Dynamic Hybrid Module-Driven NK Cell Stimulation and Release for Tumor Immunotherapy.

Natural killer (NK) cells have become a powerful candidate for adoptive tumor immunotherapy, while their therapeutic efficacy in solid tumors remains unsatisfactory. Here, we developed a hybrid module with an injectable hydrogel and hydroxyapatite (HAp) nanobelts for the controlled delivery of NK cells to enhance the therapy of solid tumors. Surface-functionalized HAp nanobelts modified with agonistic antibodies against NKG2D and 4-1BB and cytokines IL-2 and IL-21 support survival and dynamic activation. Thus, the HAp-modified chitosan (CS) thermos-sensitive hydrogel not only improved the retention of NK cells for more than 20 days in vivo but also increased NK cell function by more than one-fold. The unique architecture of this biomaterial complex protects NK cells from the hostile tumor environment and improves antitumor efficacy. The generation of a transient inflammatory niche for NK cells through a biocompatible hydrogel reservoir may be a conversion pathway to prevent cancer recurrence of resectable tumors.

The Role of Parent-Child Attachment, Hostile Attribution Bias in Aggression: A Meta-Analytic Review.

Parent-Child Attachment (PCA) and Hostile Attribution Bias (HAB) are closely related to aggression, but findings regarding their relationships are inconsistent. There is a lack of understanding of the underlying mechanism between PCA and aggression. This review employed meta-analysis approaches to investigate the associations between PCA and aggression, as well as between HAB and aggression, and the mechanism for the PCA-aggression association. An article search was conducted in CNKI, PubMed, PsycINFO, Web of Science, ProQuest, and Google Scholar. Totally, 118 studies involving general populations and those at high risk for aggression were included. Results revealed negative associations between Parent-Child Attachment Security (PCAS) and aggression (ρ = -.267, p < .001) and positive associations between Parent-Child Attachment Insecurity (PCAI) and aggression (ρ = .240, p < .05). HAB and aggression were found to be positively associated (ρ = .303, p < .001). As for the PCAS-aggression association, a larger effect size was found in females than in males. The HAB-reactive aggression association was stronger than the HAB-proactive aggression association. In Eastern culture, the association between HAB and aggression was stronger than in Western culture. HAB mediated the association between PCAS and aggression. Our findings contribute to the understanding of the occurrence and development of aggression by establishing an association between attachment theory and the social information processing model. The practical implications include interventions targeting cultivating PCAS and alleviating HAB, which might serve as effective ways to reduce aggression, yet aggression type, gender, and cultural background should be taken into consideration.

Nanorobot-Mediated Synchronized Neuron Activation.

Interactions between active materials lead to collective behavior and even intelligence beyond the capability of individuals. Such behaviors are prevalent in nature and can be observed in animal colonies, providing these species with diverse capacities for communication and cooperation. In artificial systems, however, collective intelligence systems interacting with biological entities remains unexplored. Herein, we describe black (B)-TiO2@N/Au nanorobots interacting through photocatalytic pure water splitting-induced electrophoresis that exhibit periodic swarming oscillations under programmed near-infrared light. The periodic chemical-electric field generated by the oscillating B-TiO2@N/Au nanorobot swarm leads to local neuron activation in vitro. The field oscillations and neurotransmission from synchronized neurons further trigger the resonance oscillation of neuron populations without synaptic contact (about 2 mm spacing), in different ways from normal neuron oscillation requiring direct contact. We envision that the oscillating nanorobot swarm platforms will shed light on contactless communication of neurons and offer tools to explore interactions between neurons.

Prognostic impact of high-risk factors and KRAS mutation in patients with stage II deficient mismatch repair colon cancer: a retrospective cohort study.

