An Accessible Pre-Rehabilitation Bundle for Patients Undergoing Elective Heart Valve Surgery with Limited Resources: The TIME Randomized Clinical Trial.

Background: Despite gradually increasing evidence for pre-rehabilitation for heart valve surgery, it remains underused, especially in developing countries with limited resources. The study aimed to investigate the feasibility and effects of an innovative three-day pre-rehabilitation bundle for patients undergoing elective heart valve surgery. Methods: This was a single-center, assessor-blind, randomized clinical trial. A total of 165 patients were randomly assigned to either usual care (control group, n = 83) or usual care with an additional 3-day pre-rehabilitation bundle (Three-day of Inspiratory muscle training, aerobic Muscle training, and Education (TIME) group, n = 82). The main outcome of the study was the incidence of postoperative pulmonary complications (PPCs). Secondary outcomes included the feasibility of the intervention, duration of the non-invasive ventilator, length of stay, and PPCs-related medical costs on discharge. Results: Of 165 patients 53.94% were male, the mean age was 63.41 years, and PPCs were present in 26 of 82 patients in the TIME group and 44 of 83 in the control group (odds ratio (OR), 0.60; 95% CI, 0.41-0.87, p = 0.006). The feasibility of the pre-rehabilitation bundle was good, and no adverse events were observed. Treatment satisfaction and motivation scored on 10-point scales, were 9.1 ± 0.8 and 8.6 ± 1.4, respectively. The TIME group also had fewer additional PPCs-related medical costs compared to the control group (6.96 vs. 9.57 thousand CNY (1.01 vs. 1.39 thousand USD), p < 0.001). Conclusions: The three-day accessible pre-rehabilitation bundle reduces the incidence of PPCs, length of stay, and PPCs-related medical costs in patients undergoing elective valve surgery. It may provide an accessible model for the expansion of pre-rehabilitation in countries and regions with limited medical resources. Clinical Trial Registration: This trial was based on the Consolidated Standards of Reporting Trials (CONSORT) guidelines. This trial was registered in the Chinese Clinical Trial Registry (identifier ChiCTR2000039671).

Fabrication of fish gelatin / sodium alginate double network gels for encapsulation of probiotics.

BACKGROUND: To improve the environmental resistance of probiotics, and particularly their survival in the gastrointestinal environment, a fish gelatin (FG) / sodium alginate (SA) double network gelation (FSDN) was developed to encapsulate them. Thermal treatment and calcium ion inducement were adopted to fabricate fish gelatin and sodium alginate gels. It was feasible to scale up this process. The effects of FG concentration (0-60 g/L) on FSDN properties, including morphology, water-holding capacity, and encapsulation efficiency were evaluated. RESULTS: The results indicated that the addition of FG could improve the transparency, rehydration, and water-holding capacity of FSDN. Scanning electronic microscope (SEM) images revealed that FSDN had a denser and more complete structure than SA. Encapsulation efficiency improved from 15.85% to 91.91% as the FG concentration ranged from 0 to 50 g/L. Bifidobacterium longum embedded by FSDN showed better thermal stability than when it was free. Compared with bare probiotics (1.7%), the encapsulated ones exhibited higher viability (above 15%) in simulated gastric fluid. CONCLUSION: In conclusion, interpenetrating FSDN is an effective barrier constituent and could achieve the targeted delivery of probiotics. It is a potential new delivery carrier for the oral administration of probiotics. © 2021 Society of Chemical Industry.

Co-operation of α-galactosylceramide-loaded tumour cells and TLR9 agonists induce potent anti-tumour responses in a murine colon cancer model.

