Tumor suppressive role of the epigenetic master regulator BRD3 in colorectal cancer.

Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.

Population Pharmacokinetic Modeling of Unbound Meropenem in Patients Undergoing Continuous Renal Replacement Therapy: An Observational Cohort Study.

BACKGROUND: The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach. METHODS: This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained. RESULTS: The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (%fT>4×MIC) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target %fT>MIC of 100%. CONCLUSIONS: This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines. CLINICAL TRIAL REGISTRATION: UMIN000024321.

Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.

Validation and development of population pharmacokinetic model of vancomycin using a real-world database from a nationwide free web application.

INTRODUCTION: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT). METHODS: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC. RESULTS: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age. CONCLUSIONS: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users.

Efficacy of thoracic endovascular aortic repair for aorto-esophageal fistula due to esophageal cancer: a systematic review and meta-analysis.

Aorto-esophageal fistula (AEF) due to esophageal cancer (EC) is a life-threatening condition characterized by sudden hemorrhage, which often causes sudden death. To evaluate the efficacy and safety of thoracic endovascular aortic repair (TEVAR) for AEF due to EC, we performed a systematic review and meta-analysis. We searched the MEDLINE (PubMed) databases, the Cochrane Library databases, Ichushi-Web (the databases of the Japan Medical Abstract Society), and CiNii (Academic information search service of the National Institute of Information from Japan) from January 2000 to November 2023 for articles about TEVAR for an emergent aortic hemorrhage (salvage TEVAR [S-TEVAR]), and the prophylactic procedure (P-TEVAR). Six studies (140 cases) were eligible for meta-analysis. The 90-day mortality of S-TEVAR and P-TEVAR was 40% (95% CI 23-60, I2 = 36%) and 8% (95% CI 3-17, I2 = 0%), respectively. Post-S-TEVAR hemorrhagic and infectious complications were 17% (95% CI 3-57, I2 = 71%) and 20% (95% CI 5-57, I2 = 66%), respectively. Post-P-TEVAR hemorrhagic and infectious complications were 2% (95% CI 0-10, I2 = 0%) and 3% (95% CI 1-12, I2 = 0%), respectively. TEVAR for AEF due to EC may be a useful therapeutic option to manage or prevent hemorrhagic oncological emergencies.

Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers.

BACKGROUND: Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. METHODS: We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. RESULTS: Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. CONCLUSIONS: Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.

Model-Informed Precision Dosing of Vancomycin in Adult Patients Undergoing Hemodialysis.

Model-informed precision dosing (MIPD) maximizes the probability of successful dosing in patients undergoing hemodialysis. In these patients, area under the concentration-time curve (AUC)-guided dosing is recommended for vancomycin. However, this model is yet to be developed. The purpose of this study was to address this issue. The overall mass transfer-area coefficient (KoA) was used for the estimation of vancomycin hemodialysis clearance. A population pharmacokinetic (popPK) model was developed, resulting in a fixed-effect parameter for nonhemodialysis clearance of 0.316 liters/h. This popPK model was externally evaluated, with a resulting mean absolute error of 13.4% and mean prediction error of -0.17%. KoA-predicted hemodialysis clearance was prospectively evaluated for vancomycin (n = 10) and meropenem (n = 10), with a correlation equation being obtained (slope of 1.099, intercept of 1.642; r = 0.927, P < 0.001). An experimental evaluation using an in vitro hemodialysis circuit validated the developed model of KoA-predicted hemodialysis clearance using vancomycin, meropenem, vitamin B6, and inulin in 12 hemodialysis settings. This popPK model indicated a maximum a priori dosing for vancomycin-a loading dose of 30 mg/kg, which achieves the target AUC for 24 h after first dose with a probability of 93.0%, ensured by a predialysis concentration of >15 µg/mL. Maintenance doses of 12 mg/kg after every hemodialysis session could achieve the required exposure, with a probability of 80.6%. In conclusion, this study demonstrated that KoA-predicted hemodialysis clearance may lead to an upgrade from conventional dosing to MIPD for vancomycin in patients undergoing hemodialysis.

High RRN3 expression is associated with malignant characteristics and poor prognosis in pancreatic cancer.

