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BACKGROUND AND AIMS: Sarcopenia has been associated with poor prognosis in patients with malignant tumors. However, its impact on the outcomes of patients with biliary tract cancer (BTC) undergoing surgical resection remains unclear and warrants further review. This study aims to summarize the available evidence on this issue. METHODS: A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies up to March 10, 2024. We extracted data on overall survival (OS), recurrence free survival (RFS), and postoperative major complications from the included studies as the outcomes of interest. Following data synthesis and analysis, we assessed the heterogeneity and performed subgroup analyses. Additionally, the potential for publication bias was evaluated. RESULTS: A total of 26 studies involving 4292 BTC patients were ultimately retrieved. The findings indicated that sarcopenia was significantly associated with reduced OS in BTC patients after surgery (adjusted HR: 2.03, 95% CI: 1.65-2.48, P < 0.001, I2 = 57.4%). Moreover, sarcopenia may also be linked to poorer RFS (adjusted HR: 2.15, 95% CI: 1.79-2.59, P < 0.001, I2 = 0%) and increased postoperative major complications (OR: 1.22, 95% CI 1.02-1.47, P = 0.033, I2 = 29.2%) as well. Notably, no significant publication bias was detected through funnel plots and Egger's tests. CONCLUSION: Sarcopenia is associated with poorer OS in BTC patients following surgery. Additionally, it may serve as a prognostic indicator for poorer RFS and increased postoperative major complications. Further studies are warrant to standardize existing definitions and validate these findings.
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Neoplasias do Sistema Biliar , Complicações Pós-Operatórias , Sarcopenia , Humanos , Sarcopenia/diagnóstico por imagem , Sarcopenia/complicações , Neoplasias do Sistema Biliar/cirurgia , Neoplasias do Sistema Biliar/complicações , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Prognóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/diagnóstico , Taxa de SobrevidaRESUMO
Food waste is one of the important reservoirs of antibiotic resistance genes ï¼ARGsï¼, and its resource utilization has potential environmental risks. Anaerobic digestion ï¼ADï¼ technology can concurrently achieve resource recovery and ARGs removal, which is one of the popular resource technologies for food waste management. However, the removal efficiency of ARGs during the AD process is limited, and thus the safety of digestate for agricultural use is still questioned. Therefore, how to improve the performance of ARGs removal during the AD process is critical for efficient and environmentally friendly bioconversion of food waste. This study summarized the transmission pathways and mechanisms of ARGs in food wasteï¼ discussed the effects of different operation parameters on the transmission of ARGs in food waste during the AD processï¼ described the research progress of exogenous addition of conductive materials, feedstock pretreatment, etc., strategies to enhance the removal of ARGsï¼ and analyzed the migration regularity and removal mechanism of ARGs in food waste during the AD process, which mainly included microbial community structure evolution, mobile genetic element changes, and environmental factor changes. Finally, this study prospected the future improvement of methane yield and ARGs removal in the AD process of food waste based on the existing research.
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Resistência Microbiana a Medicamentos , Anaerobiose , Resistência Microbiana a Medicamentos/genética , Eliminação de Resíduos/métodos , Reatores Biológicos/microbiologia , Alimentos , Biodegradação Ambiental , Perda e Desperdício de AlimentosRESUMO
To detect and analyze the changes of microorganisms in expressed prostatic secretion (EPS) of patients with IIIB prostatitis before and after low-intensity pulsed ultrasound (LIPUS) treatment, and to explore the mechanism of LIPUS in the treatment of chronic prostatitis (CP). 25 patients (study power was estimated using a Dirichlet-multinomial approach and reached 96.5% at α = 0.05 using a sample size of 25) with IIIB prostatitis who were effective in LIPUS treatment were divided into two groups before and after LIPUS treatment. High throughput second-generation sequencing technique was used to detect and analyze the relative abundance of bacterial 16 s ribosomal variable regions in EPS before and after treatment. The data were analyzed by bioinformatics software and database, and differences with P < 0.05 were considered statistically significant. Beta diversity analysis showed that there was a significant difference between groups (P = 0.046). LEfSe detected four kinds of characteristic microorganisms in the EPS of patients with IIIB prostatitis before and after LIPUS treatment. After multiple comparisons among groups by DESeq2 method, six different microorganisms were found. LIPUS may improve patients' clinical symptoms by changing the flora structure of EPS, stabilizing and affecting resident bacteria or opportunistic pathogens.
