PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

Landscape of DNA damage response gene alterations in breast cancer: A comprehensive investigation.

BACKGROUND: DNA damage response (DDR) gene alterations are prevalent in breast cancer (BC) and important for treatment decisions. Intensive studies on DDR alterations in BC are still needed. METHODS: The authors included 438 patients with metastatic breast cancer from their next-generation sequencing database and 1091 patients with early-stage breast cancer from The Cancer Genome Atlas (TCGA) database in the analysis to characterize molecular alterations in the DDR pathway. RESULTS: Germline DDR mutations were more prevalent in younger patients and those with HER2-negative cancers. Tumors with germline DDR mutations more commonly had somatic DDR mutations, especially those with germline Fanconi anemia (FA) pathway mutations. Notably, 66.67% (four of six) of patients with germline PALB2 mutations had tumors that harbored somatic PALB2 mutations. No differences in prognosis were observed in patients with germline or tumor somatic DDR mutations compared to patients and tumors that were wild-type. Compared to early BC, the frequency of somatic DDR mutations in metastatic cancers was significantly higher (24.89% vs. 16.02%, p < .001). Higher tumor mutation burdens were observed in cancers with somatic DDR mutations, but not in cancers with germline DDR mutations. Furthermore, tumors with somatic DDR mutations showed an abundance of anticancer immunological phenotypes. Somatic FA and mismatch repair pathway mutations were associated with increased expression of immune checkpoint molecules. Although most DDR genes were significantly positively associated with expression of proliferation-related genes, PARP3 expression was negatively correlated with MKI67 expression. Lower PARP3 expression was associated with a worse prognosis in TCGA database by multivariate Cox analysis. CONCLUSIONS: Patients with germline FA mutations more frequently have tumors with somatic DDR mutations. Somatic DDR mutations lead to anticancer immunological phenotypes in BC. No differences in prognosis according to germline or somatic DDR mutations were found.

Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer.

BACKGROUND: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear. METHODS: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed. FINDINGS: First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer. CONCLUSIONS: After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.

Modeling and optimization of cascaded lasing in a holmium doped fluoride fiber laser with efficient output at 3.92†µm.

In this paper, we investigate the output performance of a continuous-wave Ho3+-doped fluoride fiber laser operating at 3.92 µm from the 5I5 → 5I6 transition of Ho3+ using numerical simulation. A double-clad Ho3+-doped fluoroindate fiber with a doping concentration of 10.0 mol.% is assumed, with direct pumping at 888 nm. We propose simultaneous lasing on the 5I6 → 5I7 transition to enhance the slope efficiency while reducing the threshold and heat accumulation. Simulation results indicate that a slope efficiency of 17% and a threshold of 2.5 W can be obtained using a 9 cm-long fiber. Moreover, with the heat accumulation reduced by >40%, watt level laser output can be achieved in this cascade system at room temperature without the gain fiber being damaged by heat accumulation. The theoretical maximum output power of 1.27 W is 6 times higher than the highest reported value (197 mW), which is limited by the fiber damage due to excess heat load.

Exploring the microbiota-Alzheimer's disease linkage using short-term antibiotic treatment followed by fecal microbiota transplantation.

Gut microbiota is proven to be involved in the development of beta amyloid (Aß) pathology in Alzheimer's disease (AD). Since there are difficulties in translating microbiota findings based on germ-free mice into clinical practice, here, we used short-term antibiotic cocktail treatment to develop a novel model with a near-germ-free status and without impacting Aß pathology. Three months old APPSWE/PS1ΔE9 mice were fed with antibiotic cocktails for two weeks by gavage to obtain a near "germ-free" status, and then received the donor fecal matter from the 16 months old APPSWE/PS1ΔE9 mice for 7 consecutive days. Fecal pellets were collected prior to antibiotics treatment, following antibiotic exposure, prior to and following fecal microbiota transplantation for gut microbiota analysis. Also, Aß pathology, astrocyte and microglia morphology were further explored. Pre-antibiotic-treated mice successfully allowed engraftment of gut microbiota following 7 consecutive days gavage with aged APPSWE/PS1ΔE9 mice microbiota. Microbiota reconstitution by transplantation was largely attributable to the donor source (e.g. g_Coriobacteriaceae and g_Clostridium) and led to a significant increase in Aß plaques. Surprisingly, astrocyte activation around Aß plaques was suppressed rather than microglia, the well-recognized plaque phagocytic cell type in Aß clearance, following microbiota engraftment. Our findings provide a novel framework for understanding the mechanisms of AD through the gut-brain axis and the translation of gut microbiota manipulation from bench to clinical practice.