BACKGROUND: Pancreatic cancer has an extremely poor prognosis and is one of the most chemoresistant cancers. Targeting cancer cell transcriptional complexes may enhance chemotherapy effectiveness. RNA-polymerase I (Pol-I)-mediated transcription is an essential initial step for ribosome biogenesis and is related to cancer cell proliferation. RRN3 is a Pol-I-specific transcription initiation factor. In this study, we aimed to elucidate the function and clinical significance of RRN3 in pancreatic cancer. METHODS: We performed immunohistochemical staining to detect RRN3 protein expression in 96 pancreatic cancer tissues and analyzed the relationship between RRN3 protein expression, clinicopathological factors, and cancer patient prognosis. Moreover, we evaluated RRN3 function in vitro and in vivo using proliferation, invasion, and chemosensitivity assays in PANC-1 and SW1990 cell lines, with/without depleting RRN3 expression. RESULTS: RRN3 was mainly expressed in cancer cell nuclei. High levels of RRN3 expression were associated with Ki-67 expression and shorter overall survival. Additionally, proliferation and invasion ability were decreased when RRN3 was silenced with siRNA, compared to non-targeting siRNA-transfected cells. Chemosensitivity analysis showed that inhibition of RRN3 enhanced the sensitivity of pancreatic cancer cell lines to gemcitabine and paclitaxel. RRN3 siRNA-transfected PANC-1 tumors showed significantly reduced tumor volumes and high gemcitabine sensitivity compared to the control in a mouse xenograft model. CONCLUSION: High levels of RRN3 expression are associated with poor prognosis and cancer malignancy, such as proliferation, invasion ability, and chemosensitivity in pancreatic cancer. RRN3 targeting with anticancer drugs may be a promising therapeutic strategy to overcome refractory pancreatic cancer.

Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice.

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and ß-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis.

Preoperative evaluation of oral hygiene may predict the overall survival of patients with esophageal cancer.

BACKGROUND: Previously, the association between tooth loss and prognosis after esophagectomy was reported; however, the presence of periodontal disease has not been assessed. This study investigated the association between the degree of oral hygiene, as evaluated by tooth loss and periodontal disease, and the prognosis of patients with esophageal cancer. METHODS: A total of 163 esophageal cancer patients who underwent surgery with perioperative oral care and examination were enrolled. We assessed the periodontal pocket depth for the presence of periodontal disease and established a periodontal pocket index, defined as the sum of the periodontal pocket depth of the remaining tooth divided by the total count of the remaining teeth. Patients were divided into three groups: Group A (tooth loss < 13 and periodontal pocket index < 3.67); Group B (tooth loss < 13 and periodontal pocket index ≥ 3.67); and Group C (tooth loss ≥ 13). Overall survival and cancer-specific survival were analyzed, and a multivariate analysis was performed. RESULTS: There was a significant difference in the 5-year overall survival rates between the groups (A:B:C = 74.8%:62.8%:50.5%; p = 0.0098), but not in the 5-year cancer-specific survival rates (A:B:C = 80.2%:64.2%:62.2%; p = 0.0849). In multivariate analysis, oral hygiene (tooth loss < 13 and periodontal pocket index ≥ 3.67 + tooth loss ≥ 13; p = 0.041) was a significant independent poor prognostic factor for overall survival. CONCLUSIONS: Oral evaluation, focusing on tooth loss and periodontal disease, is meaningful in predicting the long-term prognosis of postoperative esophageal cancer patients.

GET4 is a novel driver gene in colorectal cancer that regulates the localization of BAG6, a nucleocytoplasmic shuttling protein.