Background: Deficient mismatch repair (dMMR) is associated with a good prognosis in patients with stage II colon cancer and observation is recommended after surgery in these patients. In contrast, patients with high-risk factors and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with a poor prognosis in colon cancer. However, the prognosis and treatment of patients with dMMR colon cancer combined with high-risk factors or KRAS mutation remains unclear. This study aimed to evaluate whether patients with dMMR colon cancer combined with high-risk factors or KRAS mutation require further treatment. Methods: This single-center retrospective study included patients who received radical surgical resection and mismatch repair (MMR) immunohistochemical detection at The Sixth Affiliated Hospital of Sun Yat-sen University between May 2011 and March 2021. The high-risk factors and KRAS mutation were assessed by clinicopathological data and targeted sequencing. Associations with disease-free survival (DFS) were evaluated using multivariable Cox models. Results: Among the 1,357 patients with stage II colorectal cancer included, 226 of these patients had dMMR. Patients in the dMMR group were more likely to be younger [<50 years: odds ratio (OR) =0.401, 95% CI: 0.288-0.558, P<0.001], with poor differentiation (OR =5.800, 95% CI: 3.437-9.787, P<0.001), no perineural invasion (OR =0.132, 95% CI: 0.047-0.368, P<0.001), and more than 12 excised lymph nodes (OR =0.427, 95% CI: 0.188-0.968, P=0.042). The disease-free survival (DFS) of patients with stage II dMMR colon cancer with high-risk factors was similar to that of patients without high-risk factors (hazard ratio (HR) =1.285, 95% CI: 0.273-6.051, P=0.607). A total of 836 patients had complete data regarding KRAS status. Compared with KRAS wild-type patients, patients with KRAS gene mutation had a trend of poor prognosis in patients with stage II colon cancer (HR=1.483, 95% CI: 0.983-2.239, P=0.061). In addition, dMMR appeared to be a protective factor in patients with KRAS mutation (HR =0.138, 95% CI: 0.019-1.002, P=0.0501). Conclusions: The survival of patients with stage II dMMR colon cancer with high-risk factors was similar to that of patients without high-risk factors, regardless of the presence of KRAS mutation.

[Anti-photoaging effects and mechanisms of active ingredients of Chinese medicine: a review].

Skin photoaging is exogenous aging caused by long-term ultraviolet radiation, which not only affects skin appearance, but also has a close relationship with the development of skin cancer. Saponins, flavonoids, polyphenols, polysaccharides, and extracts of Chinese medicine have been found to have anti-skin photoaging effects in recent studies. Various mechanisms such as anti-oxidative stress damage, inhibition of matrix metalloproteinase expression, promotion of collagen synthesis, inhibition of inflammatory response, DNA damage repair, enhancement of cell autophagy, and inhibition of melanin synthesis can improve the symptoms of skin photoaging and delay the photoaging process. With the active ingredients of Chinese medicine for anti-skin photoaging as the entry point, the study systematically discussed the research progress of the mechanisms underlying the anti-photoaging effects of active ingredients of Chinese medicine in recent years, in order to provide theoretical reference for the development of new anti-photoaging drugs and methods.

Proteome profiling reveals changes in energy metabolism, transport and antioxidation during drought stress in Nostoc flagelliforme.

BACKGROUND: Drought is an important abiotic stress that constrains the growth of many species. Despite extensive study in model organisms, the underlying mechanisms of drought tolerance in Nostoc flagelliforme remain elusive. RESULTS: We characterized the drought adaptation of N. flagelliforme by a combination of proteomics and qRT-PCR. A total of 351 differentially expressed proteins involved in drought stress adaptation were identified. It was found that the expression of several nutrient influx transporters was increased, including molybdate ABC transporter substrate binding protein (modA), sulfate ABC transporter substrate-binding protein (sbp) and nitrate ABC transporter (ntrB), while that of efflux transporters for toxic substances was also increased, including arsenic transporting ATPase (ArsA), potassium transporter (TrkA) and iron ABC transporter substrate-binding protein (VacB). Additionally, photosynthetic components were reduced while sugars built up during drought stress. Non-enzymatic antioxidants, orange carotenoid protein (OCP) homologs, cytochrome P450 (CYP450), proline (Pro) and ascorbic acid (AsA) were all altered during drought stress and may play important roles in scavenging reactive oxygen species (ROS). CONCLUSION: In this study, N. flagelliforme may regulates its adaptation to drought stress through the changes of protein expression in photosynthesis, energy metabolism, transport, protein synthesis and degradation and antioxidation. HIGHLIGHTS: • A total of 351 DEPs involved in adaptation to drought stress were identified. • Changes in the expression of six OCP homologs were found in response to drought stress. • Differential expression of transporters played an important role in drought stress adaptation. • Most PSII proteins were downregulated, while PSI proteins were unchanged in response to drought stress. • Sugar metabolism was upregulated in response to drought stress.

