Antibiotic-Induced Gut Microbiota Dysbiosis Modulates Host Transcriptome and m6A Epitranscriptome via Bile Acid Metabolism.

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N6-methyladenosine (m6A), the most abundant mammalian mRNA modification. However, which and how gut microbiota-derived metabolites reprogram host transcriptome and m6A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota-derived metabolites impact host transcriptome and m6A epitranscriptome using multiple mouse models and multi-omics approaches. Various antibiotics-induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ-free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid-producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m6A epitranscriptome in multiple tissues. Mechanistically, the expression of m6A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology. Collectively, these results demonstrate that antibiotic-induced gut dysbiosis regulates the landscape of host transcriptome and m6A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.

A potential strategy for bladder cancer treatment: inhibiting autophagy to enhance antitumor effects of Nectin-4-MMAE.

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer. During the course of this study, we identified that autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder cancer. Nectin-4-MMAE rapidly internalized into bladder cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder cancer cells treated with Nectin-4-MMAE, which suggested autophagy was activated by Nectin-4-MMAE. Furthermore, autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells. Additionally, we detected the participation of the AKT/mTOR signaling cascade in the induction of autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an autophagy inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

CD80-Fc fusion protein as a potential cancer immunotherapy strategy.

The activation of T lymphocytes is a crucial component of the immune response, and the presence of CD80, a membrane antigen, is necessary for T-cell activation. CD80 is usually expressed on antigen-presenting cells (APCs), which can interact with cluster of differentiation 28 (CD28) or programmed cell death ligand 1 (PD-L1) to promote T-cell proliferation, differentiation and function by activating costimulatory signal or blocking inhibitory signal. Simultaneously, CD80 on the APCs also interacts with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells to suppress the response of specific effector T cells, particularly in the context of persistent antigenic stimulation. Due to the pivotal role of CD80 in the immune response, the CD80-Fc fusion protein has emerged as a promising approach for cancer immunotherapy. This review primarily focused on the crucial role of CD80 in the cancer immunotherapy. We also reviewed the current advancements in the research of CD80-Fc fusion proteins. Finally, we deliberated on the challenges encountered by CD80-Fc fusion proteins and proposed the potential strategies that could yield the benefits for patients.

A collagen-binding SIRPαFc fusion protein for targeted cancer immunotherapy.

Collagen is abundant but exposed in tumor due to the abnormal tumor blood vessels, thus is considered as a tumor-specific target. The A3 domain of von Willebrand factor (vWF A3) is a kind of collagen-binding domain (CBD) which could bind collagen specifically. Previously we reported a chemosynthetic CBD-SIRPαFc conjugate, which could block CD47 and derived tumor-targeting ability by CBD. CBD-SIRPαFc conjugate represented improved anti-tumor efficacy with increased MHC II+ M1 macrophages, but the uncertain coupling ratio remained a problem. Herein, we produced a vWF A3-SIRPαFc fusion protein through eukaryotic expression system. It was examined at both molecular and cellular levels with its collagen affinity, uninfluenced original affinity to targets and phagocytosis-promoting function compared to unmodified SIRPαFc. Living imaging showed that vWF A3-SIRPαFc fusion protein derived the improved accumulation and retention in tumor than SIRPαFc. In the MC38 allograft model, vWF A3-SIRPαFc demonstrated a superior tumor-suppressing effect, characterized by increased MHC II+ M1 macrophages and T cells (particularly CD4+ T cells). These results revealed that vWF A3-SIRPαFc fusion protein derived tumor-targeting ability, leading to improved anti-tumor immunotherapeutic efficacy compared to SIRPαFc. Altogether, vWF A3 improved the anti-tumor efficacy and immune-activating function of SIRPαFc, supporting targeting tumor collagen as a possible targeted strategy.

A nomogram for predicting the risk of new vertebral compression fracture after percutaneous kyphoplasty.

