A rat-based preclinical platform facilitating transcatheter hepatic arterial infusion in immunodeficient rats with liver xenografts of patient-derived pancreatic ductal adenocarcinoma.

Liver metastases from pancreatic ductal adenocarcinoma (PDAC) are highly fatal. A rat-based patient-derived tumor xenograft (PDX) model is available for transcatheter therapy. This study aimed to create an immunodeficient rat model with liver xenografts of patient-derived primary PDAC and evaluate efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived PDACs were transplanted into the livers of 21 rats each (totally, 63 rats), randomly assigned into hepatic arterial infusion, systemic venous infusion, and control groups (n = 7 each) four weeks post-implantation. Computed tomography evaluated tumor volumes before and four weeks after treatment. Post-euthanasia, resected tumor specimens underwent histopathological examination. A liver-implanted PDAC PDX rat model was established in all 63 rats, with first CT identifying all tumors. Four weeks post-treatment, arterial infusion groups exhibited significantly smaller tumor volumes than controls for all three tumors on second CT. Xenograft tumors histologically maintained adenocarcinoma features compared to original patient tumors. Ki67 expression was significantly lower in arterial infusion groups than in the other two for the three tumors, indicating reduced tumor growth in PDX rats. A liver-implanted PDAC PDX rat model was established as a rat-based preclinical platform. Arterial cisplatin infusion chemotherapy represents a potential therapy for PDAC liver metastasis.

Multicenter randomized controlled trial of intensive uric acid lowering therapy for CKD patients with hyperuricemia: TARGET-UA.

BACKGROUND: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients. METHODS: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment. RESULTS: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups. CONCLUSION: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146).

Impact of Tumor Subclassifications for Identifying an Appropriate Surgical Strategy in Patients with Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. The impact of these subclassifications for identifying appropriate surgical strategies remains unclear. PATIENTS AND METHODS: This study included 118 patients with ICC who underwent liver resection. Based on the pathological examination results, the participants were divided into the small duct-type ICC group (n = 64) and large duct-type ICC group (n = 54). The clinicopathological features and postoperative outcomes were compared between the two groups to investigate the impact of subclassification for selecting appropriate surgical strategies. RESULTS: Ten patients in the small duct-type ICC group had synchronous or metachronous hepatocellular carcinoma. The large duct-type ICC group had higher proportions of patients who underwent major hepatectomy, extrahepatic bile duct resection, portal vein resection, and lymph node sampling or dissection than the small duct-type ICC group. The large duct-type ICC group had significantly higher incidences of lymph node metastasis/recurrence and pathological major vessel invasion than the other. The small duct-type ICC group exhibited significantly higher recurrence-free and overall survival rates than the large duct-type ICC group. Further, the large duct-type ICC group had a significantly higher incidence of lymph node metastasis/recurrence than the small duct-type ICC at the perihilar region group. CONCLUSIONS: Suitable surgical strategies may differ between the small and large duct-type ICCs. In patients with large duct-type ICCs, hepatectomy with lymph node dissection and/or biliary reconstruction should be considered, whereas hepatectomy without these advanced procedures can be suggested for patients with small duct-type ICCs.

Impact of frailty on long-term outcomes after liver resection for hepatocellular carcinoma in elderly patients: A prospective study.

BACKGROUND: sFrailty affects short-term outcomes after liver resection in elderly patients. However, frailty's effects on long-term outcomes after liver resection in elderly patients with hepatocellular carcinoma (HCC) are unknown. METHODS: This prospective, single-center study included 81 independently living patients aged ≥65 years scheduled to undergo liver resection for initial HCC. Frailty was evaluated according to the Kihon Checklist, a phenotypic frailty index." We investigated and compared postoperative long-term outcomes after liver resection between patients with and without frailty. RESULTS: Of the 81 patients, 25 (30.9%) were frail. The proportion of patients with cirrhosis, high serum alpha-fetoprotein level (≥200 ng/mL), and poorly differentiated HCC was higher in the frail group than in the nonfrail group (n = 56). Among the patients with postoperative recurrence, the incidence of extrahepatic recurrence was higher in the frail group than in the nonfrail group (30.8% vs. 3.6%, P = 0.028). Moreover, the proportion of patients who underwent repeat liver resection and ablation for recurrence who met the Milan criteria tended to be lower in the frail group than in the nonfrail group. Although there was no difference in disease-free survival between the two groups, the overall survival rate in the frail group was significantly worse than that in the nonfrail group (5-year overall survival: 42.7% vs. 77.2%, P = 0.005). Results of the multivariate analysis indicated that frailty and blood loss were independent prognostic factors for postoperative survival. CONCLUSION: Frailty is associated with unfavorable long-term outcomes after liver resection in elderly patients with HCC.

