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A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the coronavirus disease 2019 (COVID-19) mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis., Internal medicine, 62(3), pp. 411-417; 2023

Skin diseases are common in children. However, the prevalence of childhood skin diseases in Japan has not been reported extensively. In this study, dermatologists conducted face-to-face examinations of primary school children over a 10-year period to determine the prevalence of each skin disease. Atopic dermatitis (AD, 12.3%) was the most common disease among first graders, followed by eczema other than AD (9.7%), molluscum contagiosum (1.9%), and verruca vulgaris (1.1%). Among sixth graders, acne vulgaris was most common (9.6%), followed by AD (8.9%), eczema other than AD (6.7%), and verruca vulgaris (3.1%). The prevalence of AD remained stable among first graders after 2010, at approximately 10%-15%, but it increased slightly among sixth graders. Of the 87 children who had AD in first grade, 51 (58.6%) were in remission in sixth grade. On the other hand, AD was diagnosed in 30 (4.5%) sixth graders who had been among the 665 children who did not have it in first grade. The more severe the symptoms were in first grade, the more likely a child was to still have AD in sixth grade, and the more severe the later symptoms tended to be. This study investigated recent trends in skin diseases in Japanese primary school children and found that the prevalence of some skin diseases differed between first and sixth graders. It was also found that children with moderate AD in first grade were more likely to be moderate in sixth grade than those with mild AD.

TRAIL and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin (PFT)-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability, and increasing apoptosis. On the basis of these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with PFT-μ. The combination of TRAIL plus PFT-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared with cells treated with either agent alone. When applied alone, PFT-μ increased Annexin V+ cells in both caspase-dependent and -independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, PFT-μ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared with treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that PFT-μ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL. Mol Cancer Ther; 12(4); 341–51. ©2013 AACR.

PDF file - 94K, Expression of DR4 and DR5 on human panreatic cancer cell lines

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non–small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA–dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.

Supplementary Figure S1 from Platelet-Derived Growth Factor-AA Is an Essential and Autocrine Regulator of Vascular Endothelial Growth Factor Expression in Non–Small Cell Lung Carcinomas

Perineural invasion (PNI) at Auerbach's plexus in colorectal cancer (CRC), known as intramural PNI, is associated with adverse prognostic outcomes. This study aimed to characterize the three-dimensional (3D) architecture of CRC with intramural PNI and to evaluate the morphological features of tumor invasion around nerve tissue. Serial tissue sections from two cases of CRC were stained with cytokeratin AE1/AE3 and an anti-S-100 protein antibody. 3D models were reconstructed by scanning the virtual slides. In one case, intramural PNI was observed at the horizontal invasive front. The 3D reconstruction model showed tumor cells that appeared to infiltrate along the nervous meshwork, the structure of which was preserved. In the other case, intramural PNI was observed both at and behind the horizontal invasive front, and the 3D reconstruction model showed that the tumor cells appeared to be involved with nerve cells at the focal part of the horizontal invasive front. However, the nervous meshwork structure was not well identified in cancer-involved areas. This is the first study to characterize the 3D structure of tumor invasion around nerve tissue in CRC, demonstrating the morphological features of intramural PNI in CRC.

We report a case of pathologic complete response after successful treatment for advanced hepatocellular carcinoma (HCC) complicated with portal venous tumor thrombus by atezolizumab and bevacizumab followed by radical resection. The patient was a male in his 60s. During follow-up for chronic hepatitis B, abdominal ultrasonography revealed a huge tumor located in the right lobe of the liver with the portal vein thrombosed by the tumor. The tumor thrombus extended to the proximal side of the left branch of the portal vein. The patient’s tumor marker levels were elevated (AFP, 14,696 ng/ml; PIVKA-II, 2,141 mAU/ml). Liver biopsy revealed poorly differentiated hepatocellular carcinoma. The lesion was categorized as advanced stage according to the BCLC staging system. As systemic therapy, atezolizumab plus bevacizumab was administered. Imaging showed marked shrinkage of the tumor and portal venous thrombus with a remarkable decrease of tumor marker levels after 2 courses of chemotherapy. After 3 additional courses of chemotherapy, radical resection was considered possible. The patient underwent right hemihepatectomy and portal venous thrombectomy. A pathological examination revealed a complete response. In conclusion, for advanced HCC, atezolizumab plus bevacizumab was considered effective and was safely administered without influencing the perioperative course. This may be an appropriate neoadjuvant therapy regimen for advanced-stage HCC.