BACKGROUND: New vertebral compression fractures (NVCFs) are common adverse events in percutaneous kyphoplasty (PKP). The present study aimed to investigate the risk factors for NVCFs in patients after PKP and to construct a nomogram for the prediction of the risk of re-fracture. METHODS: We retrospectively analyzed the medical records of patients after PKP surgery between January 2017 and December 2020. Patients were divided into an NVCF group (n = 225) and a control group (n = 94) based on the presence or absence of NVCFs, respectively, at follow-up within 2 years after surgery. Lasso regression was used to screen for risk factors for re-fracture. Based on the results, a Lasso-logistic regression model was developed, and its prediction performance was evaluated using receiver operating characteristic curves, calibration, and decision curve analysis. The model was visualized, and a nomogram was constructed. RESULTS: A total of eight potential predictors were obtained from Lasso screening. Advanced age, low body mass index, low bone mineral density, lack of anti-osteoporosis treatment, low preoperative vertebral body height, vertebral body height recovery ≥ 2, cement leakage, and shape D (lack of simultaneous contact of bone cement with the upper and lower plates) were included in the logistic regression model. CONCLUSIONS: A nomogram for predicting postoperative NVCF in PKP was developed and validated. This model can be used for rational assessment of the magnitude of the risk of developing NVCFs after PKP, and can help orthopedic surgeons make clinical decisions aimed at reducing the occurrence of NVCFs.

Unlocking potential: clinical benefits of enlarging the nail bed explored through continuous W-shaped incisions.

PURPOSE: Nail bed atrophy, a common condition for which conservative treatments have limited efficacy, continues to present challenges in determining the optimal surgical intervention. This study introduces a novel technique for nail bed expansion. MATERIALS AND METHODS: A total of 34 patients with nail bed atrophy, selected between 2015 and 2020 (ChiCTR2000036232), were randomized into a control group (n = 17) and a surgical group (n = 17). While no specialized treatment was administered to the control group, the surgical group underwent continuous W-shaped incisions on the ventral side of the digits. RESULTS: Following a 12-month follow-up period, changes in nail bed height, width, area, esthetic satisfaction, pain levels, and tactile sensation were assessed in both groups. In the surgical group, the height, width, and area of the nail bed increased significantly by 1.50 ± 0.49 times, 1.16 ± 0.23 times, and 1.69 ± 0.60 times, respectively, compared to the preoperative measurements. The newly-formed nail plate exhibited improved esthetics, characterized by its smoothness and transparency, a marked improvement over the control group (p < 0.05). Furthermore, this surgical approach showed significant effects, regardless of whether it was applied to fingers or toes. CONCLUSION: The continuous W-shaped incision technique demonstrated substantial benefits and could be a practical therapeutic approach for nail bed enlargement.

Targeting CD47 enhanced the antitumor immunity of PD-L1 blockade in B-cell lymphoma.

Background: Only a subset of B-cell lymphoma (BCL) patients can benefit from immune checkpoint inhibitors targeting PD-1/PD-L1. Materials & methods: In the A20 model, SIRPα-Fc and anti-PD-L1 were employed to target CD47 and PD-L1 simultaneously. Flow cytometry, immunofluorescence and quantitative polymerase chain reaction were used to unravel the potential mechanisms. Results: Simultaneously targeting CD47 and PD-L1 activated CD8+ T cells with an increased release of effector molecules. Furthermore, infiltration of F4/80+iNOS+ M1 macrophages was enhanced by the dual therapy. Conclusion: Anti-CD47 therapy could sensitize BCL tumors to anti-PD-L1 therapy in a CD8+ T-cell- and M1-macrophage-dependent manner by promoting cytotoxic lymphocyte infiltration, which may provide a potential strategy for BCL treatment by simultaneously targeting CD47 and PD-L1.

Immune checkpoint inhibitors targeting PD-1/PD-L1 have become effective agents for cancer treatment. However, only a minority of patients benefit from this treatment in the clinic because of the limited response rate. Targeting CD47/SIRPα restores macrophage function and improves the response of antitumor immunity. Here, combination immunotherapy targeting CD47/SIRPα and PD-1/PD-L1 was investigated to increase the response rate and antitumor effect of PD-L1 monotherapy in B-cell lymphoma (BCL). This study broadens the application of the combination therapy and provided a promising strategy for B-cell lymphoma treatment by simultaneous targeting of PD-1/PD-L1 and CD47/SIRPα axis.

A bifunctional fusion protein protected against diabetic nephropathy by suppressing NLRP3 activation.

