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Neuroblastoma (NB) has high morality rates and is the most common malignant tumor found in children. High aggregation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment results in immunosuppression and affects therapeutic effectiveness. At present, doxorubicin (DOX) and dopamine (DA) are the specific drugs used to selectively remove or mature MDSCs. The aim of the present study was to explore the feasibility and underlying mechanism of targeting elimination of MDSCs via DOX or DA administration to alleviate tumor immunosuppression in NB. In the present study, a BALB/c tumor-bearing mouse model was established, and mice were grouped into the control, DOX2.5, DOX5 and DA50 mg/kg groups. DOX or DA were injected intravenously on days 7 and 12 after inoculation, following which the parameters related to the signal transducer and activator of transcription (STAT) pathway in MDSCs, the proportion of MDSCs, T cell infiltration, programmed death-1 (PD-1) on the surface of T cells, the number of regulatory T cells (Tregs), polarization of tumor-related macrophages (TAMs) and tumor growth were compared between the groups on days 14, 17 and 23 after inoculation. The results demonstrated that following DOX or DA administration, STAT1/phosphorylated (p)-STAT1 decreased, whereas STAT3/p-STAT3, STAT5/p-STAT5 and STAT6/p-STAT6 increased, which was accompanied by a decrease in the MDSC proportion in each experimental group. Simultaneously, T cell infiltration in tumors was increased, whereas expression of PD-1, the number of Tregs, TAM polarization and tumor growth were inhibited. The most significant findings were observed in the DOX2.5 mg/kg group. To conclude, low dose DOX or DA administration could effectively regulate the STAT pathway to eliminate MDSCs, alleviate immunosuppression and improve the immune response against NB tumor cells.

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS‐CoV‐2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS‐CoV‐2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169+ expressing monocytes in the peripheral blood. Systemic levels of pro‐inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro‐inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus‐specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS‐CoV‐2 was observed in asymptomatic patients. In addition, asymptomatic COVID‐19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro‐inflammatory and more protective immune responses against SARS‐CoV‐2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID‐19., We show that asymptomatic patients elicit a different repertoire of immune responses from symptomatic patients. Our data suggest that asymptomatic patients could limit symptom development with a well‐balanced inflammatory response and more protective immune responses against SARS‐CoV‐2.

A Ku-band relativistic transit-time oscillator with a three-cavity extractor and a distance-tunable reflector was proposed in our previous work [Ling et al., Phys. Plasmas 24(1), 013103 (2017)]. Recently, a new experiment was carried out on this device with an intense relativistic electron beam generator that produces electron beams with a duration of 55 ns and voltage of 0.4–1 MV. In preliminary experiments, mode competition was found with three main frequencies of which the reasons are analyzed theoretically and experimentally. The results show that plasmas generated from the collector's surface are most likely to cause this problem. To solve this problem, the collector structure is extended axially. With an input voltage of 600 kV and a current of 11.7 kA, a microwave output power 1.9 GW with pulse width 26 ns and frequency 12.42 GHz is obtained under a 0.7 T guiding magnetic field. These experimental results effectively confirm the potential of high power capacity of this proposed Ku band transit-time oscillator.

Background Type 2 diabetes has been associated with increased risk of gynecologic cancers, yet the effect of gestational diabetes mellitus (GDM) on gynecologic cancers is unclear. Objectives To examine associations between GDM history and subsequent gynecologic cancers in parous women, and to explore whether gestational hypertension (GH) plays a role in the associations. Study design The population-based cohort study included 15,941 individuals from the Swedish Twin Registry. The history of GDM and GH was ascertained based on self-reports. Incident cases of gynecologic cancers (including cancers of the cervix, uterus, ovaries and other female genitalia) were obtained from the National Patients Registry and the Swedish Cancer Registry. Generalized estimating equation models were applied to analyze associations between GDM and gynecologic cancers. Stratified analysis was used to explore whether associations between GDM and gynecologic cancers differed by GH. Additive and multiplicative interactions were calculated between GDM and GH. Results Of all participants, 350 (2.2%) had GDM, and 1762 (11.1%) had incident gynecologic cancers. No statistically significant associations were found between GDM and risks of any gynecologic cancers. However, GDM was associated with an increased risk of ovarian cancer (OR = 5.29, 95% CI: 1.63–17.19) in women with GH. Interactions between GDM and GH were observed on the additive scale (Attributable proportion due to interaction: 0.86, 95% CI 0.42–1.30, P Conclusions The associations between GDM and risks of gynecologic cancers were not evident, but the effect of GDM on the risk of ovarian cancer was modified by GH. Further validation in larger cohorts is warranted.