Dendritic cells (DCs) and invariant natural killer T (iNKT) cells play important roles in linking innate immunity and adaptive immunity. Mature DCs activated by Toll-like receptor (TLR) agonists directly activate iNKT cells and the iNKT ligand α-galactosylceramide (α-Galcer) can induce DC maturation, resulting in enhanced protective immune responses. In the present study, we aimed to boost anti-tumour immunity in a murine colon cancer model by synergizing DCs and iNKT cells using α-Galcer-loaded tumour cells (tumour-Gal) and the TLR9 agonist cytosine-phosphorothioate-guanine (CpG1826). The vaccine strategy was sufficient to inhibit growth of established tumours and prolonged survival of tumour-bearing mice. Importantly, the immunization induced an adaptive memory immune response as the survivors from primary tumour inoculations were resistant to a tumour re-challenge. Furthermore, injection of tumour-Gal with CpG1826 resulted in iNKT cell activation and DC maturation as defined by interferon (IFN)-γ secretion by iNKT, natural killer (NK) cells and interleukin (IL)-12 by DCs. Immunohistochemistry analysis revealed that cluster of differentiation (CD)4(+) T-cells and CD8(+) T-cells played important roles in anti-tumour immunity. Additionally, the vaccine redirected Th2 (T-helper cell type 2) responses toward Th1 (T-helper cell type 1) responses with increases in IL-2, IFN-γ expression and decreases in IL-4 and IL-5 expression after immunization with tumour-Gal with CpG1826. Taken together, our results demonstrated a novel vaccination by synergizing tumour-Gal and CpG1826 against murine colon cancer, which can be further developed as tumour-specific immunotherapy against human cancer.

Pseudomonas aeruginosa mannose-sensitive hemagglutinin promotes T-cell response via toll-like receptor 4-mediated dendritic cells to slow tumor progression in mice.

Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) as a drug may kill tumor cells and has been used clinically. However, the antitumor immune response of PA-MSHA is not completely understood. In this study, we found that treating Lewis lung carcinoma (3LL)-bearing mice with PA-MSHA plus 3LL antigen led to slower tumor progression and longer survival. After PA-MSHA treatment, T-cell number and dendritic cell maturation were both increased significantly at the tumor site. In addition, PA-MSHA in vitro stimulation resulted in the maturation of bone marrow-derived dendritic cells (BMDCs) from naive mice, showing higher costimulatory molecule expression, more cytokine secretion, lower endocytic activity, and stronger capacity to enhance T-cell activation. Toll-like receptor (TLR)4 but not TLR2 was required in the maturation process. More importantly, PA-MSHA-induced DCs were essential for PA-MSHA to enhance activation, expansion, and interferon (IFN)-γ secretion of TLR4-mediated T cells, which play a role in the antitumor effect of PA-MSHA. Thus, this study reveals PA-MSHA as a novel TLR4 agonist that elicits antitumor immune response to slow tumor progression.

Isolation and culture of hepatic stellate cells from mouse liver.

Hepatic stellate cells (HSCs) are the primary extracellular matrix-producing cells within the liver and have numerous vital functions. A robust protocol for the isolation and culture of HSCs is important for further investigations of cell functions and related mechanisms in liver disease. The volume of the mouse liver is much smaller than that of the rat liver, which makes it much more difficult to isolate mouse HSCs (mHSCs) than rat HSCs. At present, isolating mHSCs is still a challenge because there is no efficient, robust method to isolate and culture these cells. In the present study, C57BL/6J mice were intravenously injected with liposome-encapsulated dichloromethylene diphosphate (CL2MDP) to selectively eliminate Kupffer cells from the liver. The mouse livers were then perfused in situ, and the mHSCs were isolated with an optimized density gradient centrifugation technique. In the phosphate buffer solution (PBS)-liposome group, the yield of mHSCs was (1.37 ± 0.23) × 10(6)/g liver, the cell purity was (90.18 ± 1.61)%, and the cell survival rate was (94.51 ± 1.61)%. While in the CL2MDP-liposome group, the yield of mHSCs was (1.62 ± 0.34) × 10(6)/g liver, the cell purity was (94.44 ± 1.89)%, and the cell survival rate was (94.41 ± 1.50)%. Based on the yield and purity of mHSCs, the CL2MDP-liposome treatment was superior to the PBS-liposome treatment (P < 0.05, P < 0.01). This study established successfully a robust and efficient protocol for the separation and purification of mHSCs, and both a high purity and an adequate yield of mHSCs were obtained.

A Three-Day Prehabilitation Program is Cost-Effective for Preventing Pulmonary Complications after Heart Valve Surgery: A Health Economic Analysis of a Randomized Trial.