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Próstata , Prostatite , Ondas Ultrassônicas , Humanos , Masculino , Prostatite/terapia , Prostatite/microbiologia , Prostatite/metabolismo , Próstata/microbiologia , Próstata/metabolismo , Próstata/patologia , Adulto , Bactérias/metabolismo , Bactérias/genética , Pessoa de Meia-Idade , Terapia por Ultrassom/métodos , Microbiota , RNA Ribossômico 16S/genéticaRESUMO
The application prospects of composite sponges with antibacterial and drug-carrying functions in the field of medical tissue engineering are extensive. A solution of cassava silk fibroin (CSF) was prepared with Ca(NO3)2 as a solvent, which was then combined with chitosan (CS) to create a sponge-porous material by freeze-drying. The CSF-CS composite sponge with a mesh structure was successfully fabricated through hydrogen bonding. Scanning electron microscopy (SEM), Fourier transform infrared absorption (FTIR) and X-ray diffraction (XRD) were employed to investigate the appearance and structure of the cassava silk's fibroin materials, specifically examining the impact of different mass percentages of CS on the sponge's structure. The swelling rate and mechanical properties of the CSF-CS sponge were analyzed, along with its antibacterial properties. Furthermore, by incorporating ibuprofen as a model drug into these loaded sponges, their potential efficacy as efficient drug delivery systems was demonstrated. The results indicate that the CSF-CS sponge possesses a three-dimensional porous structure with over 70% porosity and an expansion rate exceeding 400% while also exhibiting good resistance against pressure. Moreover, it exhibits excellent drug-carrying ability and exerts significant bacteriostatic effects on Escherichia coli. Overall, these findings support considering the CSF-CS composite sponge as a viable candidate for use in drug delivery systems or wound dressings.
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BACKGROUND: A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC. METHODS: This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis. RESULTS: A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size. CONCLUSION: Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study. TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT04118855.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Axitinibe , Carcinoma de Células Renais , Neoplasias Renais , Terapia Neoadjuvante , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Axitinibe/uso terapêutico , Axitinibe/farmacologia , Masculino , Feminino , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Estudos Prospectivos , Nefrectomia/métodosRESUMO
Background: This study investigates the potential impact of high progesterone (P) level on the day following human chorionic gonadotropin (HCG) injection on the clinical pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET). Methods: Retrospective analysis was conducted on 6418 cycles of IVF-ET performed at Liuzhou Maternal and Child Health Hospital between August 2020 to December 2021. Excluding cycles with progesterone levels ≥1.5ng/ml on HCG injection, a total of 781 cycles were identified according to the standard, and they were divided into five groups according to the progesterone level on the day after HCG: Group A: progesterone level < 2.5 ng/ml (n = 128); Group B: 2.5 ng/ml ≤ progesterone level < 3.5 ng/ml (n = 174); Group C: 3.5 ng/ml ≤ progesterone level < 4.5 ng/ml (n = 153); Group D: 4.5 ng/ml ≤ progesterone level < 5.5 ng/ml (n = 132); Group E progesterone level ≥5.5 ng/ml(n=194). Comparative analyses of clinical data, including general clinical data, and clinical pregnancy outcomes such as clinical pregnancy rate, miscarriage rate, and live birth rate were performed among these groups. Results: There were significant differences in estradiol levels on HCG injection, but there were no differences in available embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Binary logistic regression analysis showed that there was no significant correlation between P level on the day after HCG injection and the live birth rate. Conclusion: Under the condition of low P level on HCG injection, high progesterone levels on the day after HCG injection does not affect the clinical pregnancy outcomes of IVF-ET.