Bifidobacterium Lactis Probio-M8 regulates gut microbiota to alleviate Alzheimer's disease in the APP/PS1 mouse model.

PURPOSE: Studies have shown that Alzheimer's disease is associated with significant alterations in the gut microbiota. But the effect of probiotics and/or prebiotics on Alzheimer's disease still remains to be explored. The aim of this study was to determine whether Bifidobacterium Lactis Probio-M8 could alleviate Alzheimer's disease pathophysiologies in the APP/PS1 transgenic mouse model. METHODS: 4-month old APP/PS1 mice were randomly put into two groups and fed with either Probio-M8 or saline water for 45 days. Fecal samples of mice were collected at the beginning and the end of the treatment period to determine the composition of the gut microbiota via 16S ribosomal RNA sequencing technology. The number and size of Aß plaques in the brain were quantified. In addition, Y maze, novel object recognition and nest building were employed to access cognitive function in the 8-months old APP/PS1 mice at the end of the treatment period. CONCLUSION: Our results demonstrated that Probio-M8 reduced Aß plaque burden in the whole brain and protected against gut microbiota dysbiosis. Furthermore, Probio-M8 could alleviate cognitive impairment in the APP/PS1 mouse.

Anxiety and depression are risk factors for recurrent pregnancy loss: a nested case-control study.

BACKGROUND: To evaluate the interaction of depression and anxiety with the development of recurrent pregnancy loss (RPL). METHODS: A nested case-control study involving 2558 participants was conducted with data from the prospective Miscarriage Woman Cohort study between 2017 and 2019 in the province of Gansu, China. The questionnaire data, self-rating anxiety scale and self-rating depression scale were collected after each participant's first miscarriage. Information on RPL outcomes was obtained from the medical records within the subsequent 2 years. All patients diagosed RPL were recruited as cases whilst a randomly selected group of women with only one miscarriage in the past were recruited as controls. The logistic regression and the interaction effects between anxiety and depression and RPL were analysed. RESULTS: The prevalence of anxiety (n = 325, 28.7% vs. n = 278, 19.5%) and depression symptoms (n = 550, 48.6% vs. n = 589, 41.3%) for the 1132 RPL cases were higher than 1426 non-RPL controls (P < 0.001). After adjusting for possible confounding variables, the odds ratio (OR) value, reflecting the multiplicative interaction, was 1.91 (95% CI 1.50-2.44, P < 0.001) for cases with both anxiety and depression symptoms compared with the non-RPL group. The relative excess risk of interaction value, reflecting the additive interaction between anxiety and depression to RPL was 1.15 (95% CI 0.32-4.21). Moreover, the adjusted OR for RPL cases with mild anxiety and severe depression was 2.77 (95% CI 1.07-44.14, P < 0.001), for RPL cases with severe anxiety and mild depression was 4.23 (95% CI 1.01-22.21, P < 0.001), for RPL cases with severe anxiety and moderate depression was 4.34 (95% CI 1.03-21.28, P < 0.001) and for RPL cases with severe anxiety and severe depression was 5.95 (95% CI 1.09-45.09, P < 0.05). CONCLUSIONS: Either depression or anxiety alone could increase the risk of subsequent RPL. Anxiety and depression had a synergistic effect after the first miscarriage which increased the development of subsequent RPL disease.

Single-pixel neural network object classification of sub-Nyquist ghost imaging.

A single-pixel neural network object classification scenario in the sub-Nyquist ghost imaging system is proposed. Based on the neural network, objects are classified directly by bucket measurements without reconstructing images. Classification accuracy can still be maintained at 94.23% even with only 16 measurements (less than the Nyquist limit of 1.56%). A parallel computing scheme is applied in data processing to reduce the object acquisition time significantly. Random patterns are used as illumination patterns to illuminate objects. The proposed method performs much better than existing methods for both binary and grayscale images in the sub-Nyquist condition, which is also robust to environment noise turbulence. Benefiting from advantages of ghost imaging, it may find applications for target recognition in the fields of remote sensing, military defense, and so on.

Mid infrared light treatment attenuates cognitive decline and alters the gut microbiota community in APP/PS1 mouse model.

