G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Malacoplakia is a rare granuloma disease mainly occurred in the urinary system, it is even rarer for renal malacoplakia invading the descending colon complicated with bladder malacoplakia. In this study, one such case was reported. Imaging examination suggested that the left kidney was a large patchy mixed density shadow, and enhancement scan lesion was uneven enhancement. CT guided renal puncture biopsy was performed, and postoperative pathology suggested renal malacoplakia. Transurethral cystoscopy was performed, and postoperative pathology confirmed that it was malacoplakia of the bladder. The effect of conservative antibiotic treatment was not good. The patient underwent radical nephrectomy + left hemicolectomy under general anesthesia, and postoperative pathology confirmed the diagnosis of renal malacoplakia, which involved the mucosa of the intestinal tube and the entire muscular layer. The patient was followed up for 6 months after surgery, and no recurrence was seen on CT.

Objective:To compare the efficacy and safety of programmed death-1(PD-1)inhibitors in combination with chemotherapy versus chemotherapy alone in patients with metastatic bladder cancer.Methods:A retrospective analysis was performed on the clinical data of 77 cases of metastatic bladder cancer who were admitted to the First Affiliated Hospital of Zhengzhou University from January 2014 to October 2022. According to the different clinical treatment regimens, they were divided into two groups. Patients treated with PD-1 inhibitors combined with gemcitabine and cisplatin (GC) regimen were referred to as IGC group, and patients who received GC chemotherapy alone were referred to as GC group. There were 24 cases in IGC group, including 18 males and 6 females, with a median age of 60 (56, 67) years old. Seventeen cases had a history of smoking. Fifteen cases had an Eastern Cooperative Oncology Group (ECOG) score of 0 and 9 cases had a score of 1. Twenty-three cases suffered distant metastasis (stage M 1). Two cases suffered lymph node metastasis only, 6 cases with liver metastasis, 8 cases with lung metastasis, and 8 cases with bone metastasis. There were 53 cases in GC group, including 45 males and 8 females, with a median age of 63 (55, 69) years old. Thirty-one cases had a history of smoking. Thirty cases had an ECOG score of 0 and 23 cases had a score of 1, 48 cases suffered stage M 1, 2 cases suffered lymph node metastasis only. Nineteen cases suffered liver metastasis. Twenty-seven cases suffered lung metastasis. And 23 cases suffered bone metastasis. There was no statistically significant difference in the above general information between the two groups ( P>0.05). Kaplan-Meier method was used to plot the survival curves, and the difference of median progression-free survival (mPFS) and median overall survival (mOS) between the two groups was compared by log-rank test. Finally, the difference in adverse reactions between the two groups was compared. Results:The objective response rate (ORR) was 41.7% and the disease control rate (DCR) was 87.5% in the IGC group.As a comparison, the ORR was 43.4% and the DCR was 83.0% in the GC group. The differences in ORR ( P=0.887) and DCR ( P=0.871) between the two groups were not statistically significant. All patients were followed up for 3 to 45 months, with a median follow-up time of 24 (14, 43) months. The mPFS was 7.0 (95% CI 5.7-8.3) months in the GC group and 8.0 (95% CI 3.0-13.1) months in the IGC group, and the difference was statistically significant between the two groups ( P=0.026). The mOS of patients in the GC group was 16.0 (95% CI 14.4-17.6) months, the mOS was not yet reached in the IGC group, and patients in the IGC group had longer mOS with a statistically significant difference ( P=0.022). All patients experienced treatment-related adverse reactions. Grade 3-4 adverse reactions occurred in 8 cases (33.3%) in the IGC group and in 16 cases (30.2%) in the GC group, and no adverse reaction-related deaths were observed( P=0.992). The most common adverse reactions in both groups were anemia, including 18 cases (75.0%) in IGC group and 38 cases (71.7%) in GC group. There were 4 cases (16.7%) of grade 1-2 hypothyroidism in the IGC group but no patients with hypothyroidism were found in the GC group, and the difference was statistically significant ( P=0.012). There were 8 cases (33.3%) and 4 cases (7.5%) of grade 1-2 skin adverse reactions in the IGC and GC groups, respectively, and the difference was statistically significant ( P=0.011). The immune-related adverse reactions of PD-1 inhibitors in IGC group were 1 case of hyperthyroidism (4.2%), 4 cases of hypothyroidism (16.7%), 1 case of adrenal insufficiency (4.2%), and 1 case of immune colitis (4.2%). Conclusions:Compared with chemotherapy alone, PD-1 inhibitors combined with chemotherapy for metastatic bladder cancer can effectively prolong the mPFS and median mOS. The adverse reactions of the two groups were tolerable, and there was no significant difference in the incidence of grade 3-4 adverse reactions. In general, PD-1 inhibitors combined with chemotherapy in the treatment of metastatic bladder cancer is safe and feasible, but attention should be paid to the immune-related adverse reactions of PD-1 inhibitors.