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Gonadotropina Coriônica , Transferência Embrionária , Fertilização in vitro , Resultado da Gravidez , Taxa de Gravidez , Progesterona , Humanos , Feminino , Gravidez , Progesterona/sangue , Transferência Embrionária/métodos , Fertilização in vitro/métodos , Gonadotropina Coriônica/administração & dosagem , Estudos Retrospectivos , Adulto , Nascido Vivo/epidemiologia , Indução da Ovulação/métodosAssuntos
Hepatectomia , Laparoscopia , Neoplasias Hepáticas , Humanos , Laparoscopia/métodos , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Cirurgia Assistida por Computador/métodos , Fluorescência , Prognóstico , Corantes Fluorescentes/administração & dosagemRESUMO
Spermatogonial stem cells (SSCs) are capable of transmitting genetic information to the next generations and they are the initial cells for spermatogenesis. Nevertheless, it remains largely unknown about key genes and signaling pathways that regulate fate determinations of human SSCs and male infertility. In this study, we explored the expression, function, and mechanism of USP11 in controlling the proliferation and apoptosis of human SSCs as well as the association between its abnormality and azoospermia. We found that USP11 was predominantly expressed in human SSCs as shown by database analysis and immunohistochemistry. USP11 silencing led to decreases in proliferation and DNA synthesis and an enhancement in apoptosis of human SSCs. RNA-sequencing identified HOXC5 as a target of USP11 in human SSCs. Double immunofluorescence, Co-immunoprecipitation (Co-IP), and molecular docking demonstrated an interaction between USP11 and HOXC5 in human SSCs. HOXC5 knockdown suppressed the growth of human SSCs and increased apoptosis via the classical WNT/ß-catenin pathway. In contrast, HOXC5 overexpression reversed the effect of proliferation and apoptosis induced by USP11 silencing. Significantly, lower levels of USP11 expression were observed in the testicular tissues of patients with spermatogenic disorders. Collectively, these results implicate that USP11 regulates the fate decisions of human SSCs through the HOXC5/WNT/ß-catenin pathway. This study thus provides novel insights into understanding molecular mechanisms underlying human spermatogenesis and the etiology of azoospermia and it offers new targets for gene therapy of male infertility.
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Apoptose , Proliferação de Células , Espermatogênese , Tioléster Hidrolases , Via de Sinalização Wnt , Humanos , Masculino , Células-Tronco Germinativas Adultas/metabolismo , Apoptose/genética , Azoospermia/metabolismo , Azoospermia/genética , Azoospermia/patologia , beta Catenina/metabolismo , beta Catenina/genética , Proliferação de Células/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Espermatogênese/genética , Espermatogônias/metabolismo , Espermatogônias/citologia , Testículo/metabolismo , Testículo/citologia , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo , Via de Sinalização Wnt/genéticaRESUMO
BACKGROUND: Cell division cycle associated 5 (CDCA5) plays ontogenetic role in various human cancers. However, its specific function and regulatory mechanism in ccRCC remain uncertain. METHODS: Immunohistochemistry and western blots were performed to investigate the expression of CDCA5 in ccRCC tissues. Genetic knockdown and upregulation of CDCA5 were performed to investigate its functional roles in ccRCC proliferation, migration, apoptosis and sunitinib resistance. Furthermore, Co-IP assay and LC-MS/MS were performed to investigate the underlying mechanisms. RESULTS: We found that CDCA5 expression is frequently upregulated in ccRCC tumors and is associated with poor prognosis of ccRCC patients. Functionally, CDCA5 promotes proliferation, migration, and sunitinib resistance, while inhibiting apoptosis in ccRCC cells. In vivo mouse xenograft model confirms that silencing of CDCA5 drastically inhibits the growth of ccRCC. Mechanistically, we discovered that CDCA5 interacts with Eukaryotic Translation Elongation Factor 1 Alpha 1 (EEF1A1) to regulate mTOR signaling pathway, thereby promoting ccRCC progression. CONCLUSIONS: Taken together, our results demonstrate the significant role of CDCA5 in ccRCC progression. The findings may provide insights for the development of new treatment strategies targeting CDCA5 for ccRCC patients.