This study investigated associations between total isoflavones and their categories (daidzein, genistein, glycitein) intake and the risks for metabolic disorders. We used the data of 6786 Chinese adults from the Nutrition Health Atlas Project. We performed multiple logistic regression and restricted cubic spline models assessing the risks for metabolic disorders (non-alcoholic fatty liver disease (NAFLD), hyperlipidaemia, hypertension, diabetes and overweight/obesity) in each category of isoflavones. Higher total isoflavones, daidzein and genistein intake were inversely associated with NAFLD (p p p

Introduction Decline in physical function varies substantially across older individuals due to several extrinsic modifiable factors such as dietary patterns, physical activity and social support. We aimed to determine the association of these factors and their interaction with mobility and muscle strength decline. Methods We analyzed data from 1686 functionally healthy individuals aged 60 + from the population-based Swedish National study on Aging and Care in Kungsholmen (SNAC-K). The Mediterranean Diet Score (MDS) was calculated based on a validated food frequency questionnaire. Self-reported physical activity was categorized based on current recommendations, and social support was measured according to participants’ perceived material and psychological support from relatives and friends. Participants’ physical function was assessed over 12 years through changes in walking speed (m/s) and chair stand time (s). Linear mixed models adjusted for socio-demographic and clinical factors were used. In order to explore the combined effect of the different exposures, two indicator variables were created by cross-classifying individuals' levels of Mediterranean diet adherence and social support or physical activity. Results Participants with a high adherence to Mediterranean diet were primarily [year] = 0.001; p = 0.024) and chair-stand time (β*time[year] = -0.014; p = 0.008). The potential protective effect of Mediterranean diet was highest among participants reporting high social support (β*time[year] = -0.065, p = 0.026 for chair stands) and high physical activity (β*time[year] = 0.010, p = 0.001 for walking speed), beyond the effect of each exposure individually. Conclusion A higher adherence to Mediterranean diet, especially in combination with recommended levels of physical activity and high social support, may contribute to delay the decline in physical function observed with aging.

A 20% global increase in the number of obese individuals is likely to occur by 2030. Projections for the US alone suggest that 85% of the population may be overweight or obese by 2030. This is a worrying trend, as obese individuals exhibit many symptoms of metabolic syndrome (MS). In the first section of this review, we cover recent literature describing how obesity and aging have a similar impact on the immune system by contributing to chronic low-grade inflammation. In the second section, we describe potential interventions that could mitigate physiological changes associated with obesity and aging, and discuss future studies that would be necessary to elucidate the impact of obesity on immunity and metabolic health in order to further the advancement of precision medicine

Emerging evidence suggests that olfactory function is closely linked to memory function. The aims of this study were to assess whether olfactory and episodic memory functions follow similar age-related decline trajectories, to identify different patterns of decline, as well as predictors of the patterns. 1023 participants from the Memory and Aging Project were followed for up to 8 years with annual episodic memory and odor identification assessments. Trajectories were modelled using growth mixture models. Multivariate logistic regression was used to identify pattern predictors. Three patterns of joint trajectories were identified; Class 1- stable average performance in both functions (n=690, 67.4%); Class 2- stable average episodic memory and declining odor identification (n=231, 22.6%); and Class 3- decline in both functions (n= 102, 10.0%). Class predictors included age, sex, APOE ε4 status, cognitive activity level and BMI. Participants in Class 3 were most likely to develop dementia. Episodic memory and olfactory function show similar trajectories in aging. Such classification can contribute to a better understanding of the factors related to cognitive decline and dementia.

A novel in-syringe temperature-controlled liquid–liquid microextraction based on solidified floating ionic liquid (in-syringe TC-LLME-SFIL) combined with high performance liquid chromatography was developed for the simultaneous determination of monuron, chlorotoluron, atrazine, monolinuron, propazine and prometryn in commercial vegetable protein drinks. The samples were deproteinized by trichloroacetic acid and further cleaned up by solid phase extraction column. The ionic liquid tributyldodecylphosphonium tetrafluoroborate ([P4 4 4 12]BF4) was used as extraction solvent and dispersed into the depurated sample solution to form fine droplets with the assistance of heating and vortex. With the help of an ice bath, the ionic liquid phase solidified and floated on the surface of aqueous phase. After separation from the aqueous phase, the solidified ionic liquids were dissolved with acetonitrile and the resulting solution was analyzed by high performance liquid chromatography. Some extraction parameters, including type and amount of adsorbent, type and amount of ionic liquids, amount of NaCl, melting temperature and time of ionic liquid, vortex time, pH of sample solution, ice bath temperature and time, were investigated and optimized by single-factor experiment, Plackett-Burman design and Box-Behnken design. The results showed that good linearities (r ≥ 0.9994) were obtained in the concentration range of 7.8–1000.0 μg/L. The limits of detection and quantification were in the range of 0.25–2.59 μg/L and 0.82–8.63 μg/L, respectively. The spiked recoveries were 81.26–118.42% with the relative standard deviation (RSD, n = 3) lower than 8.17%. The present method was successfully applied to the simultaneous determination of triazine and phenylurea herbicides in vegetable protein drinks.

