and viral RNA detection. RESULTS: Eight hundred eighty-two of 1,804 (48.89%) patients with MS and 2,129 of 3,060 (69.58%) patients with NMOSD were receiving DMDs. There were no alterations in the patients' DMD regimen during January 15, 2020, to March 15, 2020, the 3-month period. None of the patients with MS treated with DMDs had COVID-19. However, 2 patients with relapsing NMOSD were diagnosed with COVID-19-related pneumonia. After treatment, both patients recovered from pneumonia and neither patient experienced new attacks due to predisposing SARS-CoV-2 infection in the following 2 months. CONCLUSIONS: No increased risk of COVID-19 infection was observed in patients with MS or NMOSD, irrespective of whether these patients received DMDs. A battery of stringent preventive measures adopted by neurologists to reduce COVID-19 infection in these patients may have contributed to low risk of COVID-19 infection.

Efficacy and Safety of Teriflunomide in Chinese Patients with Relapsing Forms of Multiple Sclerosis: A Subgroup Analysis of the Phase 3 TOWER Study.

BACKGROUND: Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study. METHODS: TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54). RESULTS: Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (-71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning. CONCLUSIONS: Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1.

Monitoring Chemical and Biological Electron Transfer Reactions with a Fluorogenic Vitamin K Analogue Probe.

We report herein the design, synthesis, and characterization of a two-segment fluorogenic analogue of vitamin K, B-VKQ, prepared by coupling vitamin K3, also known as menadione (a quinone redox center), to a boron-dipyrromethene (BODIPY) fluorophore (a lipophilic reporter segment). Oxidation-reduction reactions, spectroelectrochemical studies, and enzymatic assays conducted in the presence of DT-diaphorase illustrate that the new probe shows reversible redox behavior on par with that of vitamin K, provides a high-sensitivity fluorescence signal, and is compatible with biological conditions, opening the door to monitor remotely (i.e., via imaging) redox processes in real time. In its oxidized form, B-VKQ is non-emissive, while upon reduction to the hydroquinone form, B-VKQH2, BODIPY fluorescence is restored, with emission quantum yield values of ca. 0.54 in toluene. Density functional theory studies validate a photoinduced electron transfer intramolecular switching mechanism, active in the non-emissive quinone form and deactivated upon reduction to the emissive dihydroquinone form. Our results highlight the potential of B-VKQ as a fluorogenic probe to study electron transfer and transport in model systems and biological structures with optimal sensitivity and desirable chemical specificity. Use of such a probe may enable a better understanding of the role that vitamin K plays in biological redox reactions ubiquitous in key cellular processes, and help elucidate the mechanism and pathological significance of these reactions in biological systems.

Influence of miR-30b regulating humoral immune response by genetic difference.

Investigation of genetic difference will be beneficial to researchers to understand the origins and nature of diseases. Previous studies have revealed that L-kynurenine (L-Kyn) level was changed significantly in patient with cancer and that miR-30b play different role in tumor cells and immune cells. Moreover, it has been also conformed that miR-30b involved in the process of L-Kyn-mediated suppression of humoral immune responses induced by lipopolysaccharide (LPS) in human normal B cells separated from volunteers' peripheral blood. Nevertheless, the miR-30b role regulating humoral immune response in B lymphoma cells has been still unclear due to the genetic difference between normal cells and tumor cells. The current study demonstrated that the selected concentration of L-Kyn (100, 1000 µM) significantly reduced the immunoglobulin M secretion induced by LPS when compared with the control group in B lymphoma, CH12.LX, and BCL-1 cells, which had, at least, incomplete dependence on Aryl hydrocarbon receptor, the receptor of L-Kyn. In addition, although L-Kyn (100 µM) significantly attenuated the expression of miR-30b in BCL-1 cells rather than in CH12.LX cells, no significant differences in the strength of L-Kyn-mediated suppression of humoral immune responses induced by LPS were detected by enzyme-linked immunosorbent assay between the LPS (10 µg/ml) + L-Kyn (100 µM) group and the LPS (10 µg/ml) + L-Kyn (100 µM) + miR-30b mimics/miR-30b inhibitor group in CH12.LX and BCL-1 cells, respectively. Further data also showed that mouse Bach2 mRNA was a novel target of miR-30b. These results suggest that genetic difference among cells has a great influence on the miR-30b role in the process of L-Kyn-mediated suppression of humoral immune responses induced by LPS.

Impact of constitutional isomerism on phosphorescence and anion-sensing properties of donor-acceptor organoboron Pt(II) complexes.

A new dimesitylboryl-functionalized molecule (NBppy) and its corresponding N^C chelate platinum(II) complex (Pt-NBppy) have been synthesized and fully characterized. The photophysical and electronic properties of NBppy and Pt-NBppy were examined and compared to their constitutional isomers, BNppy and Pt-BNppy, respectively. Due to the presence of the electron-donating diphenylamino group, the NBppy and BNppy compounds exhibit intense donor­acceptor charge transfer (CT) and bright blue fluorescence. Pt-NBppy displays weak phosphorescence, originating from a mixture of MLCT/π→π* and CT transitions while Pt-BNppy displays bright phosphorescence originating from a CT transition. The Lewis acidity of the isomers was examined by fluoride titration experiments, which established that BNppy exhibits much higher affinity towards fluoride ions than NBppy. In addition, while the phosphorescence of Pt-BNppy is quenched by fluoride addition, Pt-NBppy demonstrates an unusual turn-on phosphorescent response towards fluoride ions, which illustrate the distinct impact of constitutional isomers on phosphorescence and anion sensing.

