Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer.

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

High-performance and functional fully bio-based polylactic acid/polypropylene carbonate blends by in situ multistep reaction-induced interfacial control.

Using a solvent-free radical grafting technique, glycidyl methacrylate (GMA) and maleic anhydride (MAH) were used as functionalized graft monomers, styrene (St) as a copolymer monomer, and grafted onto polylactic acid (PLA). A series of PLA-g-(GMA/MAH-co-St) graft copolymers were prepared by adjusting the GMA/MAH ratio. Subsequently, the prepared graft copolymers were used as a compatibilizer with PLA and polypropylene carbonate (PPC) for melt blending to prepare PLA/PPC/PLA-g-(GMA/MAH-co-St) blends. The effects of changes in the GMA/MAH ratio in the graft copolymer on the thermodynamics, rheology, optics, degradation performance, mechanical properties, and microstructure of the blend were studied. The results found that GMA, MAH, and St were successfully grafted onto PLA, and the PLA-g-(GMA/MAH-co-St) graft copolymer obtained from the reaction had a good toughening effect on the PLA/PPC blend system, which significantly improved the mechanical properties of the PLA/PPC/PLA-g-(GMA/MAH-co-St) blend without reducing its degradation performance, resulting in a biodegradable blend material with excellent comprehensive performance. In the PLA-g-(GMA/MAH-co-St) grafting reaction system, when GMA/MAH = 1.5/1.5 (w/w), the grafting degree of the graft copolymer increased most significantly, from 0.83 phr to 1.51 phr. This composition of graft copolymer can effectively improve the compatibility between PLA and PPC. The resulting PLA/PPC blend can maintain good melt flow properties (MFR of 14.51 g/10 min), high transparency, and low haze (light transmittance of 91.56 %, haze of 20.5 %), while significantly improving its thermal stability (T95%, Tmax, and Et increased by 12.87 °C, 20.33 °C, and 32.00 kJ/mol, respectively). Moreover, when introducing PLA-g-(GMA/MAH-co-St) (GMA/MAH = 1.5/1.5 (wt/wt)) graft copolymer into the system, the toughness of the PLA/PPC/PLA-g-(GMA/MAH-co-St) blend system is optimal, with the notch impact strength and fracture elongation increasing to 184.6 % and 535.4 % of the PLA/PPC blend, respectively, at which point the fracture surface of the impact sample shows a wrinkled fracture feature indicative of toughness.

Improving the properties of polylactic acid/polypropylene carbonate blends through cardanol-induced compatibility enhancement.

Cardanol (CD) is used as a reactive compatibilizer, and blended with polylactic acid (PLA) and polypropylene carbonate (PPC) resin (70/30(w/w)) to obtain a series of PLA/PPC/CD blends. The systematic study was conducted on the thermal properties, optical properties, rheological properties, mechanical properties, and microscopic morphology of the blend, by varying amounts of CD added to the blends. A detailed explanation and comprehensive analysis of the reaction mechanism between CD and PLA/PPC have been made. The study found that CD acts as a "bridge" between the PLA and PPC, forming the structure of a block copolymer (PLA-b-CD-b-PPC), and the copolymer can greatly improve the compatibility of PLA and PPC. When the amount of CD reaches 8 wt%, only one Tg is observed in the blend, simultaneously, PLA/PPC has already transitioned from a partially compatible system to a completely compatible system. At the same time, the addition of CD does not have any negative impact on the thermal stability of the PLA/PPC blend under processing temperature conditions, and the thermal stability of the PLA/PPC/CD blends can even be improved under extreme conditions. In addition, the addition of CD allows the PLA/PPC/CD blends to maintain a high light transmittance while reducing the opacity of the blend (the light transmittance remains above 92 %, and the opacity is reduced from 37 % to about 24 %), demonstrating excellent optical properties. Moreover, the elongation at break and impact strength of the PLA/PPC/CD blend both show a trend of first increasing and then decreasing with the increase of CD amount. When the CD amount varies within the range of 6- 8 wt%, the blends undergoes a brittle-ductile transition, and its toughness is greatly improved while the rigidity can also meet practical needs. When the amount of CD in the system increases to 12 wt%, the toughness of the blend reaches its peak, and its elongation at break and impact strength reach 513.24 % and 9211.5 J/m2 respectively (increased to 2442.84 % and 270.73 % of the PLA/PPC blend). Concurrently, the fracture surface of the blend exhibits large-scale plastic flow in the direction of the applied force, with marked shear yield phenomena, showing obvious characteristics of tough fracture.