It is a tough challenge for many decades to decipher the complex relationships between cell behaviors and cellular physical properties. Single particle tracking (SPT) with high spatial and temporal resolution has been applied extensively in cell research to understand physicochemical properties of cells and their bio-functions by tracking endogenous or exogenous probes. This review describes the fundamental principles of SPT as well as its applications in intracellular mechanics, membrane dynamics, organelles distribution, and processes of internalization and transport. Finally, challenges and future directions of SPT are also discussed.

INTRODUCTION: Whether depression is a prodromal phase or risk factor for dementia is under debate. We aimed to unveil the nature of depression-dementia association by looking into the time window of depression occurrence.METHODS: Dementia-free twins (n = 41,727) from the Swedish Twin Registry were followed-up for 18 years. Data were analyzed using generalized estimating equation (GEE) for all individuals and conditional logistic regression for co-twin matched pairs.RESULTS: In the GEE model, multi-adjusted odds ratios (ORs; 95% confidence intervals [CIs]) of dementia were 1.46 (1.09-1.95) for mid-life, 2.16 (1.82-2.56) for late-life, 2.24 (1.49-3.36) for mid- to late-life, and 2.65 (1.17-5.98) for lifelong depression. The ORs in conditional logistic regression and in GEE did not differ significantly (P = 0.60). Education ≥8 years attenuated dementia risk associated with mid-life depression.DISCUSSION: Not only late-life depression, but also mid-life depression is associated with dementia. Genetic and early-life environmental factors could not account for this association. Education ≥8 years might buffer the impact of mid-life depression on dementia.

Background High agglomeration of myeloid-derived suppressor cell (MDSC) in tumor microenvironment resulted in immune escape and affected therapeutic effects. Doxorubicin (DOX) or dopamine (DA) is found the specific drug to selectively remove or maturate MDSC. How to effectively eliminate MDSC in neuroblastoma (NB) and its mechanism need to be clarified. Procedure In the present study, BALB/c tumor-bearing mice model were established by NB cells injection, then grouped into DOX2.5 mg/kg group, DOX5 mg/kg group, DA50 mg/kg group and control group. DOX or DA were injected intravenously in advance, then quantity and distribution of MDSC, proliferation and infiltration of T cell, Treg level and TAM polarization, MDSC related functional molecules in vivo and expression of proteins in signal transducer and activator of transcription (STAT) pathway in MDSC were detected and compared respectively at 14 d, 17 d and 23 d after inoculation. The tumor growth were compared between the groups. Results After DOX or DA administration, in each experimental group, MDSC ratio all decreased. STAT1, p-STAT1 and activated caspase-3 decreased, but STAT3, p-STAT3, STAT5, p-STAT5, STAT6, p-STAT6, Arg-1 and IDO increased. Simutaneously, compared with the control group, T cell proliferation in tumor first increased and then inhibited, infiltration of T cells increased, TAM polarization and Treg level reduced, the tumor growth was inhibited. Changes in above indicators were most significant in DOX2.5mg/kg group. Conclusions Low-dose DOX administration can eliminate MDSC in NB by regulating STAT signaling pathway in MDSC, thus remove immunosuppression and improve immune efficacy of NB.

Background It remains unclear whether and to what extent health behaviours may prolong survival and compress the period of survival with disability. Objective To identify modifiable health behaviours that are associated with later disability onset and longer disability-free survival. Design This population-based cohort study used data from the Swedish National Study on Ageing and Care in Kungsholmen (SNAC-K) ranging between 2001 and 2016. Setting and subjects A total of 3,041 disability-free adults aged ≥60 years were followed up to 15 years. Methods Data on health behaviours were collected at baseline. Information on limitations in activities of daily living was obtained at baseline and during the follow-up. Laplace regression was used to model the median age at death and disability occurrence as a function of health behaviours. Results Never smoking, moderate alcohol drinking, rich social network and high leisure activity were individually related to longer survival by 1–3 years. Participants with high leisure activity lived 1.6 years (95% CI: 0.9–2.3) more without a disability. After combining lifestyle factors, social network, and leisure activities into a 4-level ‘health behaviour profile’, people with the healthiest behaviour profile lived 2.8 years (95% CI: 1.3–4.2) longer, had disability 3.5 years (95% CI: 1.7–5.3) later and lived 0.7 years (95% CI, 0.4–1.1) more without a disability compared to those with the least healthy behaviours profile. Conclusions These findings suggest that health behaviours could prolong the lifespan, and leisure activities may further compress years lived with disability among older adults.

SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients revealed a dramatic increase in the number of immature neutrophils. This increase strongly correlated with disease severity and was associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts was observed for CD8 T-cells and VD2 γδ T-cells, which both exhibited increased differentiation and activation. ROC analysis revealed that the count ratio of immature neutrophils to CD8 or VD2 T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.