Background: While prehabilitation (pre surgical exercise) effectively prevents postoperative pulmonary complications (PPCs), its cost-effectiveness in valve heart disease (VHD) remains unexplored. This study aims to evaluate the cost-effectiveness of a three-day prehabilitation program for reducing PPCs and improving quality adjusted life years (QALYs) in Chinese VHD patients. Methods: A cost-effectiveness analysis was conducted alongside a randomized controlled trial featuring concealed allocation, blinded evaluators, and an intention-to-treat analysis. In total, 165 patients scheduled for elective heart valve surgery at West China Hospital were randomized into intervention and control groups. The intervention group participated in a three-day prehabilitation exercise program supervised by a physiotherapist while the control group received only standard preoperative education. Postoperative hospital costs were audited through the Hospital Information System, and the EuroQol five-dimensional questionnaire was used to provide a 12-month estimation of QALY. Cost and effect differences were calculated through the bootstrapping method, with results presented in cost-effectiveness planes, alongside the associated cost-effectiveness acceptability curve (CEAC). All costs were denominated in Chinese Yuan (CNY) at an average exchange rate of 6.73 CNY per US dollar in 2022. Results: There were no statistically significant differences in postoperative hospital costs (8484 versus 9615 CNY, 95% CI -2403 to 140) or in the estimated QALYs (0.909 versus 0.898, 95% CI -0.013 to 0.034) between the intervention and control groups. However, costs for antibiotics (339 versus 667 CNY, 95% CI -605 to -51), nursing (1021 versus 1200 CNY, 95% CI -330 to -28), and electrocardiograph monitoring (685 versus 929 CNY, 95% CI -421 to -67) were significantly lower in the intervention group than in the control group. The CEAC indicated that the prehabilitation program has a 92.6% and 93% probability of being cost-effective in preventing PPCs and improving QALYs without incurring additional costs. Conclusions: While the three-day prehabilitation program did not significantly improve health-related quality of life, it led to a reduction in postoperative hospital resource utilization. Furthermore, it showed a high probability of being cost-effective in both preventing PPCs and improving QALYs in Chinese patients undergoing valve surgery. Clinical Registration Number: This trial is registered in the Chinese Clinical Trial Registry (URL: https://www.chictr.org.cn/) with the registration identifier ChiCTR2000039671.

SPINK4 modulates inhibition of glycolysis against colorectal cancer progression.

Dysregulation of glycolysis is frequently linked to aggressive tumor activity in colorectal cancer (CRC). Although serine peptidase inhibitor, Kazal type 4 (SPINK4) has been linked to CRC, its exact linkage to glycolytic processes and gene expression remains unclear. Differentially expressed genes (DEGs) were screened from two CRC-related datasets (GSE32323 and GSE141174), followed by expression and prognostic analysis of SPINK4. In vitro techniques such as flow cytometry, western blotting, transwell assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to assess SPINK4 expression in CRC cells. Its effects on apoptosis, glycolysis, and the cell cycle were also investigated. Finally, the impact of SPINK4 overexpression on tumor development was assessed using a xenograft model, while histological and immunohistochemical analyses characterized SPINK4 expression patterns in CRC tissues. SPINK4 expression was downregulated in CRC, correlating with poor patient prognosis. In vitro assays confirmed that overexpression of SPINK4 reduced CRC cell proliferation, invasion, and migration, while its knockdown promoted these processes and caused G1 arrest. SPINK4 also regulated apoptosis by altering caspase activation and Bcl-2 expression. Besides, SPINK4 overexpression altered glycolytic activity, reduced 2-Deoxy-D-glucose (2-DG) absorption, and controlled critical glycolytic enzymes, resulting in alterations in metabolic pathways, whereas SPINK4 knockdown reversed this effect. SPINK4 overexpression significantly reduced tumor volume in vivo, indicating its inhibitory role in carcinogenesis. Moreover, high expression of SPINK4, hexokinase 2 (HK2), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and pyruvate kinase M2 (PKM2) was observed in CRC tissues. As a key inhibitor of glycolytic metabolism in CRC, SPINK4 promises metabolic intervention in CRC therapy due to its impact on tumor growth and cell proliferation.