Background: Cardiovascular events, including pericarditis, myocarditis, and myocardial ischaemia, have been reported as complications following COVID-19 vaccination. Case summary: A 28-year-old Japanese woman diagnosed 10 years earlier with systemic lupus erythematosus and antiphospholipid syndrome was admitted to our hospital because of chest pain and Raynaud’s phenomenon. She had received a second dose of the COVID-19 BNT162b2 mRNA vaccine 28 days earlier. 123I-β-methyl iodophenyl pentadecanoic acid (BMIPP) and 201thallium dual myocardial single-photon emission computed tomography demonstrated mildly reduced perfusion of BMIPP in the mid-anterior wall of the left ventricle. Coronary angiography revealed normal coronary arteries; additionally, an endomyocardial biopsy was performed. Histopathological evaluation revealed a normal myocardium without cell infiltration. However, immunostaining for the severe acute respiratory coronavirus (SARS-CoV)/severe acute respiratory coronavirus 2 (SARS-CoV-2) spike protein was positive in the small intramural coronary arteries. The administration of azathioprine (50 mg/day) and amlodipine (5 mg/day) and increases in her prednisolone (10 mg/day) and aspirin doses led to improvements in the symptoms of the patient. Discussion: Our data lead us to speculate that two events in the timeline of the patient, namely, receiving COVID-19 vaccination and the presence of SARS-CoV/SARS-CoV-2 spike protein in small intramural coronary arteries, may be related to the myocardial microangiopathy observed in this patient., European Heart Journal - Case Reports, 7(3), art. no. ytad102; 2023

Pembrolizumab is a novel immune-checkpoint inhibitor used for treatment of microsatellite instability-high (MSI-H) colorectal cancer. Several studies have reported clinical complete response (CR) after treatment with pembrolizumab, but none has confirmed pathological CR. Here we provide the first description of pathological CR with R0 resection after immune-checkpoint therapy. A 45-year-old man presented at our hospital with abdominal distention and highly elevated tumor markers. Contrast-enhanced abdominal CT showed a 110 × 75 mm bulky mass with markedly swollen lymph nodes and an isolated peritoneal metastasis in the pelvic space. Biopsy revealed poorly differentiated adenocarcinoma. We diagnosed ascending colon cancer cT4aN2bM1c Stage IVc. A biopsy specimen obtained during systemic chemotherapy (FOLFOXIRI) was confirmed pathologically as MSI-H, after which the treatment was changed to pembrolizumab. The tumor markers rapidly decreased to within normal ranges after three courses of treatment. After twenty courses, CT revealed shrinkage of the main tumor, lymph node metastases, and the peritoneal metastasis, and we performed extended right hemi-colectomy with dissection of the peritoneal metastasis. No residual tumor cells were found histologically. The patient achieved pathological CR and the postoperative course was uneventful. An accurate diagnosis and appropriate follow up are crucial for obtaining sufficient therapeutic effect of pembrolizumab.

A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the COVID-19 mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis.