Improvement of properties of polylactic acid/polypropylene carbonate blends using epoxy soybean oil as an efficient compatibilizer.

Epoxidized soybean oil (ESO) was used as a compatibilizer and blended with polylactic acid (PLA) and polypropylene carbonate (PPC) resin to prepare a series of PLA/PPC/ESO blends with varying compositions. The influence of the variation in the amount of ESO added to the blend system on the thermal properties, optical properties, rheological properties, mechanical properties, and microscopic morphology of the blends was studied. The research indicates that ESO can react with PLA and PPC to form a chemical bond interface, which improves the compatibility of PLA and PPC to a certain extent. With the increase in the amount of ESO added to the blend (1- 5 phr), the complete decomposition temperature, storage modulus, loss modulus, complex viscosity, notched impact strength, and elongation at break of the blend all show a trend of continuous increase. At the same time, the melt flow rate, light transmittance, and tensile strength of the blend do not show significant fluctuations. When the amount of ESO in the system is 5 phr, compared with the PLA/PPC blend, the notched impact strength and elongation at break of the PLA/PPC/ESO blend increase from 4270.3 J/m2, 43.89 % to 8560.4 J/m2, 211.28 %, respectively, and its tensile strength and transmittance still remain around 63 MPa, 92 %. This improves the toughness of the blend while maintaining its rigidity, demonstrating excellent mechanical and optical properties. At this time, the microscopic morphology of the fracture surface of the impact sample also shows obvious characteristics of tough fracture. However, when the amount of ESO added to the blend is excessive (6 phr), the compatibility of the blending system decreases, which will degrade the performance of the blending material and ultimately destroy the phase morphology of the blend and reduce its mechanical properties.

The Effect of Functionalized SEBS on the Properties of PP/SEBS Blends.

Styrene (St) was used as comonomer and glycidyl methacrylate (GMA) as grafting monomer to prepare SEBS-g-(GMA-co-St) graft copolymers via melt grafting. Then, the graft copolymers were employed as a compatibilizer for melt blending polypropylene (PP) and hydrogenated styrene-butadiene-styrene (SEBS) triblock copolymers. The effects of the amount of GMA in the graft copolymers on thermal properties, rheology, crystallization, optical and mechanical properties, and microstructure of the blends were investigated. The results show that GMA and St were successfully grafted onto SEBS. The GMA amount in the graft copolymer significantly influenced the comprehensive properties of PP/SEBS/SEBS-g-(GMA-co-St) blends. The epoxy groups of GMA reacted with PP and SEBS, forming interfacial chemical bonds, thereby enhancing the compatibility between PP and SEBS to varying extents. After introducing SEBS-g-(GMA-co-St) into PP/SEBS blends, crystallinity decreased, crystal size increased while transmittance remained above 91% with rising GMA amount in the graft copolymers, indicating excellent optical properties. Notched impact strength and elongation at break of the blends showed a trend of first increasing and then decreasing with increased amounts of GMA in the graft copolymers. When the amount of GMA in the graft copolymers was 3 wt%, the blends exhibited optimal toughness with notched impact strength and elongation at break of 30,165.82 J/m2 and 1445.40%, respectively. This was attributed to the tightest dispersion interface adhesion and maximum matrix plastic deformation, consistent with the mechanical performance results.

The effect of propofol combined with sufentanil on anesthetic effect, cognitive function, and hemodynamics in patients undergoing intertrochanteric fracture surgery evaluated by propensity score matching.