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BACKGROUND: With introduction of "cone unit," which is the smallest resectable anatomical area supplied by a tertiary branch of Glissonean pedicle, more precise subsegmental anatomical resection has been proposed.1 Super-selective intra-arterial ICG staining, delivering ICG and lipiodol mixing to arterial branch using interventional radiology, has been proved feasibility especially for complicated anatomy.2-6 It was difficult to uniformly mix water-soluble ICG with lipophilic lipiodol, rendering to inconsistency development of liver segment between angiography and laparoscopy. Nano-ICG is a uniform mixing of ICG and lipiodol.7 We demonstrated an exclusive "two-step" method to perform LAR for cranial S7 via super-selective intra-arterial nano-ICG staining guidance. METHODS: A 70-year-old male was admitted. CT scan showed tumor was located in cranial S7 with 2.1*1.9 cm. Preoperative AFP was 4.66 ng/ml and PIVKA-II was 2332 mAU/ml. The liver function was Child-Pugh class A and ICG-15R was 7.8%. Given that tumor was confined to cranial S7, precise anatomical sub-segmentectomy was warranted. This study was approved by the West China Hospital, Sichuan University Ethics Committee (approval number: 2023-2327). RESULTS: The operation was performed "two step." "First step" was super-selective intra-arterial nano-ICG embolization in intervention room, while "second step" was performed in operation room. ICG demarcation line was clearly identified even after 7 hr. After full mobilization of right hemiliver, we performed transparenchymal approach to find and clamp pedicle of cranial S7 under fluorescence guidance. Operation time was 150 min with 20 ml of blood loss with uneventful course. CONCLUSIONS: Although LAR of S7 remains challenging, super-selective intra-arterial nano-ICG positive staining guidance might be a feasible and safe option.
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Hepatectomia , Verde de Indocianina , Laparoscopia , Neoplasias Hepáticas , Humanos , Masculino , Idoso , Laparoscopia/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Hepatectomia/métodos , Corantes/administração & dosagem , Óleo Etiodado/administração & dosagem , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/diagnóstico por imagem , Coloração e Rotulagem/métodos , PrognósticoRESUMO
Background: Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. Objective: To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. Methods: A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. Results: With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. Conclusion: PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.
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Antígenos de Superfície da Hepatite B , Neoplasias , Humanos , Vírus da Hepatite B/fisiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Antígenos E da Hepatite B , Estudos Retrospectivos , DNA Viral , Fatores de Risco , Neoplasias/tratamento farmacológicoRESUMO
Hepatectomy is widely considered a potential treatment for hepatocellular carcinoma (HCC). Unfortunately, one-third of HCC patients have tumor recurrence within 2 years after surgery (early recurrence), accounting for more than 60% of all recurrence patients. Early recurrence is associated with a worse prognosis. Previous studies have shown that microvascular invasion (MVI) is one of the key factors for early recurrence and poor prognosis in patients with HCC after surgery. This paper reviews the latest literature and summarizes the predictors of MVI, the correlation between MVI and early recurrence, the identification of suspicious nodules or subclinical lesions, and the treatment strategies for MVI-positive HCC. The aim is to explore the management of patients with MVI-positive HCC.