Open abdomen therapy is an effective method for the treatment of severe intra-abdominal infections, abdominal hypertension and other critical abdominal diseases. Bases on systematic reviews of indications, classification and staging of wounds, principles and approaches of open abdomen therapy, abdominal closure measures, and management of enteroatmospheric fistula, the Chinese expert consensus on open abdomen therapy provides 12 recommendations with evidence and specific explanations. This consensus is the first systematic work in China to elaborate on open abdomen therapy, helping clinicians to standardize this technique and improve the treatment outcomes of critical abdominal diseases. In this review, we make interpretations on key points of this consensus one by one.

The protection of open abdomen (OA) wound is a significant subject in the field of trauma surgery. The key technical challenge in the early stage of OA wound management involves promoting granulation tissue filling between intestinal segments, reducing intestinal wall abrasion, and preventing the development of enteroatmospheric fistulas (EAF). Hydrogels, characterized by their high water content and exceptional biocompatibility, serve as extracellular matrix-mimicking materials, and are extensively employed in various medical and healthcare applications. In this review, we discuss the application of hydrogel developed by natural biomaterials in OA wounds protection, taking into consideration the unique pathophysiological characteristics of the OA wounds. This review aims to provide valuable insights for the development of hydrogel materials for early-stage OA wound protection in future research.

Open abdomen therapy is an effective method for the treatment of severe intra-abdominal infections, abdominal hypertension and other critical abdominal diseases. Bases on systematic reviews of indications, classification and staging of wounds, principles and approaches of open abdomen therapy, abdominal closure measures, and management of enteroatmospheric fistula, the Chinese expert consensus on open abdomen therapy provides 12 recommendations with evidence and specific explanations. This consensus is the first systematic work in China to elaborate on open abdomen therapy, helping clinicians to standardize this technique and improve the treatment outcomes of critical abdominal diseases. In this review, we make interpretations on key points of this consensus one by one.

The protection of open abdomen (OA) wound is a significant subject in the field of trauma surgery. The key technical challenge in the early stage of OA wound management involves promoting granulation tissue filling between intestinal segments, reducing intestinal wall abrasion, and preventing the development of enteroatmospheric fistulas (EAF). Hydrogels, characterized by their high water content and exceptional biocompatibility, serve as extracellular matrix-mimicking materials, and are extensively employed in various medical and healthcare applications. In this review, we discuss the application of hydrogel developed by natural biomaterials in OA wounds protection, taking into consideration the unique pathophysiological characteristics of the OA wounds. This review aims to provide valuable insights for the development of hydrogel materials for early-stage OA wound protection in future research.

Objective:To investigate the clinicopathological characteristics, treatment methods and prognosis of renal primary neuroendocrine neoplasms.Methods:The clinical data of 42 patients with renal neuroendocrine neoplasms admitted to the First Affiliated Hospital of Zhengzhou University from October 2011 to June 2021 were retrospectively analyzed.There were 17 males and 25 females. The median age was 60.0 (50.0, 67.0) years old.The CT enhancement scan lesion was slightly intensified with less intensification than normal renal parenchyma.The clinic manifestation included lumbar abdominal pain in 7 cases, hematuria in 3 cases, abdominal distension in 1 cases, and asymptomatic in 8 cases. The average diameter of tumor was 8.0 (4.0, 10.0) cm. The tumor of 13 cases was in the left, and 6 cases was in the right. 6 cases were in T 1 stage, 11 cases were in T 2, 11 cases were in T 3, and 14 cases were in T 4.17 cases had lymph node metastasis, 11 cases had distant metastasis.The surgical method was radical nephrectomy in 27 cases, nephrectomy in 5 cases and interventional embolization in 4 case, and no operation in 6 cases, including 5 with chemotherapy alone and 1 with supportive care.Patients were classified by WHO Classification of renal tumors of the urinary system and the male reproductive organs (2016) into high-differentiated renal neuroendocrine tumors (NET, including carcinoid and atypical carcinoids) and high-grade renal neuroendocrine carcinoma (NEC, including small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma). The clinicopathological characteristics and prognosis of the 2 groups were compared, and the Cox proportional regression risk model was used to analyze the clinical factors affecting the prognosis. Results:In the NET group, 12 cases were carcinoids and 7 cases were atypical carcinoids. In the NEC group, 23 cases were small cell carcinomas.The mean Ki-67 index of 42 cases was 35% (4.5%, 62.5%). The proportion of positive expression of the neuroendocrine markers CD56, chromogranin A (CgA), and synapsin (Syn) were (37/42), (15/42), and (38/42), respectively. A total of 42 patients were followed up, and the median follow-up time was 60 (35, 99) months, and the median survival time was 25 (15, 60) months. The 3-year and 5-year overall survival rates were 40.0% and 21.2%. The 3-year and 5-year overall survival rates in the NET group were 72.6% and 42.3%.The 3-year and 5-year overall survival rates in the NEC groups were 6.3% and 0, respectively. The mean Ki-67 index was 3% (2%, 10%) in the NET group, 2 patients received postoperative chemotherapy and 3 patients had early progression after initial treatment.The mean Ki-67 index in the NEC group was 60% (40%, 80%), 15 patients received postoperative chemotherapy, and 13 patients had early progression of initial treatment.There were statistically differences in treatment method, postoperative chemotherapy, Ki-67 index, and early disease progression (all P <0.05) between the two groups.The results of univariate analysis showed that sex, age, early progression, treatment method, tumor differentiation, and Ki-67 index were all factors influencing patient prognosis (all P <0.05). Cox multivariate analysis showed that poorly differentiated NEC ( HR=13.964, P=0.003) and early progression ( HR=3.626, P=0.018) were independent risk factors for patient survival, and renal radical surgery ( HR=0.197, P=0.033) was independent protective factors for patient survival. Further subgroup analysis showed that the median survival time of the NEC patients with adjuvant chemotherapy after surgery was significantly longer compared with the patients without adjuvant chemotherapy (21 and 9 months, P=0.012). Conclusions:Primary renal neuroendocrine tumors are clinically rare, often manifested as lumbar and abdominal pain, and radical renal surgical treatment is preferred.The NET has a better prognosis and NEC prognosis is extremely poor, but NEC patients can have survival benefit from chemotherapy. NEC and early progression of the disease are independent prognostic risk factors, and radical renal surgical treatment is an independent protective factor for prognosis.