Efficacy and safety of neoadjuvant nab-paclitaxel plus gemcitabine therapy in patients with borderline resectable pancreatic cancer: A multicenter single-arm phase II study (NAC-GA trial).

Background: Nab-paclitaxel plus gemcitabine is a standard treatment for metastatic/locally advanced pancreatic cancer. The effectiveness of neoadjuvant therapy with nab-paclitaxel plus gemcitabine (GnP-NAT) in patients with borderline resectable pancreatic cancer (BRPC) remains unclear. Patients and Methods: This single-arm phase II trial included 61 patients with BRPC that were treated with two cycles of GnP-NAT, (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2), on days 1, 8, and 15 over a 4-week period, which comprised one cycle. The primary endpoint was overall survival time. In the absence of disease progression, patients underwent planned pancreatectomy. Results: Median overall survival, the primary endpoint, was 25.2 months, and the median recurrence-free survival was 12.3 months. The overall rate of grade 3/4 events was 73.8%. One patient, who had a history of radiation therapy for past esophageal cancer, died from exacerbation via pneumonia. The overall resection rate was 73.8% (n = 45), and the R0 resection rate was 63.9% (n = 39). Overall, postoperative complications were found in 19 patients (42%) with 24 events, and nine patients (20%) with nine events ≥ grade IIIa, based on Dindo's classification. Conclusions: This protocol treatment is thought to be a feasible, safe, and promising treatment regimen, but we caution against its use in patients with a history of interstitial lung disease and/or prior pulmonary irradiation. The survival data from this study suggest the need for further investigations of GnP-NAT efficacy in patients with BRPC, as well as prospective evaluation of adverse events. Clinical Trial Registration: UMIN Clinical Trials Registry, UMIN000024154 and ClinicalTrials.gov, NCT02926183.

Application of Indocyanine Green Fluorescence Imaging for Tumor Localization during Robot-Assisted Hepatectomy.

The efficacy of indocyanine green (ICG) fluorescence imaging for visualizing hepatic tumors in robot-assisted hepatectomy (RAH) should be validated. This study included 30 consecutive patients with 33 collective tumors who underwent RAH. ICG was administered at a dose of 0.5 mg/kg before surgery. ICG fluorescence imaging was performed intraoperatively. In total, 28 patients with a combined total of 31 tumors underwent ICG fluorescence imaging. Further, 26 (84%) tumors were identified on hepatic surfaces prior to hepatic transection. The fluorescence signals of eight tumors were detected on hepatic raw surfaces during parenchymal dissection, thereby enabling surgeons to adjust the transection planes to ensure appropriate surgical margins. One patient with intrahepatic cholangiocarcinoma tested positive for cancer cells at the dissected stump of the bile duct. However, in all patients in whom ICG fluorescence imaging was used, negative surgical margins were achieved at the site of the dissected hepatic parenchyma. On the other hand, one of two patients with ICG contraindications had a positive surgical margin surrounding the dissected hepatic parenchyma. The median operative time and volume of blood loss were 259 (range: 124-594) min and 150 (range: 1-1150) mL, respectively. ICG fluorescence imaging facilitates the easy identification of hepatic tumors, even in RAH. Hence, it can be useful for confirming appropriate surgical margins.

Efficacy and safety of tazobactam/ceftolozane in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice.

INTRODUCTION: This single-center study evaluated the efficacy and safety of tazobactam/ceftolozane (TAZ/CTLZ) in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice. METHODS: This study included 50 patients, including 35 with intraabdominal abscess or peritonitis, 5 with liver abscess, 4 with cholecystitis, and 6 with cholangitis with sepsis. Of the 50 patients, 29 received TAZ/CTLZ and metronidazole after a prior antibacterial therapy failure, including tazobactam/piperacillin, cefmetazole, and levofloxacin. Source control was performed in 36 patients. RESULTS: The clinical response could be evaluated in 49 patients. The clinical cure rate at end-of-therapy was 91.8% (45 of 49 patients) and that at test-of-cure was 89.6% (43 of 48 patients). Of 5 patients in whom clinical response at test-of-cure was a failure, 1 developed infectious disease during chemoradiotherapy for recurrent cancer and 4 after liver resection or pancreatoduodenectomy. Three of the 4 patients were associated with pancreatic juice leakage. Isolated pathogens were eradicated or presumably eradicated in 27 of 31 (87.1%) patients in whom microbiological response at test-of-cure could be evaluated. The response rate for AmpC-producing Enterobacteriaceae was 87.5%. Nausea was observed in two patients. Aspartate and alanine aminotransferase activities were increased in 3 of the 50 (6.0%) patients. The activities improved after the antibiotic discontinuation. CONCLUSIONS: This observational study demonstrated that TAZ/CTLZ in combination with metronidazole has a favorable effect without major drug-related adverse events for intraabdominal infection in the hepato-biliary-pancreatic field in clinical practice although the efficacy of TAZ/CTLZ may decrease in compromised patients.