The aim of our study was to analyze the expressions of nuclear factor of activated T cells (NFAT)-related substances including long noncoding RNA NRON which participates in pathophysiology of Sjögren’s syndrome (SS), and to assess the histologic findings in individuals with SS. In this study, the expressions of NRON, NFATc1, CD3/CD4, and proviral integration site for Moloney murine leukemia virus (PIM)-1 were examined by in situ hybridization, immunohistochemical analysis, and immunofluorescence in labial salivary glands (LSGs) obtained from 16 patients with SS and five controls. The microcell count method has been applied to calculate the NFATc1-positive area/infiltrating cell area in LSGs, and we compared those results to the infiltrating cell area, focus score, serum immunoglobulin G, and the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index. The NRON expression in the nuclei of cell-infiltration lesions of the SS patients were prominent. The NFATc1 expression was strong in the cytoplasm of infiltrating mononuclear cells and weak in ducts of both SS and controls. In SS, the NFATc1-positive area/infiltrating cell area was positively correlated with the infiltrating cell area and focus score. CD3/CD4 was expressed in infiltrating mononuclear cells, and PIM-1 colocalized with NFATc1 in the cytoplasm. These results suggest NRON along with NFATc1/PIM-1 in SS LSGs might participate in SS pathophysiology., Applied immunohistochemistry & molecular morphology, 29(10), pp. 734-740; 2021

Purpose This study aimed to evaluate the clinical courses of patients with surgically resected stage IA pulmonary adenocarcinoma (Ad) who exhibited heterogeneous ground-glass nodules (GGNs) or part-solid nodules on thin-section computed tomography (TSCT) and to clarify the prognostic differences between them. Materials and methods The cases of 242 patients with proven pulmonary Ad with heterogeneous GGN or part-solid nodule who underwent surgical resection were retrospectively reviewed. After surgery, they were examined pathologically. Disease-free survival (DFS) and overall survival (OS) were also investigated. Results There were no cases of recurrent pulmonary Ad or death from the primary disease in the heterogeneous GGN group. In the part-solid nodule group, recurrent pulmonary Ad and death from the primary disease were observed in 12 and 6 of 181 patients, respectively. Heterogeneous GGNs were associated with significantly longer DFS than part-solid nodules (p = 0.042). While, there was no significant difference in OS between the two groups (p = 0.134). Pathological diagnoses were available for all 242 patients. 181 part-solid nodules were classified into 116 invasive Ads, 54 minimally invasive Ads (MIAs), and 11 Ad in situ (AIS) lesions, and 61 heterogeneous GGNs were classified into 18 invasive Ads, 25 MIAs, and 18 AIS lesions. Conclusion Heterogeneous GGNs were significantly associated with longer DFS than part-solid nodules. Pathologically, there were significant differences between the heterogeneous GGNs and part-solid nodules.

Hepatic sclerosing haemangiomas are rare benign tumours that are often difficult to distinguish from malignant tumours because these tumours do not show the typical imaging features of cavernous haemangiomas. We report a case of a sclerosing haemangioma that showed restricted diffusion and was difficult to differentiate from a malignancy. A 60-year-old female was referred to our hospital for evaluation of a hepatic mass that was incidentally diagnosed after a CT scan for right lower quadrant abdominal pain. Contrast-enhanced dynamic CT showed hepatic capsular retraction, with a small peripheral enhancement of the mass. The lesion appeared homogeneously hypointense on T1W images, heterogeneously hyperintense on T2W images, hyperintense on diffusion-weighted images, and hypointense on apparent diffusion coefficient (ADC) map. The lesion was suspected to be a cholangiocellular carcinoma and was surgically resected, but a final diagnosis of hepatic sclerosing haemangioma was made. Hepatic sclerosing/sclerosed haemangiomas are usually considered to show an increased ADC, which is useful for distinguishing them from malignant tumours. However, in this particular case, most of the lesion contained many obliterated or narrowed vascular channels, which might have acted as septa restricting the diffusion of water molecules in the intervening fibrous and/or hyalinised tissue. Hepatic sclerosing haemangiomas in the process of becoming completely fibrotic may show restricted diffusion, similar to malignant tumours.

In past reports, the incidence of gastric perforation accounts for 0.08 to 3.6% of all gastric cancers, and the proportion of perforated gastric cancer(PGC)in gastric perforations is 26 to 32%. In the treatment of PGC, critical care for peritonitis, diagnosis of gastric cancer and curability for gastric cancer are required simultaneously, so it is not easy to decide the treatment strategies. Therefore, for the purpose to consider treatment strategies for PGC, we conducted a clinicopathological study on PGC in our hospital for the past 12 years. There were 22 cases of PGC, and we analyzed clinicopathologically 19 cases excluding perforation during endoscopic resection and perforation during chemotherapy. The R0 surgery group tended to have a good prognosis even in PGC cases, and there was surgery-related death in the one-stage gastrectomy group. So it was considered desirable to perform radical surgery after the general condition was stable by the treatment of peritonitis was given priority in the PGC.