Alzheimer's disease (AD) as the first most neurodegenerative disease in the elderly still has no effective therapy, suggesting that the intervention toolbox for AD should be expanded. One newly developed strategy involves the use of photobiomodulation, such as near infrared or far infrared light, which has proven to attenuate AD-associated pathology. However, the efficacy of mid infrared light (MIR) in treating AD is under investigated. With this in mind, we assessed the benefits of MIR light of peak wavelength 7.7-10 µm treatment on APP/PS1 transgenic mice. We found that APP/PS1 mice treated with MIR light had improved learning and memory abilities and reduced amyloid-ß (Aß) plaque load in the brain. We also surprisingly found that the gut microbiota composition in APP/PS1 mice treated with MIR light returned to normal (wild type mice) levels. Together, these findings suggested a novel non-invasive and promising avenue for AD treatment via photobiomodulation, and also proposed that future target for AD might be the gut microbiota via the brain-gut-skin axis.

The influence of cryoballoon manipulation on luminal esophageal temperature during ablation for atrial fibrillation.

BACKGROUND: Esophageal injury is related to a reduction in luminal esophageal temperature (LET) in second-generation cryoballoon (CB) ablation; however, methods to prevent these reductions in temperature have not been well characterized. METHODS: Esophageal temperature was continuously monitored using a LET probe in patients undergoing pulmonary vein (PV) isolation using the second-generation CB. A rotational maneuver of the CB was performed if the initial ablation resulted in a decrease of more than 4℃ in LET. The refrigerant injector near the distal CB pole was used as a fluoroscopic marker to measure the nearest distance between the CB and the LET probe. RESULTS: A total of 52 consecutive patients were enrolled in this study. The rotation was applied in 19 patients and 20 PVs (seven left superior pulmonary veins [LSPVs], seven left inferior PVs [LIPVs], and six right inferior PVs [RIPVs]) with a reduction in LET of more than 4℃ during freezing. The nadir temperature of CB applications was similar before and after CB rotation in all PVs. There was significant difference in the minimum LET before and after rotation during freezing in LSPVs (28.4 ± 3.7 vs 32.4 ± 2.3℃, P = .02), LIPVs (28.4 ± 1.4 vs 32.6 ± 2.7, P = .01) and RIPVs (26.1 ± 4.3 vs 34.0 ± 1.3℃, P = .002). The differences in mean balloon to LET distance were measured for all veins before and after rotation; LSPV (right anterior oblique [RAO], 11.0 ± 1.7 vs 13.8 ± 4.5 mm, P = .05); LIPV (RAO, 10.7 ± 4.3 vs 14.6 ± 6.1 mm, P = .03); RIPV (LAO, 11.8 ± 5.5 vs 14.2 ± 5.7 mm, P = .01). CONCLUSIONS: CB rotational maneuvers during ablation can prevent significant reduction in LET and may prevent esophageal injury during the procedure.

MicroRNA-206 Downregulates Connexin43 in Cardiomyocytes to Induce Cardiac Arrhythmias in a Transgenic Mouse Model.

BACKGROUND: MicroRNAs (miRNAs) are critical modulators of various physiological and pathological processes, but their role in cardiac arrhythmias remains yet to be completely understood. Connexin43 (Cx43) is an important cardiac gap junction protein and a potential target of miR-206, and downregulation of Cx43 induces ventricular tachyarrhythmias. METHODS: We investigated the effects of miR-206 overexpression on the adult mouse heart and in cardiac arrhythmias. Luciferase activity assay was employed to validate Cx43 as a direct target of miR-206. Expression of Cx43 was measured in cardiac muscle cell line HL-1 securely expressing miR-206. An inducible miR-206 overexpression mouse model was established to evaluate the in vivo effect of miR-206 on Cx43 expression and cardiac rhythm. RESULTS: MiR-206 directly recognised 3'-untranslated region of Cx43 mRNA to inhibit its expression in HL-1 cells. Induction of miR-206 in the adult mouse heart suppressed Cx43 expression, particularly in the atria and ventricle. Importantly, miR-206 overexpression also induced abnormal heart-rate and PR interval, and shortened life-span in the experimental mice. CONCLUSIONS: In cardiomyocytes, miR-206 is a upstream regulator of Cx43, and its overexpression downregulates Cx43 to induce abnormal heart-rate and PR interval.