Study on Influencing Factors of Frailty in Elderly Patients with Type II Diabetes.

The purpose of this study was to analyze the influencing factors of frailty in elderly patients with type II diabetes. 332 elderly patients with type II diabetes admitted to our hospital from May 2018 to December 2019 were selected as the study subjects. The degree of frailty was evaluated by the Fried fragility phenotype scale, and the general information and the clinical data of patients were collected by inquiry and questionnaire survey. After that, all the data were analyzed by SPSS 20.0. Univariate analysis showed that there were significant differences in age, medication types, dietary habits, exercise tolerance, exercise capacity, body balance, coordination ability, urinary incontinence, anxiety, etc., in elderly patients with type II diabetes who suffered from different degrees of frailty (P < 0.01). In addition, there were significant differences in the presence of coronary heart disease, heart failure, atrial fibrillation, pulmonary diseases, osteoarticular diseases, anemia, and other blood diseases of elderly patients with type II diabetes who suffered from different degrees of frailty (P < 0.01). Multiple Logistic regression analyses indicated that weakened exercise tolerance, reduced exercise capacity, atrial fibrillation, anemia, and other blood diseases were the influencing factors of the frailty in elderly patients with type II diabetes. The degree of frailty in elderly patients with diabetes is affected by many factors, such as exercise tolerance, exercise capacity, atrial fibrillation, anemia, and other blood diseases; thus, reasonable intervention should be implemented for elderly patients with type II diabetes according to the influencing factors so as to effectively relieve frailty.

mFOLFOXIRI versus mFOLFOX6 as neoadjuvant chemotherapy in locally advanced rectal cancer: A Propensity Score Matching Analysis.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC). However, CRT failed to impact metastatic recurrence and the risk of side effects on bowel and genitourinary remained a concern. Neoadjuvant chemotherapy alone with mFOLFOX6 or FOLFOXIRI had been investigated in LARC. Here, we tried to compare the efficacy of mFOLFOXIRI with mFOLFOX6 as neoadjuvant chemotherapy in LARC. PATIENTS AND METHODS: Between January 2014 and December 2019, patients with LARC receiving neoadjuvant chemotherapy with mFOLFOXIRI or mFOLFOX6 were retrospective analyzed, including data from a prospective trial (NCT02217020). All patients underwent total mesorectal excision (TME). The propensity-score matching was preformed to adjust baseline potential confounders and to estimate differences in outcomes between patients receiving mFOLFOXIRI and mFOLFOX6. Survival analysis was done using Kaplan-Meier analysis and Cox proportional regression analysis. RESULTS: The median follow-up time was 31.1 months. After propensity score matching, 156 patients were available for comparison in each group. The pathological complete response (pCR) rate was 17.9% vs. 5.1% (P< .001), the incidence rate of anastomotic fistula was 3.2% vs. 9% (P = .03), the 3 year disease-free survival (DFS) rate was 75% vs. 66.7% (P = .047) and the distant metastasis rate was 16.4% versus 26.6% (P = .013) for mFOLFOXIRI and mFOLFOX6 group, respectively. Patients receiving mFOLFOXIRI had higher incidence of grade III and/or IV nausea and/or vomiting (7.6% vs. 2.5%, P = .04). CONCLUSIONS: Neoadjuvant mFOLFOXIRI regimens improved pCR rate and survival outcome, reduced the rate of distant metastasis and anastomotic fistula when comparing with propensity-score matched controls of mFOLFOX6 neoadjuvant chemotherapy. MICROABSTRACT: This trial assessed the short-term and long-term effects of neoadjuvant chemotherapy with mFOLFOXIRI and mFOLFOX6 in patients with locally advanced rectal cancer. Comparing with propensity-score matched historical control of chemoradiotherapy, neoadjuvant mFOLFOXIRI chemotherapy was well tolerated and led to higher rates of 3 year disease-free survival in patients with locally advanced rectal cancer.