The efficacy of molecular-targeted agents (MTAs) has been demonstrated in recent years. However, the results of multidisciplinary treatment including hepatic resection are still unclear. The present study evaluated the outcomes of MTA treatment for advanced, unresectable hepatocellular carcinoma (HCC), with the goal of achieving liver resection, in our department.Nine patients in whom Lenvatinib had been administered to achieve conversion surgery for unresectable HCC were included in this study. The patient characteristics were as following: median tumor size of 10 cm, vascular invasion in 5 cases, multiple tumors in 2 cases, median treatment duration of 8 weeks, dose reduction due to side effects in 4 patients, and discontinuation of treatment in 1 patient due to tumor growth.The efficacy by modified Response Evaluation Criteria in Solid Tumors (mRECIST) was partial response in 3, sustained disease in 5 and progressive disease in 1, while the liver resection rate was 88%. Four patients (50%) had recurrence after resection, and the median recurrence-free survival was 12.7 months; however, treatment for recurrence was successful and all patients are alive.Lenvatinib may improve the prognosis of HCC with vascular invasion and multiple lesions by achieving radical resection at the appropriate time for patients with tumor shrinkage.

Background/aim Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. Materials and methods LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. Results LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. Conclusion LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.

Programmed cell death ligands (PD‐Ls) are expressed in tumor cells where they bind to programmed cell death‐1, an immunocyte co–receptor, resulting in tumor cell evasion from the immune system. Chemotherapeutic drugs have been recently reported to induce the expression of PD‐L, such as PD‐L1, in some cancer cells. However, little is known regarding PD‐L2 expression and its role in oral squamous cell carcinoma (OSCC). In this study, we examined the effect of cisplatin on the expression and regulation of PD‐L2 in OSCC cell lines and analyzed malignant behavior in PD‐L2‐expressing cells using colony, transwell and transformation assays. In addition, we examined PD‐L2 expression in the tumor tissues of OSCC patients using cytology and tissue microarray methods. In OSCC cell lines, cisplatin treatment upregulated PD‐L2 expression, along with that of the drug efflux transporter ABCG2, via signal transducers and activator of transcription (STAT) 1/3 activation. Moreover, PD‐L2‐positive or PD‐L2‐overexpressing cells demonstrated upregulation in both invasion and transformation ability but not in proliferation compared with PD‐L2‐negative or PD‐L2‐silencing cells. PD‐L2 expression was also observed in OSCC cells of cytology samples and tissue from OSCC patients. The intensity of PD‐L2 expression was correlated with more malignant morphological features in the histological appearance and an invasive pattern. Our findings indicate that cisplatin‐upregulated PD‐L2 expression in OSCC via STAT1/3 activation and the expression of PD‐L2 are likely to be associated with malignancy in OSCC. The PD‐L2 expression in cisplatin‐resistant OSCC cells may be a critical factor in prognosis of advanced OSCC patients., Our findings indicate that cisplatin‐upregulated PD‐L2 expression in oral squamous cell carcinoma (OSCC) cells via STAT1/3 activation and the expression of PD‐L2 are likely to be associated with malignancy in OSCC. The PD‐L2 expression in cisplatin‐resistant OSCC cells may be a critical factor in the prognosis of advanced OSCC patients.

Recent advances in gene therapy technologies have enabled the treatment of congenital disorders and cancers and facilitated the development of innovative methods, including induced pluripotent stem cell (iPSC) production and genome editing. We recently developed a novel non-transmissible and non-integrating measles virus (MV) vector capable of transferring multiple genes simultaneously into a wide range of cells through the CD46 and CD150 receptors. The MV vector expresses four genes for iPSC generation and the GFP gene for a period of time sufficient to establish iPSCs from human fibroblasts as well as peripheral blood T cells. The transgenes were expressed differentially depending on their gene order in the vector. Human hematopoietic stem/progenitor cells were directly and efficiently reprogrammed to naive-like cells that could proliferate and differentiate into primed iPSCs by the same method used to establish primed iPSCs from other cell types. The novel MV vector has several advantages for establishing iPSCs and potential future applications in gene therapy.