Baicalin reduces blood lipids and inflammation in patients with coronary artery disease and rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of coronary artery disease (CAD) above the baseline. Baicalin possesses beneficial effects against both RA and CAD, but little is know on its clincial efficacy among patients manifesting both CAD and RA. METHODS: Three hundred seventy four patients with CAD and RA were randomized to receive either 500 mg baicalin or placebo orally everyday for 12 weeks. Lipid profile, cardiotrophin-1 (CT-1), high sensitivity C-reactive protein (hs-CRP), European League Against Rheumatism (EULAR) response were analyzed at the end of study period. RESULTS: After 12 week treatment, levels of triglycerides, total cholesterol, LDL-cholesterol and apolipoproteins, as well as CT-1 and hs-CRP, were all significantly improved in the baicalin group compared to the placebo group (1.12 ± 0.36 vs 1.87 ± 0.46 mmol/L, 2.87 ± 1.23 vs 3.22 ± 1.07 mmol/L, 1.38 ± 0.41 vs 1.16 ± 0.32 mmol/L, 1.31 ± 0.41 vs 1.23 ± 0.29 g/L, 42.9 ± 13.7 vs 128.4 ± 24.3 ng/mL, 1.64 ± 0.38 vs 3.9 ± 1.4 mg/dL, respectively). Significantly higher proportion of patients in the baicalin group (71%) reported good/moderate EULAR response than the placebo group (53%). CONCLUSION: Baicalin reduces blood lipids and inflammation in patients with both CAD and RA, supporting its further clinical application.

Caveolin-1 Plays an Important Role in the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Cardiomyocytes.

OBJECTIVES: Accumulating evidence has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) may transdifferentiate into cardiomyocytes, making BMSCs a promising source of cardiomyocytes for transplantation. However, little is known about the molecular mechanisms underlying myogenic conversion of BMSCs. METHODS: This study was designed to investigate the functional role of caveolin-1 in the cardiomyocyte differentiation of BMSCs and to explore the potential underlying molecular mechanisms. RESULTS: BMSC differentiation was induced by treatment with 10 µM 5-azacytidine, and immunofluorescence assay showed that the expression of cardiomyocyte marker cardiac troponin T (cTnT) was significantly increased compared with a control group. Meanwhile, an increased caveolin-1 expression was found during the 5-azacytidine-induced BMSC differentiation. Additionally, the role of caveolin-1 in the differentiation process was then studied by using caveolin-1 siRNAs. We found that silencing caveolin-1 during induction remarkably enhanced the expression of cardiomyocyte marker genes, including cTnT, Nkx2.5 (cardiac-specific transcription factor), α-cardiac actin and α-myosin heavy chain (α-MHC). Moreover, we observed that downregulation of caveolin-1 was accompanied by inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation. CONCLUSIONS: Taken together, these findings demonstrate that caveolin-1 plays an important role in the differentiation of BMSCs into cardiomyocytes in conjunction with the STAT3 pathway.

MiR-214 regulates the pathogenesis of patients with coronary artery disease by targeting VEGF.

Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. We aimed to investigate the correlation between the levels of circulating miR-214 and the expression of vascular endothelial growth factor (VEGF) in the pathogenesis of coronary heart disease patients to further explore the mechanism involved in the vasculogenesis. Three different cohorts, including 13 acute myocardial infarction patients, 176 angina pectoris patients, and 127 control subjects, were enrolled to investigate the expression levels of circulating miR-214 in patients with myocardial ischemia and also the relationship between plasma miR-214 and severity of coronary stenosis. Plasma miR-214 levels of participants were examined by real-time quantitative PCR. Simultaneously, plasma cardiac troponin I concentrations were measured by ELISA assays. We further detected the correlation of miR-214 and VEGF by molecular and animal assays. MiR-214 was enriched in not only diseased endothelial progenitor cells (EPCs) but also the plasma of coronary artery disease (CAD) patients. Besides, we found out miR-214 was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-214 to the 39-UTR of VEGF mRNA. Knockdown of miR-214 not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but also further promoted blood flow recovery in ischemic limbs of mice. Circulating miR-214 may be a new biomarker for CAD and as a potential diagnostic tool. And increased miR-214 level may be used to predict the presence and severity of coronary lesions in CAD patients.

Effects of C-Reactive Protein on the Cardiac Differentiation of Mouse Embryonic Stem Cells.