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Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Microvasos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Microvasos/patologia , Prognóstico , Fatores de TempoRESUMO
BACKGROUND: The optimal management of unresectable hepatocellular carcinoma (uHCC) remains an unresolved challenge. There is ongoing debate regarding the efficacy and safety of drug-eluting bead TACE (DEB-TACE) with tyrosine kinase inhibitors (TKIs). METHODS: We searched PubMed, Embase, Web of Science and the Cochrane Library for eligible studies. The main endpoints under investigation were survival outcomes, including overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Secondary outcomes encompassed tumor response rates and adverse events (AEs). Two researchers conducted the data extraction independently and assessed the quality of the studies. After pooling and analyzing the data, we assessed the heterogeneity and performed both subgroup analysis and sensitivity analysis. Additionally, we evaluated the potential for publication bias. RESULTS: Eight studies with 1513 patients were finally retrieved. Compared to monotherapy, although bigeminal therapy exhibited improved survival benefits (OS: HR: 0.56, 95 % CI 0.41-0.76, p < 0.001; TTP: HR: 0.72, 95 % CI 0.59-0.87, p = 0.001) and tumor response (ORR: RR: 1.59; 95 % CI 1.19-2.13, p = 0.002; DCR: RR: 1.14; 95 % CI 1.03-1.26, p = 0.010), the reliability of results was affected by significant heterogeneity. In the subgroup analysis, compared to DEB-TACE alone, the bigeminal therapy failed to show any statistical differences. Compared to TKIs, it demonstrated significant advantages in both survival (OS: HR: 0.49, 95 % CI 0.40-0.61, p < 0.001; TTP: HR: 0.60, 95 % CI 0.48-0.75, p < 0.001) and tumor response (ORR: RR: 2.40, 95 % CI 1.86-3.09, p < 0.001; DCR: RR: 1.36, 95 % CI 1.20-1.54, p < 0.001) while low heterogeneity was observed. Concerning safety, DEB-TACE provides no more severe AEs while TKIs-related AEs require close monitoring. CONCLUSION: Our findings suggest that DEB-TACE combined with TKIs may be a safe and effective treatment for uHCC, which is more suitable for patients in the advanced stage.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/métodos , Terapia Combinada , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidade , Resultado do Tratamento , /efeitos adversosRESUMO
Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary liver cancer. Although the genetic characterization of iCCA has led to targeted therapies for treating tumors with FGFR2 alterations and IDH1/2 mutations, only a limited number of patients can benefit from these strategies. Epigenomic profiles have emerged as potential diagnostic and prognostic biomarkers for improving the treatment of cancers. In this study, we conducted whole-genome bisulfite sequencing on 331 iCCAs integrated with genetic, transcriptomic, and proteomic analyses, demonstrating the existence of four DNA methylation subtypes of iCCAs (S1-S4) that exhibited unique postoperative clinical outcomes. The S1 group was an IDH1/2 mutation-specific subtype with moderate survival. The S2 subtype was characterized by the lowest methylation level and the highest mutational burden among the four subtypes and displayed upregulation of a gene-expression pattern associated with cell cycle/DNA replication. The S3 group was distinguished by high interpatient heterogeneity of tumor immunity, a gene-expression pattern associated with carbohydrate metabolism, and an enrichment of KRAS alterations. Patients with the S2 and S3 subtypes had the shortest survival among the four subtypes. Tumors in the S4 subtype, which had the best prognosis, showed global methylation levels comparable to normal controls, increased FGFR2 fusions/BAP1 mutations, and the highest copy-number variant burdens. Further integrative and functional analyses identified GBP4 demethylation, which is highly prevalent in the S2 and S3 groups, as an epigenetic oncogenic factor that regulates iCCA proliferation, migration, and invasion. Together, this study identifies prognostic methylome alterations and epigenetic drivers in iCCA. SIGNIFICANCE: Characterization of the DNA methylome of intrahepatic cholangiocarcinoma integrated with genomic, transcriptomic, and proteomic analyses uncovers molecular mechanisms affected by genome-wide DNA methylation alterations, providing a resource for identifying potential therapeutic targets.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Metilação de DNA , Humanos , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Colangiocarcinoma/mortalidade , Prognóstico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/mortalidade , Masculino , Feminino , Biomarcadores Tumorais/genética , Isocitrato Desidrogenase/genética , Mutação , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Sequenciamento Completo do Genoma/métodos , Idoso , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Perfilação da Expressão GênicaRESUMO
Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.