Diabetic nephropathy (DN), the principal pathogeny of end-stage renal disease (ESRD), is related to metabolic disorders, chronic inflammation, and oxidative stress. It was reported that high expression of interleukin-17A (IL-17A) was intimately related to the progression of DN, and targeting IL-17A exhibited regulating effects on inflammation and autoimmunity but had only limited impact on the oxidative stress damage in DN. Recent studies showed that interleukin-22 (IL-22) could inhibit mitochondrial damage and inflammatory response. Thus, the cytokine IL-22 was first fused to anti-IL-17A antibody for endowing the antibody with the anti-hyperglycemia and anti-inflammation activity. Our study demonstrated that the fusion molecule, anti-IL17A/IL22 fusion protein, could not only lead to the increase of M1 macrophages and the decrease of M2 macrophages, further improving the immune microenvironment, but also prevent the loss of mitochondrial membrane potential by reducing the production of ROS in murine DN model. In addition, the fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways, further synergistically restraining the production of NLRP3, thus suppressing the inflammatory response and playing beneficial effect on slowing down the progression of DN. In conclusion, our findings demonstrated that the bifunctional IL-17A antibody and IL-22 fusion protein were of great benefit to DN, which highlighted a potential therapeutic strategy. KEY POINTS: • Anti-IL17A/IL22 fusion protein could improve the immune microenvironment and reduce the production of ROS. • Anti-IL17A/IL22 fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways and then restrain the activation of NLRP3.

Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma.

Introduction: Although PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL). Methods: Subcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment. Results: Our results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy. Discussion: In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.

A novel nanobody-heavy chain antibody against Angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease mainly on account of hypercholesterolemia and may progress to cirrhosis and hepatocellular carcinoma. The discovery of effective therapy for NAFLD is an essential unmet need. Angiopoietin-like protein 3 (ANGPTL3), a critical lipid metabolism regulator, resulted in increased blood lipids and was elevated in NAFLD. Here, we developed a nanobody-heavy chain antibody (VHH-Fc) to inhibit ANGPTL3 for NAFLD treatment. RESULTS: In this study, we retrieved an anti-ANGPTL3 VHH and Fc fusion protein, C44-Fc, which exhibited high affinities to ANGPTL3 proteins and rescued ANGPLT3-mediated inhibition of lipoprotein lipase (LPL) activity. The C44-Fc bound a distinctive epitope within ANGPTL3 when compared with the approved evinacumab, and showed higher expression yield. Meanwhile, C44-Fc had significant reduction of the triglyceride (~ 44.2%), total cholesterol (~ 36.6%) and LDL-cholesterol (~ 54.4%) in hypercholesterolemic mice and ameliorated hepatic lipid accumulation and liver injury in NAFLD mice model. CONCLUSIONS: We discovered a VHH-Fc fusion protein with high affinity to ANGPTL3, strong stability and also alleviated the progression of NAFLD, which might offer a promising therapy for NAFLD.

A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer.

The SIRPαFc fusion protein can block the immunosuppressive CD47-SIRPα signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide "TKKTLRT" is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRPαFc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT-SIRPαFc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT-SIRPαFc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD-SIRPαFc accumulated in tumor tissue more effectively compared to unmodified SIRPαFc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD-SIRPαFc presented more stable and effective antitumor efficacy than SIRPαFc, along with significantly increased CD11b+F4/80+ macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRPαFc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD-SIRPαFc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.

A Novel Bifunctional Fusion Protein, Vunakizumab-IL22, for Protection Against Pulmonary Immune Injury Caused by Influenza Virus.

Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro. Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1ß, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-ß signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.

[Comparison of the effectiveness of the posterior malleolus fixed or not on treatment of different Haraguchi's classification of posterior malleolus fractures].