While the importance of working conditions on cognitive function has been tentatively suggested previously, few studies have considered cumulative effects of exposure throughout the working life. We examined the association between job demand-control status and late-life cognitive decline, taking into account exposure durations. In the population-based cohort study, Swedish National Study on Aging and Care-Kungsholmen, 2,873 dementia-free participants aged 60+ were followed up to nine years. Cognitive function was measured using the Mini-Mental State Examination. The entire working life was outlined through interview and occupations were graded with a psychosocial job-exposure matrix. Multivariate linear mixed-effects models were used. Slower cognitive decline was observed among people with high job control (β: 0.10, 95% CI: 0.03, 0.19) and demands (β: 0.15, 95% CI: 0.07, 0.22) in the longest-held job. Compared to active job, faster decline was shown in low strain (β: - 0.17, 95% CI: - 0.26, - 0.08), high strain (β: - 0.13, 95% CI: - 0.24, - 0.03), and passive job (β: - 0.22, 95% CI: - 0.34, - 0.11). Longer duration of active jobs was associated with slower cognitive decline (β: 0.24, 95% CI: 0.16, 0.32), whereas faster decline was associated with longer durations of low strain (β: - 0.12, 95% CI: - 0.19, - 0.05), high strain (β: - 0.13, 95% CI: - 0.21, - 0.04), and passive jobs (β: - 0.12, 95% CI: - 0.20, - 0.04). In conclusion, not only psychologically stressful jobs, but also low-stimulating and passive jobs are associated with faster cognitive decline in later life. Duration of exposure may play a role in the psychosocial working condition-cognitive decline association.

Our study examined whether midlife overweight (body mass index [BMI] ≥25) is associated with late-life cancer risk and explored the role of genetic and early-life environmental factors in this association. The study included 14,766 individuals from the Swedish Twin Registry, whose midlife (30-50 years) height and weight were recorded. Information on cancer diagnoses in late life (>65 years) was derived from the National Patient Registry and Cancer Registry. Generalized estimating equation (GEE) models were used to analyze unmatched case-control data (controlled for the clustering of twins within a pair). A co-twin matched case-control analysis used conditional logistic regression to compare cancer-discordant twins. Of all participants, 3968 (26.9%) were overweight and 4253 (28.8%) had cancer. In multi-adjusted GEE models using normal-weight (BMI 18.5-24.9) participants as the reference group, overweight was related to higher risk of colon cancer (OR 1.36, 95% CI: 1.00-1.84, p = 0.049), liver cancer (OR 2.00, 95% CI: 1.11-3.62), cervix uteri cancer (OR 2.86, 95% CI: 1.19-6.91) and corpus uteri cancer (OR 1.78, 95% CI: 1.14-2.78) but lower risk of nonmelanoma skin cancer (OR 0.77, 95% CI: 0.66-0.90). In conditional logistic regression analysis, these associations were attenuated becoming nonsignificance. The difference in ORs from the unmatched and matched analyses was not significant. In conclusion, midlife overweight is associated with increased risk of late-life colon, liver and uterine cancer but reduced risk of late-life nonmelanoma skin cancer. Further investigations are warranted to explore the role of genetic and early-life environmental factors in these associations.

Background: Leukocyte telomere length (LTL) is associated with the aging process and age-related degenerative diseases. The relation of peripheral blood LTL to mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and the role of folate and homocysteine (Hcy) in this relation remain unclear. Objectives: We aimed to investigate the association between LTL and the risks of MCI/AD, and to explore whether folate and Hcy may play a role in this association. Methods: This case-control study included 129 MCI subjects, 131 AD patients and 134 healthy controls. LTL was assessed using real-time polymerase chain reaction assay. Serum folate levels were tested by chemiluminescence enzyme immunoassay, and serum Hcy levels were measured using the enzymatic cycling method. Data were analyzed using multivariate logistic regression and multivariable linear regression with adjustment for potential confounders. Results: The mean LTL was 1.56 ± 0.25 in controls, 1.44 ± 0.23 in MCI, and 1.28 ± 0.28 in AD patients (p< 0.01). In multivariate logistic regression, subjects in the longest LTL tertile had lower OR for MCI (OR 0.246; 95% CI 0.101–0.597) and AD (OR 0.123; 95% CI 0.044–0.345) in comparison to subjects in the shortest tertile. Shorter LTL was dose-dependently related to the ORs of MCI and AD. Further, serum folate concentration was positively associated with LTL (p < 0.01), while serum Hcy level was negatively associated with LTL (p < 0.05). In stratified analyses, LTL-MCI/AD association varied by serum folate and Hcy level. Conclusions: Shorter LTL is associated with the risks of MCI/AD. Folate and Hcy might play an important role in this association.

OBJECTIVES To identify sex‐specific associations between risk factors and injurious falls over the short (

Lead-free ferroelectric Bi0.5Na0.5TiO3 (BNT) has attracted considerable attention taking into account environment issues and applications in micro electro mechanical systems. The effects of manganese (Mn) substitution on microstructure, lattice dynamics, and optical properties of BNT films have been investigated by X-ray diffraction, Raman scattering and ellipsometric spectra. The phase transitions as a function of temperature have been systemically explored by temperature-dependent Raman and ellipsometric spectra. The anomalous temperature-dependent behavior of Raman-active modes suggests that there is an intermediate phase between ferroelectric rhombohedral and paraelectric tetragonal phase, which is confirmed by the temperature-dependent optical band gap ( E g ) and extinction coefficient (κ) extracted from ellipsometric spectra analysis. And then, a phase diagram as a function of Mn composition has been proposed. Finally, we demonstrate that Mn-dopant is an effective approach to enhance ferroelectric properties, improve energy storage ability, and increase permittivity as well as suppress leakage current. Electrical dielectric responses indicate that there is a critical frequency and polarization relaxation behavior in the films. The present results will be helpful for the application of BNT-based lead-free multifunctional devices.