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Carcinoma de Células Renais , Fumaratos , Neoplasias Renais , RNA Longo não Codificante , Animais , Camundongos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Fumaratos/metabolismo , Glutamina , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , RNA Longo não Codificante/genética , HumanosRESUMO
BACKGROUND: Laparoscopic anatomical hepatectomy guided by near-infrared fluorescence imaging (NIR-FI) has been utilized extensively. However, it is difficult to resect "cone units" above the third branch of the Glissonean pedicle in the right posterior lobe using the laparoscopic positive or negative staining techniques. Therefore, we undertook a new laparoscopic segmentectomy based on the concept of "cone unit" assisted by interventional radiology combined with NIR-FI. METHODS: Laparoscopic segmentectomy guided by NIR-FI via super-selective hepatic arteriography and trans-arterial injection of ICG was carried out on 13 patients with early-stage HCC between September 2020 and January 2022.11 of cases were successful, and relevant pathological characteristics and perioperative outcomes were retrospectively analyzed. RESULTS: Two cases failed NIR-FI out of which one case involved over-staining to the non-target segment, and in the other case, which was to undergo laparoscopic segment V resection, only the ventral segment was stained while the imaging of the dorsal segment failed. In the intraoperative conditions, the tumor safe margin was 1.1 (0.7-1.55) cm, the interventional operation time was 50 (45.5-60.5) minutes, the operation time was 280 (242.5-307.5) minutes, the blood loss was 100 (50-200) ml, the postoperative hospital stay was 5 (4.5-5.5) days. No cases converted to laparotomy, and no serious postoperative complications developed. CONCLUSIONS: NIR-FI through super-selective hepatic arteriography and trans-arterial injection of ICG can provide a clear and lasting navigation aid for laparoscopic segmentectomy, which may have positive implication for early-stage HCC with poor preoperative liver reserves.
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Carcinoma Hepatocelular , Laparoscopia , Neoplasias Hepáticas , Humanos , Hepatectomia/métodos , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Estudos Retrospectivos , Verde de Indocianina , Laparoscopia/métodos , Imagem Óptica/métodosRESUMO
[This corrects the article DOI: 10.1016/j.omto.2019.12.007.].
RESUMO
Background: Metastatic upper tract urothelial carcinoma (mUTUC) is a malignant cancer associated with poor prognosis. Few studies have investigated the clinical outcome of a recently developed combination regimen of programmed cell death 1 (PD-1) inhibitor plus nab-paclitaxel in mUTUC. Methods: We retrospectively retrieved data from the electronic medical records of cisplatin-ineligible or cisplatin-refractory mUTUC patients from five participating Chinese centers, who received treatment of PD-1 inhibitor plus nab-paclitaxel between April 2018 and January 2022. Clinical response was assessed according to Response Evaluation Criteria in Solid Tumors criteria version 1.1 (RECIST 1.1). Duration of response (DOR), overall survival (OS), and progression-free survival (PFS) were evaluated by the Kaplan-Meier method. Results: The confirmed overall response rate (ORR) was 14/34 (41.2%), and the disease control rate (DCR) was 24/34 (70.6%). Complete response (CR) was achieved in one case, partial response (PR) in 13 cases (38.2%), stable disease (SD) in 10 cases (29.4%), and progressive disease (PD) occurred in 10 cases (29.4%). After a median follow-up period of 16.0 months [95% confidence interval (CI): 9.9-22.1], 14 deaths were reported, with a median OS of 15.0 months (95% CI: 9.9-20.1); 22 progressions were reported, with a median PFS of 6.0 months (95% CI: 2.4-9.6). Patients with visceral metastasis had a similar PFS [hazard ratio (HR): 1.28, 95% CI: 0.53-3.09, P=0.574) and OS (HR: 1.94, 95% CI: 0.64-5.83, P=0.279] to patients with lymph node metastasis only. Conclusions: This real-world study suggests that PD-1 inhibitor plus nab-paclitaxel is effective in cisplatin-ineligible and cisplatin-refractory mUTUC patients with acceptable toxicity, especially for patients with visceral metastasis.