Pancreaticoduodenectomy with celiac artery resection (PD-CAR) for unresctable locally advanced pancreatic ductal adenocarcinoma.

PURPOSE: Locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) involving the celiac artery (CeA), the common hepatic artery and the gastroduodenal artery (GDA) is considered unresectable. We developed the novel procedure of pancreaticoduodenectomy with celiac artery resection (PD-CAR) for such LA-PDACs. METHODS: From 2015 to 2018, we performed curative pancreatectomy with major arterial resection for 13 LA-PDACs as a clinical study (UMIN000029501). Of those, four patients with pancreatic neck cancer involving the CeA and GDA were candidates for PD-CAR. Prior to surgery, blood flow alterations were performed to unify the blood flow to the liver, stomach, and pancreas, resulting in feeding from the cancer-free artery. During PD-CAR, arterial reconstruction of the unified artery was performed as needed. Based on the records of PD-CAR cases, we retrospectively analyzed the validity of the operation. RESULTS: R0 resection was achieved in all patients. Arterial reconstruction was performed in three patients. In another patient, the hepatic arterial flow was maintained by preserving of the left gastric artery. The mean operative time was 669 min, and the mean blood loss was 1003 ml. Although Clavien-Dindo classification III-IV postoperative morbidities occurred in three patients, no reoperations nor mortalities occurred. Although two patients died of cancer recurrence, one patient survived for 26 months without recurrence (died of cerebral infarction), and another is alive at 76 months without recurrence. CONCLUSION: PD-CAR, which enabled R0 resection and preservation of the residual stomach, pancreas, and spleen, provided acceptable postoperative outcomes.

Deep Learning Model Based on Contrast-Enhanced Computed Tomography Imaging to Predict Postoperative Early Recurrence after the Curative Resection of a Solitary Hepatocellular Carcinoma.

We aimed to develop the deep learning (DL) predictive model for postoperative early recurrence (within 2 years) of hepatocellular carcinoma (HCC) based on contrast-enhanced computed tomography (CECT) imaging. This study included 543 patients who underwent initial hepatectomy for HCC and were randomly classified into training, validation, and test datasets at a ratio of 8:1:1. Several clinical variables and arterial CECT images were used to create predictive models for early recurrence. Artificial intelligence models were implemented using convolutional neural networks and multilayer perceptron as a classifier. Furthermore, the Youden index was used to discriminate between high- and low-risk groups. The importance values of each explanatory variable for early recurrence were calculated using permutation importance. The DL predictive model for postoperative early recurrence was developed with the area under the curve values of 0.71 (test datasets) and 0.73 (validation datasets). Postoperative early recurrence incidences in the high- and low-risk groups were 73% and 30%, respectively (p = 0.0057). Permutation importance demonstrated that among the explanatory variables, the variable with the highest importance value was CECT imaging analysis. We developed a DL model to predict postoperative early HCC recurrence. DL-based analysis is effective for determining the treatment strategies in patients with HCC.

Mechanism for exercise-mediated prevention against muscle wasting on extensor digitorum longus muscle in Spontaneously Diabetic Torii fatty rats.

We previously reported the significant increase in limb muscle strength and cross-sectional area of the type IIb muscle fibers in the extensor digitorum longus (EDL) muscle in a type 2 diabetic animal model, with Spontaneously Diabetic Torii (SDT) fatty rats (n = 6) undergoing regular treadmill exercise from 8 to 16 weeks of age compared with sedentary SDT fatty rats (n = 6). This study investigated the mechanism by which exercise training prevented skeletal muscle wasting in the EDL muscle of the SDT fatty rats. The endurance exercise for 8 weeks downregulated the expression of muscle RING-finger protein-1 (an E3 ubiquitin ligase) and upregulated the expression of CD31, insulin receptor substrate-2, and phosphorylated endothelial nitric oxide synthase in the EDL muscle of 16-week-old SDT fatty rats.Endurance exercise training might reduce muscle wasting by preventing muscle degradation and increasing the angiogenic response in the EDL muscle in type 2 diabetes.