Role of pyruvate kinase M2 in regulating sepsis (Review).

Glycolysis occurs in all living organisms as a form of energy supply. Pyruvate kinase M2 (PKM2) is one of the rate­limiting enzymes in the glycolytic process. PKM2 is considered to serve an important role in several terminal diseases, including sepsis. However, to the best of our knowledge, the specific mechanistic role of PKM2 in sepsis remains to be systematically summarised. Therefore, the present review aims to summarise the roles of PKM2 in sepsis progression. In addition, potential treatment strategies for patients with sepsis are discussed. The present review hopes to lay the groundwork for studying the role of PKM2 and developing therapeutic strategies against metabolic disorders that occur during sepsis.

Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.

Nano-energy interference: A novel strategy for blunting tumor adaptation and metastasis.

Blunting the tumor's stress-sensing ability is an effective strategy for controlling tumor adaptive survival and metastasis. Here, we have designed a cyclically amplified nano-energy interference device based on lipid nanoparticles (LNP), focused on altering cellular energy metabolism. This innovative nano device efficiently targets and monitors the tumor's status while simultaneously inhibiting mitochondrial respiration, biogenesis and ribosome production. To this end, we first identified azelaic acid (AA), a binary acid capable of disrupting the mitochondrial respiratory chain. Upon encapsulation in LNP and linkage to mitochondrial-targeting molecules, this disruptive effect is further augmented. Consequently, tumors exhibit a substantial upregulation of the glycolytic pathway, intensifying their glucose demand and worsening the tumor's energy-deprived microenvironment. Then, the glucose analog, 2-Deoxy-D-glucose (2-DG), linked to the LNP, efficiently targets tumors and competitively inhibits the tumor's normal glucose uptake. The synergetic results of combining AA with 2-DG induce comprehensive energy deficiency within tumors, blocking the generation of energy-sensitive ribosomes. Ultimately, the disruption of both mitochondria and ribosomes depletes energy supply and new protein-generating capacity, weakening tumor's ability to adapt to environmental stress and thereby inhibiting growth and metastasis. Comprehensively, this nano-energy interference device, by controlling the tumor's stress-sensing ability, provides a novel therapeutic strategy for refractory tumors.

Quantitative microbiological risk assessments for Salmonella spp. contaminated taiwanese salty chicken in the taiwanese population.

The aim of the study is to develop Salmonella spp. Quantitative microbial risk assessments (QMRA) and to evaluate the risk of Salmonellosis illness in the Taiwanese population after consumption of Taiwanese salty chicken (TSC). We assume that Salmonella spp. May contaminate the fresh raw chicken used in TSC. After transport to the diner, fresh raw chicken is received, cleaned, and surface-washed by diner staff. The TSC is then cooked and sold to consumers. We set four different cross-contamination scenarios to evaluate the contamination level of Salmonella spp. In TSC. We used a Monte Carlo simulation method, a probabilistic analysis method, and exceedance risk to evaluate the risk of Salmonellosis illness. When the exceedance risk was 5 %, and taking the Taiwanese population above 19 years old as an example, the rate of contracting Salmonellosis from the consumption of TSC will be 2.94 % (2.94 million per 100 million people) if the chef does not clean their hands, knives, or cutting boards. However, if the chef washes their hands, knives, and cutting boards with cold water and soap, the illness rate of Salmonellosis from consuming TSC will be 1.93E-04 % (193 per 100 million people). Sensitivity analysis indicates that the most important risk factor in the QMRAs of TSC is the temperature of the fresh raw chicken during transportation, following which were the Salmonella spp. Residual. If the staff of the diner separates the cooking tools used for raw ingredients and those for cooked food, the illness risk of Salmonellosis will be very low.

Feasibility and safety of 1-min sit-to-stand test in acute decompensated heart failure confirmed by lung ultrasound.