A major challenge in stem cell therapy for cardiac repair is how to obtain normally functioning stem cell-derived cardiomyocytes. We aim to address the effects of C-reactive protein (CRP) on the cardiac differentiation of embryonic stem (ES) cells. Immunostaining, Western blotting and electrophysiology were employed. A hundred fifty milligran/liters CRP significantly reduced the percentage of cardiomyocytes differentiated from mouse ES cells, while it may also promote sarcomere development compared to 30 mg/L CRP treatment. Further examination of the action potential (AP) in individual ES cell-derived cardiomyocytes showed that there exist three types of cardiomyocytes: artial-like (A-like), ventricular-like (V-like), and pacemaker-like (P-like). A hundred fifty milligran/liters CRP treatment decreased the P-like cardiomyocytes, whereas it increased the A-like. Such inhibitory effect and alteration were not significant at 30 mg/L CRP treatment. Moreover, 150 mg/L CRP significantly increased the APD90 (90% of duration of AP) and decreased the spontaneous firing rate of AP in P-like cells, while had little effect on other electrophysiological characteristics, including APA (AP amplitude) and MDP (maximum diastolic potential). This study revealed the effect of CRP on the cardiac differentiation of ES cells. It provides an in vitro pathological model and may be of importance to the future work of ES cell-based therapy in clinical applications and in vivo pathological studies.

Study on optimization of multi-UAV nucleic acid sample delivery paths in large cities under the influence of epidemic environment.

In the context of global novel coronavirus infection, we studied the distribution problem of nucleic acid samples, which are medical supplies with high urgency. A multi-UAV delivery model of nucleic acid samples with time windows and a UAV (Unmanned Aerial Vehicle) dynamics model for multiple distribution centers is established by considering UAVs' impact cost and trajectory cost. The Golden Eagle optimization algorithm (SGDCV-GEO) based on gradient optimization and Corsi variation is proposed to solve the model by introducing gradient optimization and Corsi variation strategy in the Golden Eagle optimization algorithm. Performance evaluation by optimizing test functions, Friedman and Nemenyi test compared with Golden Jackal Optimization (GJO), Hunter-Prey Optimization (HPO), Pelican Optimization Algorithm (POA), Reptile Search Algorithm (RSA) and Golden Eagle Optimization (GEO), the convergence performance of SGDCV-GEO algorithm was demonstrated. Further, the improved RRT (Rapidly-exploring Random Trees) algorithm is used in the UAV path planning, and the pruning process and logistic chaotic mapping strategy are introduced in the path generation method. Finally, simulation experiments are conducted based on 8 hospitals and 50 randomly selected communities in the Pudong district of Shanghai, southern China. The experimental results show that the developed algorithm can effectively reduce the delivery cost and total delivery time compared with simulated annealing algorithm (SA), crow search algorithm (CSA), particle swarm algorithm (PSO), and taboo search algorithm (TS), and the developed algorithm has good uniformity, robustness, and high convergence accuracy, which can be effectively applied to the multi-UAV nucleic acid sample delivery path optimization in large cities under the influence of an epidemic environment.

Optimization of urban emergency support material distribution under major public health emergencies based on improved sparrow search algorithm.

The outbreak of major public health emergencies such as the coronavirus epidemic has put forward new requirements for urban emergency management procedures. Accuracy and effective distribution model of emergency support materials, as an effective tool to inhibit the deterioration of the public health sector, have gradually become a research hotspot. The distribution of urban emergency support devices, under the secondary supply chain structure of "material transfer center-demand point," which may involve confusing demands, is studied to determine the actual situation of fuzzy requests under the impact of an epidemic outbreak. An optimization model of urban emergency support material distribution, based on Credibility theory, is first constructed. Then an improved sparrow search algorithm, ISSA, was designed by introducing Sobol sequence, Cauchy variation and bird swarm algorithm into the structure of the classical SSA. In addition, numerical validation and standard test set validation were carried out and the experimental results showed that the introduced improved strategy effectively improved the global search capability of the algorithm. Furthermore, simulation experiments are conducted, based on Shanghai, and the comparison with existing cutting-edge algorithms shows that the designed algorithm has stronger superiority and robustness. And the simulation results show that the designed algorithm can reduce vehicle cost by 4.83%, time cost by 13.80%, etc. compared to other algorithms. Finally, the impact of preference value on the distribution of emergency support materials is analyzed to help decision-makers to develop reasonable and effective distribution strategies according to the impact of major public health emergencies. The results of the study provide a practical reference for the solution of urban emergency support materials distribution problems.