Milk fat globule membrane (MFGM) protein is known to have several health benefits, including an anti-sarcopenia effect; however, its mechanism is unclear. The aim of this study was to investigate the potential mechanism of action of the MFGM protein. The MFGM protein was extracted and separated into 4 fractions, and Fraction 2 (57% of total MFGM) demonstrated the greatest effect on C2C12 cell proliferation. Milk fat globule-EGF factor 8 (MFG-E8) accounted for 82.35% of the MFGM protein. The effects of whole Fraction 2 (100μg/mL, 200μg/mL and 300μg/mL) on cell proliferation and morphology were measured. Using qRT-PCR or a Western blot assay, several regulatory factors, e.g., PI3K P85α, p-pI3K p85α (Tyr 508), Akt, p-Akt (Ser 473), mTOR and p-mTOR (Ser 2448), were measured in cells incubated with 200μg/mL of Fraction 2 with or without wortmannin. The results demonstrated that Fraction 2 induced C2C12 cell proliferation in a dose-dependent manner, upregulated the mRNA expression of mTOR and p70S6K, and activated PI3K, Akt, mTOR and P70S6K phosphorylation; however, Fraction 2 inhibited FOXO3a and 4E-BP. The results demonstrate that the MFGM protein, predominantly MFG-E8, promotes cell proliferation through the PI3K/Akt/mTOR signaling pathway. This study elucidated the molecular mechanism of the MFGM protein, primarily MFG-E8, in promoting C2C12 cell proliferation via the PI3K/Akt/mTOR/P70S6K signal pathway.

The immune system is the defense system of the host that protects it from foreign pathogens. Inflammation is one of the key processes that alert the immune system but when loss of regulation occurs, a long-term chronic inflammation settles and is likely to be detrimental to the host. Most age-related diseases are linked to a disequilibrium of circulating inflammatory molecules. We could use the analogy of "Dr Jekyll' representing the expected inflammation and immune response in general and the "Mr. Hyde" effect represented by the other face of inflammation, when it is dysregulated. This review aims to cover how immunity, inflammation and persistent infection are associated and some aspects that future studies should look into such as tissue-specific immunity and interventions. Having this knowledge will enable us to prevent inflammation to lose its regulatory network, which could potentially increase the health-span and a better quality of life for the growing elderly population.

Phytosterols are bioactive components capable of reducing cholesterol level in serum and reducing risk of arteriosclerosis. In this study, conditions for the synthesis of maximum yield of phytosterol linoleic ester (PLE) was optimized and the physicochemical properties and in vitro bioaccessibility of the PLE were assessed. Under the optimized condition of 1:1.1 mol ratio of phytosterol and linoleoyl chloride at 80 °C for 1.5 h, the conversion rate of phytosterol reached 96.1%. Its solubility in oil increased 20 times, up to 33.8%. Also, peroxide value of PLE was much lower than linoleic acid (32.9 and 47.0 mmol/kg), which means better oxidative stability. Bioaccessibility of PLE was affected by time, concentration of bile extract, and dissolved medium. It was 4.93% alone, increased by 2.5 times compare to phytosterol; or 53.46% in oil, under the condition of 40 mg/mL bile extract for 120 min. In conclusion, under the tested condition, phytosterol conversion rate, its solubility in oil and bioaccessibility were improved significantly. The method showed great potential in manufacture high quality and quantity of PLE.