Objective:To investigate the 2 years’ efficacy of intravesical instillation of domestic BCG versus epirubicin in the prevention of recurrence of intermediate-risk or high-risk non-muscular invasive bladder cancer and predictive factors of BCG instillation.Methods:From July 2015 to June 2020, 18-75 years old patients with moderate to high-risk non muscle invasive bladder cancer (NMIBC) confirmed by pathological examination were involved. The ECOG score was 0-2. Exclusion criteria included ①immune deficiency or impairment (such as AIDS), using immunosuppressive drugs or radiotherapy, suspected allergic to BCG or epirubicin or excipients of the two drugs, fever or acute infectious diseases including active tuberculosis or receiving anti tuberculosis treatment, with severe chronic cardiovascular and cerebrovascular diseases or chronic kidney disease; ②combined with other urogenital system tumors or other organ tumors; ③combined with muscle invasive bladder urothelial carcinoma (≥T 2); ④undergoing chemotherapy, radiotherapy or immunotherapy within 4 weeks (immediate instillation after surgery not included); ⑤ pregnant or lactating women; ⑥ comfirmed or suspected bladder perforation; ⑦gross hematuria; ⑧cystitis with severe bladder irritation that may affect the evaluation; ⑨participat in other clinical trials within 3 months; ⑩alcohol or drug addiction; ?any risk factors that may increasing the risk of patients. Epirubicin 50 mg was irrigated immediately after the operation(TURBT or laser resection). The patients were randomly divided into BCG15 group, BCG19 group and epirubicin group by the ratio of 2∶2∶1, and the patients were maintained intravescical instillation for 1 year. The recurrence and adverse events of the three groups were compared. Univariate and multivariate analysis was performed to predict the risk factors of BCG irrigated therapy failure. Result:By June 15, 2020, the median follow-up duration was 22.1 months(12.1, 32.3), and there was no statistical difference between the groups ( P=0.9024). There were 274 patients enrolled in BCG19 group, 277 patients enrolled in BCG15 group and 130 patients enrolled in the epirubicin group. The drop-off rate was 16.6%(113 cases)and made no difference between groups( P=0.6222). There were no significant difference in age, gender, BMI, or ECOG score( P>0.05). During the follow-up, 116 cases was detected recurrence or progression. The recurrence rate of the three groups was 14.2% and 14.8% in BCG19 group and BCG15 group, and 27.7% in the epirubicin group. There was no difference in recurrence rate between BCG19 and BCG15 group( P=0.9464). The recurrence rate of BCG19 group was lower than that of the epirubicin group ( P=0.0017). The recurrence rate of BCG15 group was lower than that of the epirubicin group ( P=0.0020). There was no difference in the cumulative recurrence free survival rate between BCG19 and BCG15 group (95% CI0.57-1.46, P=0.7173). The cumulative recurrence free survival rate of BCG 19 group was better than that of the epirubicin group( HR=0.439, 95% CI0.26-0.74, P=0.0006), and the cumulative recurrence free survival rate of BCG15 group was better than that of the epirubicin group ( HR=0.448, 95% CI0.29-0.80, P=0.0021). The total incidence of adverse events in 19 BCG19, BCG15 and epirubicin group were 74.5%, 72.6% and 69.8% respectively. There was no difference in the incidence of adverse events between BCG19 and BCG15 group( P=0.6153). The incidence of adverse events in epirubicin group was lower than that of BCG19( P=0.0051) and BCG15( P=0.0167) groups.There was no significant difference in the incidence of serious adverse events (SAE) among the three groups ( P=0.5064). Log rank test univariate analysis and Cox risk regression model multivariate analysis showed that the history of bladder cancer recurrence( HR=6.397, 95% CI1.95-20.94, P=0.0001)was independent risk factor for BCG irrigation failure. Conclusions:The 2 years’ efficacy of intravesical instillation of domestic BCG is better than than of epirubicin with good tolerance and safety. There is no difference between BCG19 and BCG15 group. BCG doesn’t increase SAE compared with epirubicin. Recurrence status was an independent prognostic factor regarding recurrence-free survival.