Aim: This study innovatively proposed the 1-min sit-to-stand test (1-min STST) as an assessment tool for functional capacity in acute decompensated heart failure (ADHF), in which its feasibility and safety were investigated. Methods: This was a prospective, single-center cohort study. The 1-min STST was performed after the first 48 h of admission when vital signs and Borg score were collected. Lung ultrasound was used to measure pulmonary edema by B-lines before and after the test. Results: Seventy-five patients were enrolled in the study, of whom 40% were in functional class IV on admission. The mean age was 58.3 ± 15.7 years and 40% of the patients were male. 95% patients accomplished the test and the average number of repetitions was 18 ± 7. No adverse event was recorded during or after the 1-min STST. Blood pressure, heart rate, and degree of dyspnea were increased after the test (all p < 0.001), while oxygen saturation was slightly decreased (97.0 ± 1.6 vs. 96.3 ± 2.0%, p = 0.003). The degree of pulmonary edema (χ2 = 8.300, p = 0.081) was not significantly changed, while there was a reduction in the absolute number of B-lines [9 (3, 16) vs. 7 (3, 13), p = 0.008]. Conclusion: The application of the 1-min STST in early stage of ADHF appeared to be safe and feasible, which induce neither adverse event nor pulmonary edema. It may serve as a new tool of functional capacity assessment, as well as a reference of exercise rehabilitation.

Efficacy and safety of digital therapeutics-based cardiac rehabilitation in heart failure patients: a systematic review.

During the coronavirus disease 2019 (COVID-19) pandemic, it has become difficult to provide centre-based cardiac rehabilitation for heart failure patients. Digital therapeutics is a novel concept proposed in recent years that refers to the use of evidence-based therapeutic interventions driven by high-quality software programs to treat, manage, or prevent a medical condition. However, little is known about the use of this technology in heart failure patients. This study aims to explore the safety and efficacy of digital therapeutics-based cardiac rehabilitation in heart failure patients and to provide new insights into a new cardiac rehabilitation model during the COVID-19 era. To identify technologies related to digital therapeutics, such as the use of medical applications, wearable devices, and the Internet, all relevant studies published on PubMed, EMBASE, Cochrane database, and China National Knowledge Internet were searched from the time the database was established until October 2021. The PEDro was used to assess the quality of included studies. We ultimately identified five studies, which included 1119 patients. The mean age was 66.37, the mean BMI was 25.9, and the NYHA classification ranged from I to III (I = 232, II = 157, III = 209). The mean 6-min walk distance was 397.7 m. The PEDro scores included in the study ranged from 4 to 8, with a mean of 5.8. Exercise training was performed in four studies, and psychological interventions were conducted in three studies. No death or serious adverse events were observed. Adherence was reported in three studies, and all exceeded 85%. The results of most studies showed that digital therapeutics-based cardiac rehabilitation significantly increases exercise capacity and quality of life in heart failure patients. Overall, although this study suggests that digital therapeutics-based cardiac rehabilitation may be a viable intervention for heart failure patients during the COVID-19 era, the efficacy of this new model in routine clinical practice needs to be further validated in a large clinical trial.

Predictive value of prognostic nutritional index on infection after radical gastrectomy: a retrospective study.

Background: The prognostic nutritional index (PNI) is a useful tool to evaluate nutritional status, which is associated with postoperative complications and prognosis of patients with cancer. Recent studies have shown that PNI has important predictive value for postoperative infection in cancer patients. However, the role and clinical value of PNI in infection after radical gastrectomy remains unclear. This study investigated the relationship between PNI and infection after radical surgery for gastric cancer (GC), focusing on the predictive value of PNI. Methods: A total of 1,111 patients with primary gastric cancer who underwent radical surgery in our hospital from December 2010 to December 2020 were included in this retrospective study. The demographic and clinicopathological data of all patients were acquired through hospital information system (HIS). Preoperative serum albumin (ALB) level and peripheral blood lymphocyte count were obtained for PNI calculation. We selected 812 patients by propensity score matching to reduce biases due to the different distributions of co-variables among the comparable groups. The factors influencing postoperative infection in the matched patients were explored using univariate and multivariate analyses. Results: Baseline characteristics significantly differed among patients with different PNI scores. After one-to-one matching, the clinicopathological data of the 2 groups were comparable, and 812 patients were included for further analysis. Among these patients, 101 developed infections, with an infection rate of 12.4%, which were mainly caused by gram-negative bacteria. The incidence of infection was significantly higher in the low PNI group than in the high PNI group. Univariate and multivariate analyses identified body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) =2.314, P=0.004], diabetes mellitus (OR =1.827, P=0.042), PNI score <45 (OR =2.138, P=0.037), combined multi-organ resection (OR =2.946, P<0.001), operation time ≥240 minutes (OR =2.744, P=0.023), and perioperative blood transfusion (OR =2.595, P=0.025) as risk factors for infection after radical surgery for GC. Conclusions: Infection is the most common complication after radical gastrectomy for GC, and a low preoperative PNI score is a risk factor for postoperative infection.