OBJECTIVE: Surgery is the most common treatment for intertrochanteric fractures of the femur. Hemodynamic fluctuations caused by general anesthesia may lead to poor prognosis in patients. Residual anesthetic drugs reduce cognitive functions in patients. We investigated the effects of propofol combined with sufentanil on the anesthetic effect, cognitive function, and hemodynamics of patients undergoing intertrochanteric fracture surgery. METHODS: The clinical data of elderly patients undergoing intertrochanteric fracture surgery were retrospectively collected. Patients were divided into a control group (propofol + fentanyl) versus a combined group (propofol + sufentanil) according to the anesthesia protocol. Propensity score matching was used to analyze the specific effects of different anesthetic regimens on patients. RESULTS: For patients with intertrochanteric fracture, propofol combined with sufentanil had a quick onset of anesthesia, a short postoperative recovery time, and low pain compared with combined anesthesia using propofol and fentanyl. Propofol combined with sufentanil can maintain the relative stability of patients' hemodynamics and reduce the damage to patients' cognitive function compared with combined anesthesia using propofol and fentanyl. Propofol combined with sufentanil anesthesia does not increase the incidence of adverse reactions after surgery. CONCLUSION: The anesthesia scheme of propofol combined with sufentanil is effective and safe in elderly patients with intertrochanteric fractures of the femur.

Multifunctional nanodrug performs sonodynamic therapy and inhibits TGF-ß to boost immune response against colorectal cancer and liver metastasis.

Liver metastasis is the leading cause of death in colorectal cancer. Immunotherapy using immune checkpoint blockade (ICB) is ineffective due to its immunological cold tumor nature. Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor-ß receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it. After delivery to the tumor, NCG under ultrasonic irradiation generated reactive oxygen species causing tumor immunogenic cell death and releasing immunostimulatory signals such as calreticulin and HMGB1, which increased tumor immunogenicity and activated the innate T lymphocyte immune response. Moreover, NCG responded to the acidic microenvironment and released Gal, inhibiting phosphorylation and inducing immunosuppressive Smad2/3 signaling. Consequently, the differentiation of MDSCs was inhibited, M1-like polarization of tumor-associated macrophages was induced, and the immunosuppressive barrier of tumor-associated fibroblasts was destroyed to increase the infiltration of effector T cells, which reversed the immunosuppression of the tumor microenvironment and improved the therapeutic efficacy of anti-PD-L1 antibodies. Notably, in the liver metastasis mouse model, combination therapy using NCG (+) and aPD-L1 inhibited the growth of colon cancer liver metastasis, manifesting potential in treating this popular yet intractable malignancy. STATEMENT OF SIGNIFICANCE: Only a limited number of patients with colorectal cancer and liver metastasis can benefit from immune checkpoint blockade therapy, as most of them are microsatellite stable, immunologically cold tumors. Interestingly, there is compelling evidence that sonodynamic therapy (SDT) can convert immunosuppressed cold tumors into hot ones, trigger tumor immunogenic cell death non-invasively, and boost cytotoxic T cells infiltration. However, its therapeutic efficacy is constrained by the abundance of transforming growth factor-ß (TGF-ß) cytokines in the tumor microenvironment. Here, we reported a TGF-ß-targeted inhibitory nanodrug that improved SDT in colon cancer and liver metastasis, reversed the immunosuppressive tumor microenvironment and boosted the immune response to anti-PD-L1 therapy in this cancer. It demonstrated the potential to cure this prevalent but incurable malignancy.

Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer.

BACKGROUND: Cisplatin-based cytotoxic chemotherapy is considered to be the first-line therapy for advanced bladder cancer (BC), but resistance to cisplatin limits its antitumor effect. Fibroblast growth factor receptor 3 (FGFR3) has been reported to contribute to the progression and cisplatin resistance of BC. Meanwhile, chromobox protein homologue 7 (CBX7) was reported to inhibit BC progression. And our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress FGFR3, but the underlying mechanism and other cancer-related functions of CBX7 are still unknown. METHODS: Silico analysis of RNA-seq data to identify the upstream regulators and downstream target genes of CBX7. The western blot analysis, quantitative real-time PCR (RT-qPCR), chromatin immunoprecipitation (ChIP)-qPCR analysis, CCK-8 assay, and nude mice xenograft models were used to confirm the enhancer of zeste homologue (EZH2)/CBX7/ FGFR3 axis. RESULTS: In this study, we first showed that CBX7 is downregulated in BC. Then, we revealed that EZH2 represses CBX7 expression by increasing H3K27me3 in BC cells. Moreover, we demonstrated that CBX7 directly downregulates FGFR3 expression and sensitises BC cells to cisplatin treatment by inactivating the phosphatidylinositol 3-kinase (PI3K)-(RAC-alpha serine/threonine-protein kinase) AKT signalling pathway. CONCLUSIONS: These results suggest that CBX7 is an ideal candidate to overcome cisplatin resistance in BC.