278 Background: To explore the efficacy and safety of neoadjuvant camrelizumab and chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma (ESCC) by an open label, single-arm, phase 2 clinical trial (ClinicalTrials.gov, Identifier number: NCT04506138). Methods: The eligible patients were arranged to receive 2 cycles of camrelizumab (200mg, day 1) combined with carboplatin (AUC = 5, day 1) and albumin paclitaxel (100 mg/m2, day 1, 8). All treatments were given intravenously in 3-week cycle. Patients underwent surgery within 4-6 weeks after the completion of neoadjuvant treatment. The primary endpoint was pathologic complete response (pCR), and secondary endpoints were major pathological response (MPR), safety and feasibility. The quality of life (QoL) was assessed by the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scale and EQ-5D-3L scale. Results: A total of 46 patients were recruited, among whom the clinical stage II, III, and IVa at baseline were 11 (23.9%), 33 (71.7%), and 2 (4.3%), respectively. Forty-five patients completed 2 cycles of neoadjuvant treatment. One patient received 1 cycle of neoadjuvant treatment and then lost to be followed up. Eight patients did not receive surgery. Except 1 patient accept exploratory surgery, 37 patients (37/46, 80.4%) achieved R0 resection. Eight patients (8/37, 21.6%) had pCR in both primary tumors and lymph nodes. MPR of primary tumors and lymph nodes was observed in 18 patients (18/37, 48.6%). During neoadjuvant treatment period, all 46 patients presented with treatment-related AEs (TRAEs) of any grade. Seven patients (7/46,15.2%) experienced grade ≥ 3 TRAEs. One patient suffered grade 5 immune-associated pneumonia. The most common TRAEs were anemia (32/46, 70.0%), followed by thrombocytopenia (15, 32.6%), leukopenia (14, 30.4%), neutropenia (13, 28.3%), rash (12, 26.1%), reactive cutaneous capillary endothelial proliferation (RCCEP) (7, 15.2%). The median interval between the first cycle of neoadjuvant treatment and surgery was 64 days (range, 56-77 days). Symptom scores in FACT-E scale were improved by neoadjuvant treatment (t = -2.60, P = 0.01). PD-L1 CPS (< 10 vs ≥ 10), PD-L1 TPS (< 1% vs ≥ 1%) and TMB (split according to top 20% of TMB value) had no effect on the pCR rate and MPR rate. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy achieved a promising pathologic response, which was effective and safe. Meanwhile, neoadjuvant treatment improved QoL of patients. Some larger multi-center trials are undergoing for further confirmation of efficacy and safety. Clinical trial information: NCT04506138.

The formation, stability and in vitro digestion of milk fat globule membrane (MFGM) proteins stabilized emulsions with 0.2 wt% β-carotene were investigated. The average particle size of β-carotene emulsions stabilized with various MFGM proteins levels (1%, 2%, 3%, 4%, 5% wt%) decreased with the increase of MFGM proteins levels. When MFGM proteins concentration in emulsions is above 2%, the average particle size of β-carotene emulsions is below 1.0 μm. A quite stable emulsion was formed at pH 6.0 and 7.0, but particle size increased with decrease in acidity of the β-carotene emulsion. β-carotene emulsions stabilized with MFGM proteins were stable with a certain salt concentrations (0–500 mMNaCl). β-carotene emulsions were quite stable to aggregation of the particles at elevated temperature and time (85 °C for 90 min). At the same time, β-carotene emulsions were stable against degradation under heat treatment conditions. In vitro digestion of β-carotene emulsion showed the mean particle size of β-carotene emulsions stabilized with MFGM proteins in the simulated stomach conditions and intestinal conditions is larger than that of initial emulsions and simulated mouth conditions. Confocal laser scanning microscopy of β-carotene MFGM proteins emulsions also showed the corresponding results to different vitro digestion model. There was a rapid release of free fatty acid (FFA) during the first 10 min and after this period, an almost constant 70% digestion extent was reached. Approximately 80% of β-carotene was released within 2 h of incubation under the simulated intestinal fluid. These results showed that MFGM protein can be used as a good emulsifier in emulsion stabilization, β-carotene rapid release as well as lipophilic bioactive compounds delivery.

The association between diabetes and cancer risk remains controversial. Hence, we examined whether midlife diabetes is related to the risk of cancer in late-life, and whether genetic and early-life environmental factors play a role in this association. This study included 25,154 twin individuals born in 1958 or earlier from the Swedish Twin Registry. Information on cancer diagnosis in late life (aged ≥ 65) during 1998-2014, was derived from the National Patient and Cancer Registries. Diabetes was ascertained based on self- or informant-reported history, patient registry and antidiabetic medication use. Midlife diabetes was defined when diabetes was diagnosed before 65 years. Data were analyzed following two strategies: (i) unmatched case-control analysis for all participants using generalized estimating equation (GEE) models, and (ii) co-twin control analysis for cancer-discordant twin pairs using conditional logistic regression. Overall, 1,766 (7.0%) had midlife diabetes and 5,293 (21.0%) had cancer in late-life. In multiadjusted GEE models, the odds ratios (95% CIs) of diabetes were 10.55 (2.95-37.67) for pharynx cancer, 5.78 (1.72-19.40) for small intestine cancer, 2.37 (1.14-4.91) for liver cancer and 0.48 (0.35-0.67) for prostate cancer. In people with diabetes, diabetes duration was dose-dependently associated with cancer risk. In conditional logistic regression analysis of 176 prostate cancer-discordant twin pairs, the association between midlife diabetes and prostate cancer in later life became stronger. Midlife diabetes increases the risk of pharynx, small intestine and liver cancers, but reduces prostate cancer risk in late life. Genetic and early-life environmental factors may partially contribute to the diabetes-prostate cancer association.