Background Tumor immune reactions not only provide host defense but also accelerate tumor immune escape and phenotype switching. Here, we examined the association of programmed cell death ligand 1 (PD-L1) expression with epithelial-mesenchymal transition (EMT)–associated markers in pancreatic ductal adenocarcinoma (PDA) within the context of the tumor microenvironment. Materials and methods PDA samples from 36 patients were analyzed for PD-L1, vimentin, E-cadherin, and Snail expressions and for PDA cell and immune cell infiltration. PD-L1 expression and EMT in PDA cell lines under conditions of altering interferon gamma (IFN-γ) signals were also assessed. Results Immunohistochemistry revealed a significant correlation between vimentin and PD-L1 expression, whereas double staining showed them to be simultaneously expressed by PDA cells. Positive vimentin expression was associated with the infiltration of a lower number of CD8+ T cells and a higher number of FoxP3+ cells and poor patient prognosis (P = 0.03). PDA tumor cells promoted PD-L1 expression and EMT under the presence of IFN-γ, which was inhibited by the signal transducer and activator of transcription (STAT)1 small interfering RNA. Conclusions Strong correlations were observed between PD-L1 expression, EMT, and the immunosuppressive tumor microenvironment. Targeting STAT1 combined with PD-1/PD-L1 immunotherapy may improve outcomes for patients with PDA.

Gastric adenocarcinoma with enteroblastic differentiation(GAED)is a rare disease that is classified as a special type in the 15th edition Japanese Classification of Gastric Carcinoma. GAED is considered to have a poor prognosis. We report about a 76-year-old man with GAED who presented with complaints of poor appetite and weight loss. He was suspected of having gastric cancer based on ultrasonography and computed tomography findings and was referred to our hospital by his home doctor. Upper gastrointestinal endoscopy revealed a gastric cancer in the lesser curvature of the gastric antrum. Distal gastrectomy was performed. Histopathology showed a moderately differentiated adenocarcinoma with a clear cytoplasm. Immunostaining was positive for Sal-like protein 4(SALL4)and negative for α-fetoprotein(AFP). The patient was diagnosed as having GAED. Vascular and lymphatic invasion were not observed. He was discharged on the 9th day after surgery. At 5 months postoperatively, he was treated with adjuvant chemotherapy, and no recurrence was noted. GAED is a rare disease with a poor prognosis. We report this case and discuss relevant literature.

Objective. The aim of this study was to evaluate a motion-activated system (MAS) that applies motion-activated energy (vibration) to prevent chest tube clogging and maintain tube patency. We performed chest tube blood flow analysis in vitro, studied MAS effects on intraluminal clot deposition in vivo, and conducted a pilot clinical test. Background. Chest tube clogging is known to adversely contribute to postoperative cardiac surgery outcomes. Methods. The MAS was tested in vitro with a blood-filled chest tube model for device acceleration and performance. In vivo acute hemothorax studies (n = 5) were performed in healthy pigs (48.0 ± 2 kg) to evaluate the drainage in MAS versus control (no device) groups. Using a high-speed camera (FASTCAM Mini AX200, 100 mm Zeiss lens) in an additional animal study (n = 1), intraluminal whole-blood activation imaging of the chest tube (32 Fr) was made. The pilot clinical study (n = 12) consisted of up to a 30 minutes device tolerance test. Results. In vitro MAS testing suggested optimal device performance. The 2-hour in vivo evaluation showed a longer incremental drainage in the MAS group versus control. The total drainage in the MAS group was significantly higher than that in the control group (379 ± 144 mL vs 143 ± 40 mL; P = .0097), indicating tube patency. The high-speed camera images showed a characteristic intraluminal blood “swirling” pattern. Clinical data showed no discomfort with the MAS use (pleural = 4; mediastinal = 8). Conclusions. The MAS showed optimal performance at bench and better drainage profile in vivo. The clinical trial showed patients’ tolerance to the MAS and device safety.