Placental mtDNA copy number and methylation in association with macrosomia in healthy pregnancy.

INTRODUCTION: Fetal growth and development depend on metabolic energy from placental mitochondria. However, the impact of placental mitochondria on the occurrence of macrosomia remains unclear. We aimed to explore the association between macrosomia without gestational diabetes mellitus (non-GDM) and changes in placental mitochondrial DNA (mtDNA) copy number and methylation. METHODS: Fifty-four newborns with macrosomia and 54 normal birthweight controls were enrolled in this study. Placental mtDNA copy number and mRNA expression of nuclear genes related to mitochondrial replication or ATP synthesis-related genes were measured by real-time quantitative polymerase chain reaction (qPCR). Methylation levels of the non-coding regulatory region D-loop and ATP synthesis-related genes were detected by targeted bisulfite sequencing. RESULTS: Newborns with macrosomia had lower placental mtDNA copy number and higher methylation rates of the CpG15 site in the D-loop region (D-CpG15) and CpG6 site in the cytochrome C oxidase III (COX3) gene (COX3-CpG6) than normal birth weight newborns. After adjusting for potential covariates (gestational age, prepregnancy BMI, and infant sex), decreased placental mtDNA copy number (adjusted odds ratio [aOR] = 2.09, 95% confidence interval [CI] 1.03-4.25), elevated methylation rate of D-CpG15 (aOR = 2.06, 95% CI 1.03-4.09) and COX3-CpG6 (aOR = 2.13, 95% CI 1.08-4.20) remained significantly associated with a higher risk of macrosomia. DISCUSSION: Reduced mtDNA copy number and increased methylation levels of specific loci at mtDNA would increase the risk of macrosomia. However, the detailed molecular mechanism needs further identification.

Relationships Between Placental Lipid Activated/Transport-Related Factors and Macrosomia in Healthy Pregnancy.

To assess associations between infants with macrosomia and placental expression levels of lipid activated/transport-related factors and umbilical cord blood lipid concentrations in healthy pregnancy. We conducted a case-control study of 38 macrosomic neonates (MS group) and 39 normal-birth-weight newborns (NC group) in a healthy pregnancy. Cord blood lipid levels were measured by automatic biochemical analyzer, mRNA and protein expression levels of placental lipid activated/transport-related factors were determined by real-time polymerase chain reaction and western blot, respectively. Compared with NC group, cord blood total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and non-esterified fatty acid (NEFA) concentrations were decreased in the MS group. The mRNA and protein expression levels of placental peroxisome proliferator-activated receptors (PPARα, PPARγ), plasma membrane fatty acid-binding protein (FABPpm), and fatty acid translocase (FAT/CD36) were significantly higher in the MS group than the NC group. And there was a weak positive correlation between the expression of PPARγ, FABP4, and FABP3 mRNA in the placenta and the HDLC (rs = 0.439; P = 0.005), NEFA (rs = 0.342; P = 0.041), and TG (rs = 0.349; P = 0.034) levels in the cord blood in the MS group, respectively. After multivariate adjustment, the logistic regression analysis showed that high placental PPARα (adjusted odds ratio [AOR] = 3.022; 95% confidence interval [CI] 1.032-8.853) and FAT/CD36 (AOR=2.989; 95%CI 1.029-8.679) and low LDLC concentration in the cord blood (AOR=0.246; 95%CI 0.080-0.759) increased the risk of macrosomia. The increased PPARα and FAT/CD36 expression levels may influence the occurrence of fetal macrosomia through regulating placental lipid transport.

Comparison of outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal GIST: An inverse probability of treatment weighting analysis.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients. METHODS: Eighty-five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis. RESULTS: The response rate to neoadjuvant imatinib was 65.9%. After the IPTW-adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence-free survival (DRFS) and disease-specific survival (DSS) compared with those who underwent upfront surgery (5-year DRFS 97.8 vs. 71.9%, hazard ratio [HR], 0.15; 95% CI, 0.03-0.87; p = 0.03; 5-year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01-0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5-year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03-1.15). CONCLUSIONS: In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor-related deaths when compared to upfront surgery and adjuvant imatinib alone.