Colorectal cancer (CRC) is one of the most common types of cancer and a significant cause of cancer mortality worldwide. Further improvements of CRC therapeutic approaches are needed. BCL2-associated athanogene 6 (BAG6), a multifunctional scaffold protein, plays an important role in tumor progression. However, regulation of BAG6 in malignancies remains unclear. This study showed that guided entry of tail-anchored proteins factor 4 (GET4), a component of the BAG6 complex, regulates the intercellular localization of BAG6 in CRC. Furthermore, GET4 was identified as a candidate driver gene on the short arm of chromosome 7, which is often amplified in CRC, by our bioinformatics approach using the CRC dataset from The Cancer Genome Atlas. Clinicopathologic and prognostic analyses using CRC datasets showed that GET4 was overexpressed in tumor cells due to an increased DNA copy number. High GET4 expression was an independent poor prognostic factor in CRC, whereas BAG6 was mainly overexpressed in the cytoplasm of tumor cells without gene alteration. The biological significance of GET4 was examined using GET4 KO CRC cells generated with CRISPR-Cas9 technology or transfected CRC cells. In vitro and in vivo analyses showed that GET4 promoted tumor growth. It appears to facilitate cell cycle progression by cytoplasmic enrichment of BAG6-mediated p53 acetylation followed by reduced p21 expression. In conclusion, we showed that GET4 is a novel driver gene and a prognostic biomarker that promotes CRC progression by inducing the cytoplasmic transport of BAG6. GET4 could be a promising therapeutic molecular target in CRC.

ASO Author Reflections: Impact of the Ratio of the Visceral Fat Area (VFA) to Psoas Muscle Area (PMA) (V/P Ratio) on Survival for Patients with Surgically Resected Esophageal Cancer.

PAST: The true impact of co-occurring muscle mass reduction and fat accumulation on patients with surgically resected esophageal cancer (EC) remains controversial. PRESENT: The current study defined reduction in muscle mass and excess body adiposity as the ratio of the visceral fat area (VFA) to the psoas muscle area (V/P ratio) on the same axial computed tomography slice at the third lumbar vertebra (L3). A high V/P ratio was associated with greater age (p = 0.03), higher body mass index (BMI) (p < 0.001), larger VFA (p < 0.001), and increased age-adjusted Charlson comorbidity index (ACCI) (p = 0.005). Multivariate analysis showed a high V/P ratio to be an independent prognostic factor for poor overall survival (OS) of EC patients who underwent surgery (p = 0.003). The prognostic value of the V/P ratio still was significant for EC patients with a BMI lower than 25 kg/m2. FUTURE: A high V/P ratio was an independent prognostic factor for OS of EC patients who underwent surgery, even BMI-defined non-obese EC patients. The V/P ratio as a surrogate marker of relative muscle mass reduction and fat accumulation may have prognostic value for EC patients regardless of body composition differences.

Impact of the Ratio of Visceral Fat Area (VFA) to Psoas Muscle Area (PMA) (V/P Ratio) on Survival for Surgically Resected Esophageal Cancer.

BACKGROUND: The synergic effects of muscle mass reduction with excess body adiposity in surgically resected esophageal cancer (EC) patients remains controversial, especially in non-obese patients. METHODS: One hundred and six patients with EC who underwent surgery between 2006 and 2014 were included in this study. Reduction in muscle mass and excess body adiposity were defined as the ratio of visceral fat area (VFA) to psoas muscle area (PMA) (V/P ratio) on the same axial computed tomography (CT) slice at the third lumbar vertebra (L3). RESULTS: A high V/P ratio was associated with greater age (p = 0.03), higher body mass index (BMI) (p < 0.001), higher VFA (p < 0.001), and increased age-adjusted Charlson comorbidity index (ACCI) (p = 0.005). Multivariate analysis revealed a high V/P ratio to be an independent prognostic factor for poor overall survival (OS) in EC patients who underwent surgery (p = 0.003). The prognostic value of the V/P ratio was still significant in EC patients with a BMI < 25. CONCLUSIONS: A high V/P ratio was associated with poor survival in surgically resected EC patients, even in non-obese patients. The V/P ratio as a surrogate marker of relative muscle mass reduction and fat accumulation may have prognostic value in EC patients regardless of body composition differences.

Potential use of EGFR-targeted molecular therapies for tumor suppressor CYLD-negative and poor prognosis oral squamous cell carcinoma with chemoresistance.