Cu(II)-ion-catalyzed solvolysis of N,N-bis(2-picolyl)ureas in alcohol solvents: evidence for cleavage involving nucleophilic addition and strong assistance of bis(2-picolyl)amine leaving group departure.

The kinetics and products for solvolysis of N-p-nitrophenyl-N',N'-bis(pyridin-2-ylmethyl) urea (7a), N-methyl-N-p-nitrophenyl-N',N'-bis(pyridin-2-yl methyl) urea (7b), and N-phenyl-N',N'-bis(pyridin-2-yl-methyl) urea (DPPU) (7c) promoted by Cu(II) ion in methanol and ethanol were studied under (s)(s)pH-controlled conditions at 25 °C. Methanolysis and ethanolysis of these substrates proceeds rapidly at a 1:1 ratio of substrate:metal ion, the half-times for decomposition of the Cu(II):7a complexes being ~150 min in methanol and 15 min in ethanol. In all cases, the reaction products are the Cu(II) complex of bis(2-picolyl)amine and the O-methyl or O-ethyl carbamate of the parent aniline, signifying that the point of cleavage is the bis(2-picolyl)-N-C=O bond. Reactions of the Cu(II):7b complexes in each solvent proceed about 3-5 times slower than their respective Cu(II):7a complexes, excluding an elimination mechanism that proceeds through an isocyanate which subsequently adds alcohol to give the observed products. The reactions also proceed in other solvents, with the order of reactivity ethanol > methanol >1-propanol >2-propanol > acetonitrile (with 0.2% methanol) > water spanning a range of 150-fold. The mechanism of the reactions is discussed, and the reactivity and mode of cleavage are compared with that of the M(II)-promoted ethanolytic cleavage of a mono-2-picolyl derivative, N-p-nitrophenyl-N'-(pyridin-2-yl-methyl) urea (4a), which had previously been shown to cleave at the aniline N-C=O bond. The large estimated acceleration of the rate of attack of ethoxide on 7b of at least 2 × 10¹6 provided by associating Cu(II) with the departing group in this urea is discussed in terms of a trifunctional role for the metal ion involving Lewis acid activation of the substrate, intramolecular delivery of a Cu(II)-coordinated ethoxide, and metal-ion-assisted leaving group departure.

Bone regeneration in a rabbit ulna defect model: use of allogeneic adipose-derivedstem cells with low immunogenicity.

Tissue engineering provides new potential treatments for the repair of bone defects. Bone-marrow-derived mesenchymal stem cells (BMSCs) represent an attractive cell source for therapeutic applications involving tissue engineering, although disadvantages, such as pain of harvest and low proliferation efficiency, are major limitations to the application of BMSCs in the clinic. Adipose-derived stem cells (ASCs) with their multilineage potential and satisfactory proliferation potential can be induced into the osteogenic lineage in vitro and can be anchored onto suitable scaffolds as seed cells to repair bone defects successfully in an autologous setting. Previous studies have indicated that both undifferentiated BMSCs and ASCs exhibit immunosuppression and immunoprivilege properties. We compare the immuno-function of undifferentiated and osteo-differentiated ASCs in vitro and explore the feasibility of applying allogeneic ASCs to the repair of ulnar bone defects in the rabbit model. Our study demonstrates that allogeneic osteogenic differentiated ASCs maintain low immunogenicity and negative immunomodulation. The allogeneic osteogenic differentiated ASCs combined with demineralized bone matrix successfully regenerate ulnar bone defects in rabbits without immunosuppressive therapies.

Vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer: a meta-analysis involving 2,444 individuals.

The association between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer (HNC) were investigated in many published studies; however, the currently available results are inconclusive. Therefore, we conducted this meta-analysis for deriving a more precise estimation of association between VEGF polymorphisms and the risk of HNC. Finally, we yield eight case-control studies involving six polymorphisms contain 2,444 individuals from PubMed, Embase, and CNKI up to January 30, 2013 (last updated on May 4, 2013). The results of meta-analysis showed that all the six polymorphisms of VEGF were not associated with risk of HNC [OR 1.25, 95 % CI (0.60-1.58) for TT vs. CC for 936 C/T; OR 1.41, 95 % CI (0.79-2.52) for GG vs. AA for -1,154 A/G; OR 0.97, 95 % CI (0.38-2.50) for CC vs. GG for 405 G/C; OR 1.44, 95 % CI (0.80-2.61) for AA vs. CC for 2,578 C/A; OR 1.27, 95 % CI (0.77-3.72) for TT vs. CC for -460 C/T; and OR 0.87, 95 % CI (0.37-2.06) for GG vs. CC for -634 G/C]. When performed subgroup analysis according to ethnicity for VEGF 936 C/T, the results suggested that it was not associated with the risk of HNC for either Asians [OR 0.84, 95 % CI (0.27-2.56) for TT vs. CC] or Caucasians [OR 2.10, 95 % CI (0.82-5.37) for TT vs. CC]. However, due to the limitations of this meta-analysis, more well designed, larger sample size, and adjusted risk factors studies are suggested to further assess the findings.