CBX7 represses the POU2F2 to inhibit the PD-L1 expression and regulate the immune response in bladder cancer.

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system worldwide. To date, immune checkpoint inhibitors (including PD-1/PD-L1) have been applied to treat patients with bladder cancer in the clinic and achieved the promising outcome. Further improvement of the anticancer efficiency of these immune therapies is crucial for bladder cancer. Our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress PD-L1 expression and PD-1 checkpoint pathway in cancer. In this study, we revealed that CBX7 downregulated the expression of POU2F2 that indirectly repressed the PD-L1 in BC cells. Depletion of CBX7 resulted in resistance to PD-1 blockade in bladder cancer. Collectively, our results suggested that the CBX7/POU2F2/PD-L1 axis plays an important role in determining the antitumor effect of PD-1 blockade in bladder cancer.

Clinical Analysis of Renal Failure Caused by Malakoplakia: A Case Report and Literature Review.

Background: A 52-year-old middle-aged woman developed fatigue, poor appetite and elevated CRE levels 6 months ago without known causes of these symptoms. After repeated anti-infective and renal function improvement treatment, her symptoms did not significantly improve and local progress. Pathological examination confirmed soft spot disease of left kidney and bladder. Tests: Plain computed tomography (CT) scan of the lungs and urinary system; CT enhancement of the abdomen and pelvis, magnetic resonance (MR) enhancement of the abdomen and pelvis; positron emission tomography (PET)-CT; ultrasonography of the urinary system; cystoscopy, biopsy; and laboratory examination including urine routine and culture, urine protein quantification, cytology and culture of drainage fluid smear, routine blood test, and assessment of C-reactive protein, sedimentation, procalcitonin, liver function, renal function, electrolytes, thyroid function, parathyroid function, and cardiac enzymes. Diagnosis: Left-sided renal and bladder malakoplakia, chronic renal insufficiency (CKD stage 4), renal anemia, complicated urinary tract infection (Escherichia coli + smooth bacilli), chronic urinary retention, abscess of the left psoas major and iliac fossa, type II diabetes mellitus, grade III hypertension (very high risk), and post cholecystectomy. Treatment: Hospitalized urinary catheterization, anti-infective treatment, diagnostic anti-tuberculosis treatment, gastrointestinal dialysis, correction of anemia treatment, nutritional support, left lumbar enlargement, iliac fossa abscess puncture drainage, left nephrectomy.

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and has the highest mortality rate. For metastatic RCC, systemic drug therapy is the most important method in addition to surgical tumor reduction. In recent years, tyrosine kinase inhibitors (TKIs) targeting the angiogenesis have been applied to treat ccRCC and achieved profound therapeutic effects. It has been reported that most patients receiving antiangiogenic therapy will develop resistance within 15 months. The mechanism of resistance to targeted therapy is extremely complex and has not been clarified. Ovarian tumor-associated protease domain-containing proteins (OTUDs) belonging to DUBs play a critical role in the tumorigenesis of solid tumors. However, the specific role of OTUDs in ccRCC is still elusive. Here, we investigated the clinicopathological role of OTUD family members in ccRCC. We demonstrated that OTUD1 was downregulated in renal cancer and involved in the poor prognosis of renal cancer. Then, we showed that OTUD1 inhibits cancer cell growth. Moreover, analysis of OTUD1 RNA-seq data indicated that OTUD1 inhibition triggers the AKT and NF-kappa B pathways in renal cancer cells. Furthermore, OTUD1 interacts with PTEN and regulates its stability. Subsequently, we revealed that downregulation of OTUD1 contributes to the sensitivity of renal cancer cells to TKIs, and this effect was blocked by TNF/NF-kappa B inhibitors and AKT inhibitors. Thus, we identified that the OTUD1-PTEN axis suppresses tumor growth and regulates the resistance of renal cancer to TKIs.

The RNF26/CBX7 axis modulates the TNF pathway to promote cell proliferation and regulate sensitivity to TKIs in ccRCC.