Clinical cancer immunotherapy: Current progress and prospects.

Immune checkpoint therapy via PD-1 antibodies has shown exciting clinical value and robust therapeutic potential in clinical practice. It can significantly improve progression-free survival and overall survival. Following surgery, radiotherapy, chemotherapy, and targeted therapy, cancer treatment has now entered the age of immunotherapy. Although cancer immunotherapy has shown remarkable efficacy, it also suffers from limitations such as irAEs, cytokine storm, low response rate, etc. In this review, we discuss the basic classification, research progress, and limitations of cancer immunotherapy. Besides, by combining cancer immunotherapy resistance mechanism with analysis of combination therapy, we give our insights into the development of new anticancer immunotherapy strategies.

Perioperative respiratory muscle training improves respiratory muscle strength and physical activity of patients receiving lung surgery: A meta-analysis.

BACKGROUND: The clinical role of perioperative respiratory muscle training (RMT), including inspiratory muscle training (IMT) and expiratory muscle training (EMT) in patients undergoing pulmonary surgery remains unclear up to now. AIM: To evaluate whether perioperative RMT is effective in improving postoperative outcomes such as the respiratory muscle strength and physical activity level of patients receiving lung surgery. METHODS: The PubMed, EMBASE (via OVID), Web of Science, Cochrane Library and Physiotherapy Evidence Database (PEDro) were systematically searched to obtain eligible randomized controlled trials (RCTs). Primary outcome was postoperative respiratory muscle strength expressed as the maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Secondary outcomes were physical activity, exercise capacity, including the 6-min walking distance and peak oxygen consumption during the cardio-pulmonary exercise test, pulmonary function and the quality of life. RESULTS: Seven studies involving 240 participants were included in this systematic review and meta-analysis. Among them, four studies focused on IMT and the other three studies focused on RMT, one of which included IMT, EMT and also combined RMT (IMT-EMT-RMT). Three studies applied the intervention postoperative, one study preoperative and the other three studies included both pre- and postoperative training. For primary outcomes, the pooled results indicated that perioperative RMT improved the postoperative MIP (mean = 8.13 cmH2O, 95%CI: 1.31 to 14.95, P = 0.02) and tended to increase MEP (mean = 13.51 cmH2O, 95%CI: -4.47 to 31.48, P = 0.14). For secondary outcomes, perioperative RMT enhanced postoperative physical activity significantly (P = 0.006) and a trend of improved postoperative pulmonary function was observed. CONCLUSION: Perioperative RMT enhanced postoperative respiratory muscle strength and physical activity level of patients receiving lung surgery. However, RCTs with large samples are needed to evaluate effects of perioperative RMT on postoperative outcomes in patients undergoing lung surgery.

Downregulation of PDGF-D Inhibits Proliferation and Invasion in Breast Cancer MDA-MB-231 Cells.