Angiotensin II type 1a receptor deficiency alleviates muscle atrophy after denervation.

The study aim was to determine if suppressed activation of angiotensin II type 1 receptor (AT1) prevents severe muscle atrophy after denervation. The sciatic nerves in right and left inferior limbs were cut in AT1a knockout homo (AT1a-/-) male mice and wild-type (AT1a+/+) male mice. Muscle weight and cross-sectional areas of type IIb muscle fibers in gastrocnemius muscle decreased at 7 and 21 days postdenervation in both AT1a-/- mice and AT1a+/+ mice, and the reduction was significantly attenuated in the denervated muscles of AT1a-/- mice compared to the AT1a+/+ mice. Gene expressions in the protein degradation system [two E3 ubiquitin ligases (muscle RING-finger protein-1 and Atrogin-1)] upregulated at 7 days postdenervation in all denervated mice were significantly lower in AT1a-/- mice than in AT1a+/+ mice. Activations of nuclear factor κB and Forkhead box subgroup O1, and protein expression of monocyte chemoattractant protein-1 were significantly suppressed in the AT1a-/- mice compared with those in the AT1a+/+ mice. In addition, suppressed apoptosis, lower infiltration of M1 macrophages, and higher infiltration of M2 macrophages were significantly observed at 21 days postdenervation in the AT1a-/- mice compared with those in the AT1a+/+ mice. In conclusion, the AT1 receptor deficiency retarded muscle atrophy after denervation.

Tumor-infiltrating lymphocytes and macrophages as a significant prognostic factor in biliary tract cancer.

BACKGROUND: The impact of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) on the prognosis of biliary tract cancer (BTC) is not completely understood. Therefore, in our study, we investigated the effects of the various immune cells infiltration in tumor microenvironment (TME). METHODS: A total of 130 patients with BTC who underwent surgical treatment at our institution were enrolled in this study. We retrospectively evaluated TILs and TAMs with immunohistochemical staining. RESULTS: With CD8-high, CD4-high, FOXP3-high, and CD68-low in TME as one factor, we calculated Immunoscore according to the number of factors. The high Immunoscore group showed significantly superior overall survival (OS) and recurrence-free survival (RFS) than the low Immunoscore group (median OS, 60.8 vs. 26.4 months, p = 0.001; median RFS not reached vs. 17.2 months, p < 0.001). Also, high Immunoscore was an independent good prognostic factor for OS and RFS (hazards ratio 2.05 and 2.41 and p = 0.01 and p = 0.001, respectively). CONCLUSIONS: High Immunoscore group had significantly superior OS and RFS and was an independent good prognostic factor for OS and RFS.

Comparison of clinicopathological characteristics between resected ampullary carcinoma and carcinoma of the second portion of the duodenum.

BACKGROUND: Few studies compared the oncological and biological characteristics between ampullary carcinoma (AC) and cancer of the second portion of the duodenum (DC-II), although both tumors arise from anatomically close locations. AIM: To elucidate differences in clinicopathological characteristics, especially the patterns of lymph node metastasis (LNM), between AC and DC-II. METHODS: This was a retrospective cohort study of 80 patients with AC and 27 patients with DC-II who underwent pancreaticoduodenectomy between January 1998 and December 2018 in two institutions. Clinicopathological factors, LNM patterns, and prognosis were compared between the two groups. RESULTS: The patients with AC and DC-II did not exhibit significant differences in 5-year overall survival (66.0% and 67.1%, respectively) and 5-year relapse-free survival (63.5% and 62.2%, respectively). Compared to the patients with DC-II, the rate of preoperative biliary drainage was higher (P = 0.042) and the rates of digestive symptoms (P = 0.0158), ulcerative-type cancer (P < 0.0001), large tumor diameter (P < 0.0001), and advanced tumor stage (P = 0.0019) were lower in the patients with AC. The LNM rates were 27.5% and 40.7% in patients with AC and DC-II, respectively, without significant difference (P = 0.23). The rates of LNM to hepatic nodes (N-He) and pyloric nodes (N-Py) were significantly higher in patients with DC-II than in those with AC (metastasis to N-HE: 18.5% and 5% in patients with DC-II and AC, respectively; P = 0.0432; metastasis to N-Py: 11.1% and 0% in patients with DC-II and AC, respectively; P = 0.0186). CONCLUSION: Although there were no significant differences in the prognosis and recurrence rates between the two groups, metastases to N-He and N-Py were more frequent in patients with DC-II than in those with AC.