Background Laparoscopic sleeve gastrectomy (LSG) is a well established treatment for severe obesity and type 2 diabetes. Although the gut microbiota is linked to the efficacy of LSG, the underlying mechanisms remain elusive. The effect of LSG for morbid obesity on the gut microbiota and bile acids was assessed here. Methods Severely obese subjects who were candidates for LSG were included and followed until 6 months after surgery. The composition and abundance of the microbiota and bile acids in faeces were assessed by 16S ribosomal RNA sequencing, quantitative PCR and liquid chromatography–mass spectrometry. Results In total, 28 patients with a mean(s.d.) BMI of 44·2(6·6) kg/m2 were enrolled. These patients had achieved excess weight loss of 53·2(19·0) per cent and showed improvement in metabolic diseases by 6 months after LSG, accompanied by an alteration in the faecal microbial community. The increase in α-diversity and abundance of specific taxa, such as Rikenellaceae and Christensenellaceae, was strongly associated with reduced faecal bile acid levels. These changes had a significant positive association with excess weight loss and metabolic alterations. However, the total number of faecal bacteria was lower in patients before (mean(s.d.) 10·26(0·36) log10 cells per g faeces) and after (10·39(0·29) log10 cells per g faeces) operation than in healthy subjects (10·83(0·27) log10 cells per g faeces). Conclusion LSG is associated with a reduction in faecal bile acids and greater abundance of specific bacterial taxa and α-diversity that may contribute to the metabolic changes.

Background/Purpose Computer‐assisted tissue imaging and analytical techniques were used to clarify the histomorphological structure of hepatic connective tissue as a practical guide for surgeons. Methods Approximately 5000 histological slides were prepared from liver specimens of five autopsied patients. Three‐dimensional (3D) reconstruction was performed and subjected to computer imaging analysis. Scanning electron microscopy was also performed on the liver specimens. Results The 3D reconstructed images revealed the running form of the vasculature and the relationship between the hepatic lobule and connective tissue. The hepatic capsule or portal pedicle was consistently located at the periphery of the hepatic lobules. An artificial intelligence random forest approach clearly segmented hepatic cells, type I collagen (CF), type III collagen (RF), and other cells. The hepatic lobule, portal region, and hepatic capsule were significantly distinguished based on CF and RF occupancy. The capsule directly covering the liver lobule with an RF concentration up to 87% was provisionally named the proper hepatic capsule. The existence of a proper hepatic ligament with distinct occupation rates of CF and RF was also suggested. Conclusions The identified proper hepatic capsule and ligament can be important markers for demarcating the dissecting layer during surgical procedures., Highlight Computer‐assisted tissue imaging and analytical techniques were used to clarify the histomorphological structure of hepatic connective tissue. Ikeda and colleagues focused on the capsule surrounding the hepatic lobule itself. The identified proper hepatic capsule and ligament appear to be an important structure for demarcating the dissecting layer during surgical procedures.

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8, and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion, and vascular invasion (P

The VentriFlo True Pulse Pump (Design Mentor, Inc., Pelham, NH, USA) is the first blood pump designed to mimic human arterial waveforms in a standard oxygenation circuit. Our aim was to demonstrate the feasibility and safety of this pump in preparation for future studies to determine possible clinical advantages. We studied four piglets (41.4-46.2 kg): three with an implanted VentriFlo pulsatile pump and one with the nonpulsatile ROTAFLOW pump (MAQUET Holding B.V. & Co. KG, Rastatt, Germany) as a control. Hemodynamics was monitored during 6-h cardiopulmonary bypass (CPB) support and for 2 h after weaning off CPB. The VentriFlo demonstrated physiologic arterial waveforms with arterial pulse pressure of 24.6 ± 5.7 mm Hg. Pump flows (2.0 ± 0.1 L/min in ROTAFLOW; 1.9 ± 0.1 L/min in VentriFlo) and plasma free hemoglobin levels (27.9 ± 12.5 mg/dL in ROTAFLOW; 28.5 ± 14.2 mg/dL in VentriFlo) were also comparable, but systemic O2 extraction (as measured by arterial minus venous O2 saturation) registered slightly higher with the VentriFlo (63.2 ± 6.9%) than the ROTAFLOW (55.4 ± 6.5%). Histological findings showed no evidence of ischemic changes or thromboembolism. This pilot study demonstrated that the VentriFlo system generated pulsatile flow and maintained adequate perfusion of all organs during prolonged CPB.

Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive tumor‐microenvironment (TME) that supports the growth of tumors and mediates tumors enabling evasion of the immune system. Expression of programmed cell death ligand 1 (PD‐L1) and loss of human leukocyte antigen (HLA) class I on tumor cells are methods by which tumors escape immunosurveillance. We examined immune cell infiltration, the expression of PD‐L1 and HLA class I by PDA cells, and the correlation between these immunological factors and clinical prognosis. PDA samples from 36 patients were analyzed for HLA class I, HLA‐DR, PD‐L1, PD‐1, CD4, CD8, CD56, CD68, and FoxP3 expression by immunohistochemistry. The correlations between the expression of HLA class I, HLA‐DR, PD‐L1 or PD‐1 and the pattern of tumor infiltrating immune cells or the patients’ prognosis were assessed. PD‐L1 expression correlated with tumor infiltration by CD68+ and FoxP3+ cells. Low HLA class I expression was an only risk factor for poor survival. PD‐L1 negative and HLA class I high‐expressing PDA was significantly associated with higher numbers of infiltrating CD8+ T cells in the TME, and a better prognosis. Evaluation of both PD‐L1 and HLA class I expression by PDA may be a good predictor of prognosis for patients. HLA class I expression by tumor cells should be evaluated when selecting PDA patients who may be eligible for treatment with PD‐1/PD‐L1 immune checkpoint blockade therapies.

Autophagy is a homeostatic process regulating turnover of impaired proteins and organelles, and p62 (sequestosome-1, SQSTM1) functions as the autophagic receptor in this process. p62 also functions as a hub for intracellular signaling such as that in the mammalian target of rapamycin (mTOR) pathway. Liver stem/progenitor cells have the potential to differentiate to form hepatocytes or cholangiocytes. In this study, we examined effects of autophagy, p62, and associated signaling on hepatic differentiation. Adult stem/progenitor cells were isolated from the liver of mice with chemically induced liver injury. Effects of autophagy, p62, and related signaling pathways on hepatic differentiation were investigated by silencing the genes for autophagy protein 5 (ATG5) and/or SQSTM1/p62 using small interfering RNAs. Hepatic differentiation was assessed based on increased albumin and hepatocyte nuclear factor 4α, as hepatocyte markers, and decreased cytokeratin 19 and SOX9, as stem/progenitor cell markers. These markers were measured using quantitative RT-PCR, immunofluorescence, and Western blotting. ATG5 silencing decreased active LC3 and increased p62, indicating inhibition of autophagy. Inhibition of autophagy promoted hepatic differentiation in the stem/progenitor cells. Conversely, SQSTM1/p62 silencing impaired hepatic differentiation. A suggested mechanism for p62-dependent hepatic differentiation in our study was activation of the mTOR pathway by amino acids. Amino acid activation of mTOR signaling was enhanced by ATG5 silencing and suppressed by SQSTM1/p62 silencing. Our findings indicated that promoting amino acid sensitivity of the mTOR pathway is dependent on p62 accumulated by inhibition of autophagy and that this process plays an important role in the hepatic differentiation of stem/progenitor cells. J. Cell. Physiol. 232: 2112-2124, 2017. © 2016 Wiley Periodicals, Inc.

Objectives: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer. Materials and Methods: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45. Results: Overexpression of PD-L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells. Conclusions: PD-L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1.