Mucinous Adenocarcinoma Predicts Poor Response and Prognosis in Patients With Locally Advanced Rectal Cancer: A Pooled Analysis of Individual Participant Data From 3 Prospective Studies.

PURPOSE: To evaluate the predictive implications and prognosis of mucinous adenocarcinoma (MAC) in locally advanced rectal cancer (LARC) with intensified neoadjuvant treatment. METHODS: Individual patient data of LARC patients from 3 prospective clinical trials was analyzed. Neoadjuvant treatment regimens comprised chemoradiotherapy (CRT) with fluorouracil (5-FU) or mFOLFOX6, neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI. The postoperative pathological result, local recurrence and disease-free survival (DFS) were retrospectively analyzed in patients with MAC and adenocarcinoma (AC) with neoadjuvant treatment. RESULTS: Totally, 743 patients were recruited, with 620 patients eligible for analysis. Fifty-three (8.5%) patients were MAC. The pathological complete response (pCR) rate and tumor downstaging rate (ypStage 0-I) between MAC and AC patients was 7.5% vs. 22.0% (P = .01) and 20.8% vs. 48.7% (P < .001), respectively. Among patients receiving preoperative CRT with 5FU or mFOLFOX6, the pCR rate and tumor downstaging rate between MAC and AC patients was 11.1% vs. 27.3% (P = .03) and 23.7% vs. 52.6% (P = .001), respectively. Regarding neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI, the pCR rate and tumor downstaging rate was 0 vs.13.2% (P = .11) and 11.8% vs. 42.5% (P = .03) between MAC and AC group, respectively. With the median follow-up time of 38.9 months, the 3-year DFS and 3-year locoregional recurrence rate was 58.4% vs. 77.6% (P = .02) and 26.0% vs. 5.7% (P = .001) in the MAC and AC group, respectively. MAC (hazard ratio [HR] 1.85, 95% confidence interval [CI], 1.15-2.98), PNI (HR 3.23, 95% CI, 1.85-5.72) and LVI (HR 2.04, 95% CI, 1.02-4.08) were independent prognosis factors and were associated with worse DFS. CONCLUSIONS: Patients with MAC of the rectum are associated with a lower pCR rate and tumor downstaging rate, higher incidence of local recurrence, and poorer DFS with neoadjuvant treatment.

Oncological and prognostic impact of lymphovascular invasion in Colorectal Cancer patients.

Objectives: Lymphovascular invasion (LVI) is correlated with unfavorable prognoses in several types of cancers. We aimed to identify the informative features associated with LVI and to determine its prognostic value in colorectal cancer (CRC) patients. Methods: We retrospectively analyzed 1,474 CRC patients admitted in Wuhan Union Hospital between 2013 and 2017 as the development cohort and 549 CRC patients from The Cancer Genome Atlas (TCGA) database as the validation cohort. Logistical and Cox regression analyses were conducted to determine the oncological and prognostic significance of LVI in CRC patients. A survival nomogram based on LVI status was established using the Wuhan Union cohort and validated using TCGA cohort. Results: The LVI detection rates were 21.64% in the Wuhan Union cohort and 35.15% in TCGA cohort. LVI was closely correlated with advanced T stage, N stage, and TNM stage. LVI positivity was an independent biomarker for unfavorable overall survival (hazard ratio [HR]=2.25, 95% confidence interval [CI]=1.70-2.96, P<0.0001) and worse disease-free survival (HR=2.34, 95% CI=1.76-3.12, P<0.0001) in CRC patients. The survival nomogram incorporating LVI exhibited good predictive performance and reliability in the Wuhan Union cohort and TCGA cohort. Conclusion: LVI is a significant indicator of advanced stage and is remarkably correlated with worse prognosis in CRC patients. The survival nomogram incorporating LVI may assist clinicians to better strategize the therapeutic options for patients with CRC.