Interleukin-8 produced from cancer-associated fibroblasts suppresses proliferation of the OCUCh-LM1 cancer cell line.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play an important role in cancer growth by interacting with cancer cells, but their effects differ depending on the type of cancer. This study investigated the role of CAFs in biliary tract cancers (BTCs), compared with pancreatic ductal adenocarcinoma (PDAC) as a comparison cohort. METHODS: We retrospectively evaluated alpha-smooth muscle actin (αSMA) expression in CAFs from 114 cases of PDAC and 154 cases of BTCs who underwent surgical treatment at our institution from 1996 to 2017. CAFs were isolated from resected specimens of BTC and PDAC, and tested for the effects of their supernatants and cytokines on cancer cell proliferation. RESULTS: PDAC patients with positive αSMA expression showed significantly shorter overall survival and recurrence-free survival than αSMA-negative patients (p = 0.003, p = 0.009, respectively). BTC patients with positive αSMA expression showed better recurrence-free survival than αSMA-negative patients (p = 0.03). CAF-conditioned medium suppressed the proliferation of cancer cells for only OCUCh-LM1 cells and not PDAC cells. Blockage of Interleukin-8 (IL-8) or its receptor C-X-C motif chemokine receptor 2 (CXCR2) by antibodies canceled the suppressive effect of the IL-8. CONCLUSIONS: CAFs are a good prognostic factor in BTC, but not for PDAC. Moreover, CAF-produced Interleukin-8 suppresses the proliferation of OCUCh-LM1 cell lines.

Laparoscopic liver resection reduces postoperative infection in patients with hepatocellular carcinoma: a propensity score-based analysis.

BACKGROUND: This study is aimed to compare the occurrence of postoperative infections between patients with hepatocellular carcinoma (HCC) undergoing laparoscopic liver resection (LLR) and those undergoing open liver resection (OLR). METHODS: This study included 446 patients who underwent initial curative liver resection for HCC 5 cm or less in size without macroscopic vascular invasion. To adjust for confounding factors between the LLR and OLR groups, propensity score matching and inverse probability weighting (IPW) analysis were performed. The incidence rates of postoperative infection, including incisional surgical site infection (SSI), organ/space SSI, and remote infection (RI), were compared between the two groups. RESULTS: An imbalance in several confounding variables, including period of surgery, extent of liver resection, difficult location, proximity to a major vessel, tumor size ≥ 3 cm, and multiple tumors, was observed between the two groups in the original cohort. After matching and weighting, the imbalance between the two groups significantly decreased. Compared with OLR, LLR was associated with a lower volume of intraoperative blood loss (140 vs. 350 mL, P < 0.001 in the matched cohort; 120 vs. 320 mL, P < 0.001 in the weighted cohort) and reduced risk of postoperative infection (2.0% vs. 12%, P = 0.015 in the matched cohort; 2.9% vs. 14%, P = 0.005 in the weighted cohort). Of the types of postoperative infections, organ/space SSI and RI were less frequently observed in the LLR group than in the OLR group in the matched cohort (1.0% vs. 6.0%, P = 0.091 for organ/space SSI; 0% vs. 6.0%, P < 0.001 for RI) and in the weighted cohort (1.2% vs. 7.8%, P < 0.001 for organ/space SSI; 0.3% vs. 5.1%, P = 0.009 for RI). CONCLUSIONS: Compared with OLR, LLR for HCC might reduce postoperative infections, including organ/space SSI and RI.

Glucagon-like peptide-1 receptor agonist, liraglutide, attenuated retinal thickening in spontaneously diabetic Torii fatty rats.