Clear cell renal cell carcinoma (ccRCC) accounts for 85% of all malignant renal tumors. Currently, the pathogenesis of ccRCC is not fully understood. Chromobox (CBX) family proteins are the major subunits of PcG complexes and are implicated in regulating mammalian development. The CBX family consists of eight members, namely, CBX1-8. Numerous studies have highlighted that each CBX protein exhibits distinct functions and prognostic roles in specific cancer types. In this study, in silico analysis indicated that CBX7 was downregulated in ccRCC and correlated with favorable prognosis in a ccRCC cohort. Subsequent studies showed that CBX7 inhibited cancer cell proliferation and invasion. Then, we showed that CBX7 downregulated ETS1 to inactivate the tumor necrosis factor (TNF) signaling pathway, which inhibited tumor proliferation and enhanced the sensitivity of ccRCC cells to tyrosine kinase inhibitors (TKIs). Moreover, we found that CBX7 was a bona fide substrate of RNF26. RNF26 promoted the degradation of CBX7 and enhanced ccRCC tumor growth. Therefore, our results revealed a novel RNF26/CBX7 axis that modulates the TNF signaling pathway in ccRCC.

USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway.

Background: Bladder cancer is the fourth and tenth most common malignancy in men and women worldwide, respectively. One of the main reasons for the unsatisfactory therapeutic control of bladder cancer is that the molecular biological mechanism of bladder cancer is complex. Gasdermin B (GSDMB) is one member of the gasdermin family and participates in the regulation of cell pyroptosis. The role of GSDMB in bladder cancer has not been studied to date. Methods: TCGA database was used to exam the clinical relevance of GSDMB. Functional assays such as MTT assay, Celigo fluorescent cell-counting assay, Annexin V-APC assay and xenografts were used to evaluate the biological role of GSDMB in bladder cancer. Mass spectrometry and immunoprecipitation were used to detect the protein interaction between GSDMB and STAT3, or GSDMB and USP24. Western blot and immunohistochemistry were used to study the relationship between USP24, GSDMB and STAT3. Results: In this study, bioinformatics analysis indicated that the mRNA expression level of GSDMB in bladder cancer tissues was higher than that in adjacent normal tissues. Then, we showed that GSDMB promoted bladder cancer progression. Furthermore, we demonstrated that GSDMB interacted with STAT3 to increase the phosphorylation of STAT3 and modulate the glucose metabolism and promote tumor growth in bladder cancer cells. Besides, we also showed that USP24 stabilized GSDMB to activate STAT3 signaling, which was blocked by the USP24 inhibitor. Conclusions: We suggested that aberrantly up-regulated GSDMB was responsible for enhancing the growth and invasion ability of bladder cancer cells. Then, we showed that GSDMB could bind to STAT3 and activate STAT3 signaling in bladder cancer. Furthermore, we also demonstrated that USP24 interacted with GSDMB and prevented GSDMB from degradation in bladder cancer cells. Therefore, the USP24/GSDMB/STAT3 axis may be a new targetable signaling pathway for bladder cancer treatment.

Modified transperitoneal versus retroperitoneal laparoscopic radical nephroureterectomy in the management of upper urinary tract urothelial carcinoma: Best practice in a single center with updated results.

OBJECTIVE: Radical nephroureterectomy remains the gold standard for the surgical treatment of upper urinary tract urothelial carcinoma (UTUC). Based on previous research, we prospectively compared the advantages of transperitoneal laparoscopic radical nephroureterectomy (TLNU) with a three-port technique in a single position versus retroperitoneal laparoscopic radical nephroureterectomy (RLNU). METHODS: We evaluated 48 patients diagnosed with UTUC at our institution from January 2015 to October 2019. The patients underwent either TLNU (n = 24) or RLNU (n = 24). We randomly assigned the patients to each technique group based on their body mass index because our experience has shown that the body mass index is the main interfering factor for this surgery. The baseline characteristics and perioperative outcomes were compared between the groups. RESULTS: We found no significant differences in the baseline characteristics, time until recovery of intestinal function, or postoperative hospital stay between the two groups. However, the TLNU group had a shorter operation time and better postoperative pain control than the RLNU group. CONCLUSION: Modified TLNU is associated with a shorter operative time and less severe postoperative pain compared with RLNU. Both techniques are safe and reliable with adequate management, and their therapeutic effects are comparable in other aspects.