BACKGROUND: Tumor suppressor CYLD dysfunction by loss of its expression, triggers malignant transformation, especially drug resistance and tumor invasion/metastasis. Although loss of CYLD expression is significantly associated with poor prognosis in a large variety of tumors, no clinically-effective treatment for CYLD-negative cancer patients is available. METHODS: We focused on oral squamous cell carcinoma (OSCC), and sought to develop novel therapeutic agents for CYLD-negative cancer patients with poor prognosis. CYLD-knockdown OSCC cells by using CYLD-specific siRNA, were used to elucidate and determine the efficacy of novel drug candidates by evaluating cell viability and epithelial-mesenchymal transition (EMT)-like change. Therapeutic effects of candidate drug on cell line-derived xenograft (CDX) model and usefulness of CYLD as a novel biomarker using patient-derived xenograft (PDX) model were further investigated. RESULTS: CYLD-knockdown OSCC cells were resistant for all currently-available cytotoxic chemotherapeutic agents for OSCC, such as, cisplatin, 5-FU, carboplatin, docetaxel, and paclitaxel. By using comprehensive proteome analysis approach, we identified epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, played key roles in CYLD-knockdown OSCC cells. Indeed, cell survival rate in the cisplatin-resistant CYLD-knockdown OSCC cells was markedly inhibited by treatment with clinically available EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib. In addition, gefitinib was significantly effective for not only cell survival, but also EMT-like changes through inhibiting transforming growth factor-ß (TGF-ß) signaling in CYLD-knockdown OSCC cells. Thereby, overall survival of CYLD-knockdown CDX models was significantly prolonged by gefitinib treatment. Moreover, we found that CYLD expression was significantly associated with gefitinib response by using PDX models. CONCLUSIONS: Our results first revealed that EGFR-targeted molecular therapies, such as EGFR-TKIs, could have potential to be novel therapeutic agents for the CYLD-negative OSCC patients with poor prognosis.

Preoperative Risk Factors and Prognostic Impact of Postoperative Complications Associated with Total Gastrectomy.

INTRODUCTION: We evaluated the risk factors for patients with gastric cancer (GC) undergoing total gastrectomy (TG) that predict postoperative complications, including anastomotic leakage, postoperative pneumonia, and heart disease. METHODS: We collected 106 patients who received TG for GC between May 2009 and May 2017 at Gunma University Graduate School of Medicine, including clinicopathologic, surgical, postoperative complication, laboratory test, and physiologic test data. RESULTS: Of 106 patients, 92 (86.8%) had no complications, and 14 (13.2%) had complications. Univariate analyses revealed that a high American Society of Anaesthesiologists physical status (ASA-PS) and neutrophil-lymphocyte ratio (NLR) of ≥3.5 significantly correlated with postoperative complications. Multivariate analyses showed that high ASA-PS was an independent prognostic factor of postoperative complications. The cancer recurrence rate was 34.8% in the noncomplication group and 71.4% in the complication group. CONCLUSION: Patients with postoperative complications are prone to recurrence and poor prognosis. For patients with high-risk GC with poor ASA-PS and high NLR, more thorough perioperative management is essential.

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer.

Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti-apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC.

CD36 Expression Is Associated with Cancer Aggressiveness and Energy Source in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an important cause of cancer-related death worldwide. CD36, a long-chain fatty acid (FA) receptor, can initiate metastasis in human oral squamous cell carcinoma (SCC), and its expression is associated with poor prognosis in several cancers. The clinical significance of CD36 expression and its function in ESCC remain unknown. METHODS: We examined the clinical significance of CD36 expression in 160 ESCC samples using immunohistochemical staining. Functional analysis was performed to determine the association between CD36 and ESCC characteristics (proliferative ability, invasive ability, and energy source dependency). RESULTS: Thirty (18.8%) ESCC cases showed high CD36 expression, indicating a significant association with progression. CD36 suppression inhibited proliferation and invasiveness in ESCC cells. ESCC cells with CD36 suppression used specific essential amino acids (EAAs) as energy sources. Cell viability depended on FAs under CD36 expression. The viability of ESCC cells with CD36 suppression depended on EAAs but not FAs. CONCLUSIONS: CD36 may be a good biomarker and therapeutic target in ESCC. Our data provide new insights into the basic mechanism of CD36-dependent energy utilization for ESCC survival. CD36 might be a key regulator of the dependency of FAs as energy source in ESCC cells.