OBJECTIVE: To investigate the effectiveness of fixation the posterior malleolus or not to treat different Haraguchi's classification of posterior malleolus fractures. METHODS: The clinical data of 86 trimalleolar fracture patients who were admitted between January 2015 and September 2019 and met the selection criteria were retrospectively reviewed. There were 29 males and 57 females; the age ranged from 26 to 82 years with a mean age of 55.2 years. According to Haraguchi's classification, 38 patients were in type Ⅰ group, 30 patients in type Ⅱ group, and 18 patients in type Ⅲ group. There was no significant difference in the general data such as gender, age, and fracture location among the 3 groups ( P>0.05). The fixation of the posterior malleolus was performed in 23, 21, and 5 patients in type Ⅰ, Ⅱ, and Ⅲ groups, respectively. The operation time, fracture healing time, full weight-bearing time, postoperative joint flatness, and joint degeneration degree of the patients in each group were recorded and compared. The American Orthopedic Foot and Ankle Society (AOFAS) ankle and hindfoot score was used to evaluate ankle function, including pain, quality of daily life, joint range of motion, and joint stability. The AOFAS scores were compared between fixation and non-fixation groups in each group. RESULTS: The procedure was successfully completed by all patients in each group, and there was no significant difference in operation time ( F=3.677, P=0.159). All patients were followed up 12-36 months with a mean time of 16.8 months. At last follow-up, 6 patients were found to have suboptimal ankle planarity, including 2 patients (5.3%) in the type Ⅰ group and 4 patients (13.3%) in the type Ⅱ group, with no significant difference between groups ( χ 2=6.566, P=0.161). The ankle joints of all the patients in each group showed mild degeneration; the fractures all healed well and no delayed union or nonunion occurred. There was no significant difference in the fracture healing time and full weight-bearing time between groups ( P>0.05). No complications such as incision infection, fracture displacement, or plate screw loosening and fracture occurred during follow-up. At last follow-up, the total scores and pain scores of the AOFAS scores in the type Ⅱ group were significantly lower than those in the type Ⅰand Ⅲ groups ( P<0.05), there was no significant difference between groups in the scores for the quality of daily life, joint range of motion, and joint stability between groups ( P>0.05). There was no significant difference in any of the scores between the unfixed and fixed groups, except for the pain and quality of daily life scores, which were significantly lower ( P<0.05) in the unfixed group of type Ⅱ group than the fixed group. CONCLUSION: Haraguchi type Ⅱ posterior malleolus fractures have a worse prognosis than types Ⅰ and Ⅲ fractures, especially in terms of postoperative pain, which can be significantly improved by fixing the posterior malleolus; the presence or absence of posterior malleolus fixation in types Ⅰ and Ⅲ has less influence on prognosis.

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment.

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer.

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.

VEGF-B antibody and interleukin-22 fusion protein ameliorates diabetic nephropathy through inhibiting lipid accumulation and inflammatory responses.

Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.

Comparison of safety between self-expanding metal stents as a bridge to surgery and emergency surgery based on pathology: a meta-analysis.

BACKGROUND: To explore the long-term oncological safety of using self-expanding metal stents (SEMS) as a bridge to surgery for acute obstructive colorectal cancer by comparing the pathological results of emergency surgery (ES) with elective surgery after the placement of SEMS. METHODS: Studies comparing SEMS as a bridge to surgery with emergency surgery for acute obstructive colorectal cancer were retrieved through the databases of Pubmed, Embase, and Cochrane libraries, and a meta-analysis was conducted based on the pathological results of the two treatments. Risk ratios (OR) or mean differences (MD) with 95% confidence intervals (CI) were calculated for the outcomes under random effects model. RESULTS: A total of 27 studies were included, including 3 randomized controlled studies, 2 prospective studies, and 22 retrospective studies, with a total of 3737 patients. The presence of perineural invasion (RR = 0.58, 95% CI 0.48, 0.71, P < 0.00001), lymphovascular invasion (RR = 0.68, 95% CI 0.47, 0.99, P = 0.004) and vascular invasion (RR = 0.66, 95% CI 0.45, 0.99, P = 0.04) in SEMS group were significantly higher than those in ES group, and there was no significant difference in lymphatic invasion (RR = 0.92, 95% CI 0.77, 1.09, P = 0.33). The number of lymph nodes harvested in SEMS group was significantly higher than that in ES group (MD = - 3.18, 95% CI - 4.47, - 1.90, P < 0.00001). While no significant difference was found in the number of positive lymph nodes (MD = - 0.11, 95% CI - 0.63, 0.42, P = 0.69) and N stage [N0 (RR = 1.03, 95% CI 0.92, 1.15, P = 0.60), N1 (RR = 0.99, 95% CI 0.87, 1.14, P = 0.91), N2 (RR = 0.94, 95% CI 0.77, 1.15, P = 0.53)]. CONCLUSIONS: SEMS implantation in patients with acute malignant obstructive colorectal cancer may lead to an increase in adverse tumor pathological characteristics, and these characteristics are mostly related to the poor prognosis of colorectal cancer. Although the adverse effect of SEMS on long-term survival has not been demonstrated, their adverse effects cannot be ignored. The use of SEMS as the preferred treatment for patients with resectable obstructive colorectal cancer remains to be carefully weighed, especially when patients are young or the surgical risk is not very high.