BACKGROUND: The platelet derived growth factor-D (PDGF-D) plays an important role in breast tumor aggressiveness. However, limited study has investigated the effect of silencing PDGF-D on the biological function of breast cancer. The purpose of this study is to clarify the potential value of PDGF-D as a target for breast cancer treatment. METHODS: Reverse transcription-polymerase chain reaction and western blot were used to detect PDGF-D expression in 5 different breast cancer cells. The lentiviral vector was usd to silence PDGF-D in MDA-MB-231 cells. Then, Methyl Thiazolyl Tetrazolium was used to detect cell viability, 5-Ethynyl-2'- deoxyuridine and a soft agar assay were used to detect cell proliferation and clonality. Additionally, cell apoptosis after PDGF-D knockdown was measured by Annexin V/ Prodium Iodide staining, and cell migration was detected by trans-well assay. Survival rate and tumor size were measured by nude mice transplantation. RESULTS: The MDA-MB-231 and SK-BR-3 cell lines showed higher PDGF-D expression than the MCF7 cell lines (P<.05). After the PDGF-D gene was silenced, the growth and colony forming abilitys ignificantly decreased (P<.05) together with the induction of apoptosis in MDA-MB-231 cells (P<.05). Moreover, MDA-MB-231 cells with PDGF-D silencing showed significantly diminished aggressive migration and invasion potential compared to other cells (P<.05). In vivo experiments also indicated that PDGF-D silencing inhibited tumor growth and improved the survival rate of tumor-bearing mice. CONCLUSION: Downregulation of PDGF-D had dramatic effects on breast cancer cell proliferation, apoptosis and migration, which indicates that it plays an important role in breast cancer development and progression.

ceRNAs in Cancer: Mechanism and Functions in a Comprehensive Regulatory Network.

Noncoding RNAs have been shown with powerful ability in post-transcriptional regulation, enabling intertwined RNA crosstalk and global molecular interaction in a large amount of dysfunctional conditions including cancer. Competing endogenous RNAs (ceRNAs) are those competitively binding with shared microRNAs (miRNAs), freeing their counterparts from miRNA-induced degradation, thus actively influencing and connecting with each other. Constantly updated analytical approaches boost outstanding advancement achieved in this burgeoning hotspot in multilayered intracellular communication, providing new insights into pathogenesis and clinical treatment. Here, we summarize the mechanisms and correlated factors under this RNA interplay and deregulated transcription profile in neoplasm and tumor progression, underscoring the great significance of ceRNAs for diagnostic values, monitoring biomarkers, and prognosis evaluation in cancer.

T-cell-based immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. CRC therapeutic strategies include surgical resection, chemotherapy, radiotherapy, and other approaches. However, patients with metastatic CRC have worse prognoses. In recent years, T-cell-based immunotherapy has elicited promising responses in B-cell malignancies, melanoma, and lung cancer, but most CRC patients are resistant to immunotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors have shown encouraging results in non-small cell lung cancer, melanoma, and other cancers, but immune checkpoint blockade is only effective for CRC subset with microsatellite instability. Other immunotherapies, such as cytokines, cancer vaccines, small molecules, oncolytic viruses, and chimeric antigen-receptor therapy, are currently in use against CRC. This review analyzes recent developments in immunotherapy for CRC treatment as well as the challenges in overcoming resistance.

Pharmacological Inhibition and Genetic Knockdown of BCL9 Modulate the Cellular Landscape of Cancer-Associated Fibroblasts in the Tumor-Immune Microenvironment of Colorectal Cancer.

Cancer-associated fibroblasts (CAFs) exert a key role in cancer progression and liver metastasis. They are activated in the tumor microenvironment (TME), but their prometastatic mechanisms are not defined. CAFs are abundant in colorectal cancer (CRC). However, it is not clear whether they are raised from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors, and whether they may stimulate metastasis-promoting communication. B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is the key transcription cofactor of ß-catenin. We studied the TME of CRC with single-cell sequencing and consequently found that Bcl9 depletion caused a pro-tumor effect of CAFs, while inhibition of abnormal activation of Wnt/ß-catenin signal through Bcl9 depletion benefited T-cell-mediated antitumor immune responses. We also identified and evaluated four types of CAFs in CRC with liver metastasis. In summary, we demonstrate cell type landscape and transcription difference upon BCL9 suppression in CAFs, as well as how CAF affects cancer associated immune surveillance by inhibition of Wnt signaling. Targeting the Wnt signaling pathway via modulating CAF may be a potential therapeutic approach.