BACKGROUND: This study aims to investigate the effect of the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide on retinal pathological findings as compared with insulin and hydralazine using an animal model of type 2 diabetes with obesity, hypertension, and hyperlipidemia. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats at 8 weeks of age were randomly assigned to three groups: the liraglutide group (SDT-lira, n = 6) received a subcutaneous injection of liraglutide from the age of 8 to 16 weeks, the SDT-ins-hyd group (n = 6) was provided both insulin against hyperglycemia and hydralazine against hypertension to match levels of both blood glucose and blood pressure to those of the liraglutide group, and the control group of SDT fatty rats (SDT-vehicle, n = 7) and a nondiabetic control group of Sprague-Dawley rats (SD, n = 7) were injected with vehicle only. Both eyeballs of all groups were collected at the age of 16 weeks. RESULTS: Retinal thickness, which was found in the SDT-vehicle group, was significantly prevented to similar levels in both the SDT-lira and SDT-ins-hyd groups. Immunohistological analysis revealed that GLP-1 receptor was not expressed in the retina of all rats. The ocular protein expression of monocyte chemoattractant protein-1, which causes a proinflammatory situation, was significantly upregulated in all SDT fatty rats as compared to SD rats, but the expression levels were similar between all SDT fatty rats. With regard to neovascularization in the eyes, there were no significant differences in protein expressions of vascular endothelial growth factor, CD31, or endothelial nitric oxide synthase in all rats. CONCLUSIONS: The present study indicates that liraglutide prevents retinal thickening, dependent on blood glucose and blood pressure levels in SDT fatty rats without ocular neovascularization. However, the effects did not improve the ocular proinflammatory state.

Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.

A case report of breakthrough infection with the SARS-CoV-2 delta variant and household transmission: Role of vaccination, anti-spike IgG and neutralizing activity.

There have been several reports of breakthrough infections, which are defined as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among individuals who had received at least two doses of vaccine at least 14 days before the onset of infection, but data on the antibody titers, including SARS-CoV-2 neutralizing antibody activity, and the clinical course of individuals with breakthrough infections are limited. We encountered a case of breakthrough infection with the SARS-CoV-2 delta variant in a 31-year-old female healthcare worker (the index case, Case 1) and a secondary case (Case 2) in her unvaccinated 33-year-old husband. We studied the role of the anti-spike immunoglobulin G (IgG) and neutralizing antibody activity in the two case patients. Case 1 had high anti-spike IgG detected on day 3 of the illness, with low neutralizing antibody activity. The neutralizing antibody activity started to increase on day 5 of the illness. In Case 2 both the anti-spike IgG and the neutralizing antibody activity remained low from days 4-11 of illness, and the anti-spike IgG gradually increased from day 9. In Case 1, the fever broke within 4 days of onset, coinciding with the rise in neutralizing antibodies, whereas the fever took 7 days to resolve in Case 2. SARS-CoV-2 infection can occur even in vaccinated individuals, but vaccination may contribute to milder clinical symptoms because neutralizing antibodies are induced earlier in vaccinated individuals than in unvaccinated individuals.

CXCR2 signaling might have a tumor-suppressive role in patients with cholangiocarcinoma.

BACKGROUND: We reported that chemokine C-X-C motif receptor 2 (CXCR2) signaling appears to play an important role in the pathogenic signaling of gastric cancer (GC), and although CXCR2 may have a role in other solid cancers, the significance of CXCR2 in cholangiocarcinoma (CCA) has not been evaluated. Herein, we determined the clinicopathologic significance of CXCL1-CXCR2 signaling in CCA. MATERIALS AND METHODS: Two human CCA cell lines, OCUG-1 and HuCCT1, were used. CXCR2 expression was examined by western blotting. We investigated the effects of CXCL1 on the proliferation (by MTT assay) and migration activity (by a wound-healing assay) of each cell line. Our immunohistochemical study of the cases of 178 CCA patients examined the expression levels of CXCR2 and CXCL1, and we analyzed the relationship between these expression levels and the patients' clinicopathologic features. RESULTS: CXCR2 was expressed on both CCA cell lines. CXCL1 significantly inhibited both the proliferative activity and migratory activity of both cell lines. CXCL1 and CXCR2 were immunohistochemically expressed in 73% and 18% of the CCA cases, respectively. The CXCL1-positive group was significantly associated with negative lymph node metastasis (p = 0.043). The CXCR2-positive group showed significantly better survival (p = 0.042, Kaplan-Meier). A multivariate logistic regression analysis revealed that CXCR2 expression (p = 0.031) and lymph node metastasis (p = 0.004) were significantly correlated with the CCA patients' overall survival. CONCLUSION: CXCR2 signaling might exert a tumor-suppressive effect on CCA cells. CXCR2 might be a useful independent prognostic marker for CCA patients after surgical resection.