We aimed to study the association of long-terms trajectories of body mass index (BMI) with contemporaneous changes in multimorbidity development in older adults. Twelve-year BMI trajectories (2001–2013) were identified in subjects aged 60+ years from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K) using growth mixture models (N=2,189). Information on chronic diseases and multimorbidity was ascertained based on clinical examinations, lab tests, medications, and inpatient and outpatient medical records. Linear mixed models were used to study the association between BMI trajectories and the speed of chronic diseases accumulation, in general and by groups of cardiovascular and neuropsychiatric diseases. Eighty percent of the study population was included in a stable BMI trajectory, 18% in a slow-decline trajectory with an accelerated BMI decline from age 78 onwards, and 2% in a fast-decline trajectory that reached underweight values before age 85. A significantly higher yearly rate of chronic disease accumulation was observed in the fast-decline versus stable trajectories (β=0.221, 95% CI 0.090-0.352) after adjusting for age, sex, education and time to death. Subjects in the slow-decline trajectory showed a significantly higher rate of cardiovascular diseases accumulation (β=0.016, 95% CI 0.000-0.031); those in the fast-decline trajectory showed a faster accumulation of both cardiovascular (β=0.020, 95% CI -0.025, 0.064) and neuropsychiatric diseases (β=0.102, 95% CI 0.064-0.139), even if the former association did not reach statistical significance. Carefully monitoring older adults with sustained weight loss seems relevant given their likelihood to develop a phenotype of rapidly accumulating chronic -especially neuropsychiatric- diseases.

Aim: We aimed to estimate the extent to which diabetes shortens disability-free survival, and identify which factors may prolong disability-free survival in older adults with diabetes. Methods: A total of 2,216 disability-free participants aged ≥60 were followed up to 15 years. Diabetes was ascertained through antidiabetic drug use, medical records, or HbA1c ≥ 6.5%. Disability-free survival was defined as the survival until the occurrence of disability. Data on behaviours (healthy vs. unhealthy), leisure activities (active vs. inactive), and social network (moderate-to-rich vs. poor) were collected at baseline. A favourable (vs. unfavourable) lifestyle profile was defined as the presence of at least one of healthy behaviours, active engagement in leisure activities, and/or moderate-to-rich social network. Data were analysed with Cox regression and Laplace regression. Results: During the follow-up, 1,345 (60.7%) participants developed disability/death. Diabetes was related to the outcome (HR 1.29, 95% CI 1.06–1.57), and shortened 2.15 (1.02–3.27) years of median disability-free survival. Additionally, disability-free survival (95% CI) was shortened by 3.29 (1.21–5.36), 3.92 (2.08–5.76) and 1.66 (0.06–3.28) years for participants with diabetes plus unhealthy behaviours, inactive leisure activities, or poor social network, respectively (reference: no diabetes plus healthy behaviours, leisure activities, or moderate-to-rich social network). Among participants with diabetes, a favourable profile led to a non-significant HR of 1.19 (0.93–1.56) for disability/death and prolonged disability-free survival by 3.26 (2.33–4.18) years than those with unfavourable profile. Conclusions: Healthy lifestyle and/or moderate-to-rich social network attenuates the risk of diabetes on disability/death and prolongs disability-free survival in people with diabetes by 3 years.

A low guiding magnetic field facilitates the compactness of high power microwave sources, thus making it more practical. In order to reduce the guiding magnetic field, a focusing cathode is introduced in a Ka-band coaxial transit time oscillator in this paper. Based on the focusing cathode with a large impedance (>100 Ω) coaxial structure, a particle-in-cell simulation is conducted. When the diode voltage is 480 kV and the beam current is 3.62 kA, a microwave with an average power of 800 MW at 31.667 GHz is obtained under a guiding magnetic field of 0.5 T, the corresponding conversion efficiency is 46%, and the saturation time is 25 ns. Meanwhile, the maximum EZ field in the diode region is 350 kV/cm; thus, electron emission beyond the cathode region is avoided. When the guiding magnetic field is 0.5 T and the voltage varies in the range of 430–510 kV, the conversion efficiency is greater than 40%. In addition, when the voltage stays at 480 kV and the guiding magnetic field is in the range of 0.45–1.0 T, the conversion efficiency is also greater than 40%.

Introduction Interleukin-22 ( IL-22 ), an IL-10 family cytokine produced by T cells and innate lymphoid cells, is implicated in inflammation and tumorigenesis. In this study, we aimed to investigate the association of IL-22 polymorphisms with the colon cancer in a Chinese population. Materials and methods Five hundred forty colon cancer cases and 540 healthy controls were recruited in the case-control study. The fluorogenic 5' exonuclease assays were used for genotype analysis of three common polymorphisms (−429C/T, +1046 T/A and +1995 A/C) of the IL-22 gene. Results Colon cancer cases had a significantly higher frequency of IL-22 –429 TT genotype [odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.24, 2.30; P = 0.001] and −429 T allele (OR = 1.35, 95% CI = 1.14, 1.60; P = 0.001) than healthy controls. The findings are still emphatic by the Bonferroni correction ( P 0.017). When stratifying by the differentiation of colon cancer, we found that colon cancer cases with poor differentiation had a significantly higher frequency of IL-22 –429 TT genotype (OR = 1.45, 95% CI = 1.02, 2.07; P = 0.04). When stratifying by the tumor location, tumor size, growth pattern and TNM stage of colon cancer, we found no statistical association. The IL-22 +1046 T/A and IL-22 +1995 A/C gene polymorphisms were not associated with colon cancer. Conclusion Our findings suggested that the IL-22 −429C/T gene polymorphisms might be associated with colon cancer.