The updates on metastatic mechanism and treatment of colorectal cancer.

Colorectal cancer (CRC) is a main cause of cancer death worldwide. Metastasis is a major cause of cancer-related death in CRC. The treatment of metastatic CRC has progressed minimally. However, the potential molecular mechanisms involved in CRC metastasis have remained to be comprehensively clarified. An improved understanding of the CRC mechanistic determinants is needed to better prevent and treat metastatic cancer. In this review, based on evidence from a growing body of research in metastatic cancers, we discuss the cellular and molecular mechanisms involved in CRC metastasis. This review reveals both the molecular mechanisms of metastases and identifies new opportunities for developing more effective strategies to target metastatic relapse and improve CRC patient outcomes.

A study of clinical and molecular characteristics in bilateral primary breast cancer.

BACKGROUND: Bilateral primary breast cancer (BPBC) is a rare type of breast cancer. Studies on the clinicopathologic and molecular characteristics of BPBC in a metastatic context are very limited. METHODS: A total of 574 unselected metastatic breast cancer patients with clinical information were enrolled in our next-generation sequencing (NGS) database. Patients with BPBC from our NGS database were regarded as the study cohort. In addition, 1467 patients with BPBC and 2874 patients with unilateral breast cancer (UBC) from the Surveillance, Epidemiology, and End Results (SEER) public database were also analyzed to determine the characteristics of BPBC. RESULTS: Among the 574 patients enrolled in our NGS database, 20 (3.5%) patients had bilateral disease, comprising 15 (75%) patients with synchronous bilateral disease and 5 (25%) patients with metachronous bilateral disease. Eight patients had bilateral hormone receptor-positive (HR+)/human epidermal growth factor receptor-negative (HER2-) tumors, and three had unilateral HR+/HER2- tumors. More HR+/HER2- tumors and lobular components were found in BPBC patients than in UBC patients. The molecular subtype of the metastatic lesions in three patients was inconsistent with either side of the primary lesions, which suggested the importance of rebiopsy. Strong correlations in clinicopathologic features between the left and right tumors in BPBC were exhibited in the SEER database. In our NGS database, only one BPBC patient was found with a pathogenic germline mutation in BRCA2. The top mutated somatic genes in BPBC patients were similar to those in UBC patients, including TP53 (58.8% in BPBC and 60.6% in UBC) and PI3KCA (47.1% in BPBC and 35.9% in UBC). CONCLUSIONS: Our study suggested that BPBC may tend to be lobular carcinoma and have the HR+/HER2- subtype. Although our study did not find specific germline and somatic mutations in BPBC, more research is needed for verification.

Trx CDSP32-overexpressing tobacco plants improves cadmium tolerance by modulating antioxidant mechanism.

The effects of overexpression of the thioredoxin-like protein CDSP32 (Trx CDSP32) on reactive oxygen species (ROS) metabolism in tobacco leaves exposed to cadmium (Cd) were studied by combining physiological measures and proteomics technology. Thus, the number of differentially expressed proteins (DEPs) in plants overexpressing the Trx CDSP32 gene in tobacco (OE) was observed to be evidently lower than that in wild-type (WT) tobacco under Cd exposure, especially the number of down-regulated DEPs. Cd exposure induced disordered ROS metabolism in tobacco leaves. Although Cd exposure inhibited the activities of superoxide dismutase (SOD), catalase (CAT), and l-ascorbate peroxidase (APX) and the expression of proteins related to the thioredoxin-peroxiredoxin (Trx-Prx) pathway, the increase in the activities of peroxidase (POD), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione reductase (GR), glutathione peroxidase (GPX), and glutathione S-transferase (GST) and their protein expression levels played an important role in the physiological response to Cd exposure. Notably, Trx CDSP32 was observed to alleviate the decrease in the expression and activities of SOD and CAT caused by Cd exposure and enhance the function of POD. Trx CDSP32 was observed to increase the H2O2 scavenging capacity of the ascorbic acid-glutathione (AsA-GSH) cycle and Trx-Prx pathway under Cd exposure, and it can especially regulate 2-Cys peroxiredoxin (2-Cys Prx) protein expression and thioredoxin peroxidase (TPX) activity. Thus, overexpression of the Trx CDSP32 gene can alleviate the oxidative damage that occurs in tobacco leaves under Cd exposure by modulating antioxidant defense systems.