Performance of Area under the Concentration-Time Curve Estimations of Vancomycin with Limited Sampling by a Newly Developed Web Application.

PURPOSE: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation. METHODS: PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUCPAT) was evaluated against the reference AUC (AUCREF) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUCBM-P) calculated using an evaluated available software with clinical data. RESULTS: Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept -15.57, median AUCPAT/AUCREF 0.93 [range 0.81-1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8-1.2. Employment of only a trough concentration was more biased (AUCPAT/AUCREF range 0.73-1.30 for 11 h, AUCPAT/AUCREF range 0.62-1.40 for 23 h). In comparison with the evaluated software, AUCPAT was not biased against the AUCBM-P (slope 1.04, intercept -15.80, median AUCPAT/AUCBM-P 1.00 [range 0.86-1.10]). CONCLUSIONS: The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.

Chest Pain after Endoscopic Submucosal Dissection for Esophageal Cancer: The Simple and Clinically Useful Surrogate Marker for Transmural Thermal Injury by Electrocoagulation.

BACKGROUND: Endoscopic submucosal dissection (ESD) of early esophageal cancer (EC) is becoming more widespread. Post-ESD coagulation syndrome (CS) has been proposed as temporary inflammatory signs that occur during the post-ESD period caused by transmural thermal injury by electrocoagulation. This retrospective study aimed to evaluate the association between chest pain and abnormal levels of inflammatory markers during the post-esophageal ESD period. We also investigate the clinical importance of chest pain to define the post-esophageal ESD CS. METHODS: We examined 42 patients with thoracic EC who underwent ESD. RESULTS: The incidence of chest pain after esophageal ESD is 35.7% and associated with elevation of WBC count on postoperative day 1 (WBC day 1) (p = 0.022). Multivariate logistic regression analysis using the procedure-related factors revealed that WBC day 1 was an independent predictive factor for chest pain (p = 0.034). The elevation of WBC count is associated with the resected esophageal circumference (p for trend = 0.018), specimen size (p = 0.031), and procedural time (p = 0.004). The incidence of post-esophageal ESD CS was estimated ranging from 11.9 to 54.8% using previously reported criteria. CONCLUSIONS: The incidence of chest pain after ESD was only associated with postoperative elevation of WBC day 1. In considering the elevation of WBC count associated with procedure-related factors, chest pain possibly reflected transmural thermal injury by electrocoagulation during ESD. Post-esophageal ESD chest pain is a simple and clinically useful surrogate marker for transmural thermal injury and is a vital sign of post-esophageal ESD CS.

Suppressed Hepatic Production of Indoxyl Sulfate Attenuates Cisplatin-Induced Acute Kidney Injury in Sulfotransferase 1a1-Deficient Mice.

Endogenous factors involved in the progression of cisplatin nephropathy remain undetermined. Here, we demonstrate the toxico-pathological roles of indoxyl sulfate (IS), a sulfate-conjugated uremic toxin, and sulfotransferase 1A1 (SULT1A1), an enzyme involved in its synthesis, in cisplatin-induced acute kidney injury using Sult1a1-deficient (Sult1a1-/- KO) mice. With cisplatin administration, severe kidney dysfunction, tissue damage, and apoptosis were attenuated in Sult1a1-/- (KO) mice. Aryl hydrocarbon receptor (AhR) expression was increased by treatment with cisplatin in mouse kidney tissue. Moreover, the downregulation of antioxidant stress enzymes in wild-type (WT) mice was not observed in Sult1a1-/- (KO) mice. To investigate the effect of IS on the reactive oxygen species (ROS) levels, HK-2 cells were treated with cisplatin and IS. The ROS levels were significantly increased compared to cisplatin or IS treatment alone. IS-induced increases in ROS were reversed by downregulation of AhR, xanthine oxidase (XO), and NADPH oxidase 4 (NOX4). These findings suggest that SULT1A1 plays toxico-pathological roles in the progression of cisplatin-induced acute kidney injury, while the IS/AhR/ROS axis brings about oxidative stress.