This work aimed to investigate the properties of emulsions prepared with milk fat globule membrane (MFGM) and its components, which are milk fat globule membrane proteins (MFGMPs) and milk fat globule membrane lipids (MFGMLs). The results demonstrated that the particle size of emulsions prepared with MFGM and MFGMPs decreased with increasing concentrations (from 1% to 4%); however, these droplet sizes were smaller than those prepared with MFGMLs of the same concentration. In addition, the emulsion prepared with MFGMLs showed a clear phase separation, as opposed to those from MFGM and MFGMPs. These results indicated that MFGMLs alone could not contribute to the stability of the emulsions. The microscopic images also confirmed that the droplet sizes of emulsions prepared with MFGM and MFGMPs were smaller than those prepared with MFGMLs. Moreover, the emulsions prepared with MFGM and MFGMPs had lower shear stress than those prepared with MFGMLs. The MFGM and MFGMPs were found to be sensitive to pH; t...

Hot stamping of patchwork blanks is flexible to adjust the mechanical properties of the component by applying patched blanks with different thicknesses and at different locations. Efficient process analysis needs a sophisticate finite element (FE) model for numerical simulation. A novel thermal–mechanical coupled FE model for hot stamping of patchwork blank was developed considering the thermal dependent failure of welding spots. The failure of the welding spots was evaluated by shear strength, which was characterized by tensile shear tests under different temperatures. Furthermore, the welding current and the arrangement of welding spots were determined to produce the patchwork blank. The locations and causes of forming defects, e.g. wrinkling and crack in hot stamping of a B-pillar with patchwork blanks, were analyzed. With numerical simulations and experimental investigations, the optimum process parameters were obtained. For predicting the thickness of typical sections and temperature distributions on the B-pillar for patchwork blank, the errors between numerical and experimental results were less than 10% in thickness distribution, and the maximum error was only 14.5% in temperature distribution. Experimental and simulation results show that the developed FE model is reliable and can be used to predict the results and improve the hot stamping process of patchwork blank.

This study aimed to investigate the stability of a complex formed with whey protein isolate (WPI) and chitosan under environmental stress. The optical density, particle size, zeta potential, chemical characteristics, electrostatic interactions, and surface morphology were evaluated for the stable complexes; the optimum conditions for the generation of the stable complex were 0.2% (wt/wt) whey protein with 0.05% (wt/wt) chitosan at pH 5.7. Under these conditions, the complex particle size was 217.8 ± 11.3 nm and the zeta potential was 16.7 ± 0.92 mV. The complex was formed through electrostatic interactions between the amine groups of chitosan (-NH3+) and carboxyl groups of whey protein (-COO−), and contained a porous network interspaced by heterogeneously sized vacuoles. The complex displayed stable physiochemical characteristics under environmental stresses including NaCl (0–75 mM) or sugar (0–5%) at ambient temperature and upon heating for 15 min at 25–65 °C, up to 65 °C for 30 min. Moreover, the complex could be stably stored for 30 d at 4 °C and for 20 d at 25 °C. The present results provide theoretical insights into the industrial production of chitosan-protein complexes and for microencapsulation of sensitive food or medicinal ingredients to increase their intestinal absorption.

In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently—resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the human γδ T cell family and its ligands before discussing parallels in mice. By covering the ontogeny and homeostasis of γδ T cells during their lifespan, we will better capture their evolution and responses to age-related stressors. Finally, we will identify knowledge gaps within these topics that can advance our understanding of the relationship between γδ T cells and aging, as well as age-related diseases such as cancer.

Introduction: The impact of prediabetes and diabetes on stroke and the development of dementia after a stroke remain unclear. Methods: A total of 2655 dementia-free participants (including a stroke-free cohort and a prevalent stroke cohort) were followed-up for 12 years. Dementia and post-stroke dementia were determined by clinical examinations and national registry data. Diabetes was ascertained via medical examination, medication use, medical records, or glycated hemoglobin (HbA1c) >= 6.5%. Prediabetes was defined as H bA1c >= 5.7% in diabetes-free participants. Results: In the stroke-free cohort, 236 participants developed ischemic stroke, and 47 developed post-stroke dementia. Diabetes was associated with ischemic stroke (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.16 to 2.67) and post-stroke dementia (HR 2.56, 95% CI 1.04 to 6.25). In the prevalent stroke cohort, diabetes was also related to dementia risk. Prediabetes was not significantly related to stroke or post-stroke dementia. Discussion: Diabetes, but not prediabetes, is associated with an increased risk of ischemic stroke and post-stroke dementia.