High N6-methyladenosine-activated TCEAL8 mRNA is a novel pancreatic cancer marker.

N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their malignant transformation. In this study, we analyzed gene expression and m6A modification in cancer tissues, ducts, and acinar cells derived from pancreatic cancer patients using MeRIP-seq. We found that dozens of RNAs highly modified by m6A were detected in cancer tissues compared with ducts and acinar cells. Among them, the m6A-activated mRNA TCEAL8 was observed, for the first time, as a potential marker gene in pancreatic cancer. Spatially resolved transcriptomic analysis showed that TCEAL8 was highly expressed in specific cells, and activation of cancer-related signaling pathways was observed relative to TCEAL8-negative cells. Furthermore, among TCEAL8-positive cells, the cells expressing the m6A-modifying enzyme gene METTL3 showed co-activation of Notch and mTOR signaling, also known to be involved in cancer metastasis. Overall, these results suggest that m6A-activated TCEAL8 is a novel marker gene involved in the malignant transformation of pancreatic cancer.

Emerging roles of long noncoding and circular RNAs in pancreatic ductal adenocarcinoma.

An international project on the human genome revealed that various RNAs (e.g., messenger RNAs, microRNAs, and long noncoding RNAs [lncRNAs] and their subclass circular RNA [circRNA)) are involved in the pathogenesis of different human diseases, including cancer. Recent studies have highlighted the critical roles of lncRNAs and circRNA in pancreatic ductal adenocarcinoma (PDAC), especially in the epithelial-mesenchymal transition, a phenomenon regulating cancer metastasis. Growing research in this field has indicated that the tertiary structure of lncRNAs supposedly regulates biological function via RNA-RNA or RNA-protein associations, aiding early diagnosis and therapy selection for various diseases, including cancer. Here we describe the emerging roles of ncRNAs in PDAC and highlight how these ncRNAs can be used to detect and control this intractable cancer.

Narrative Restrictions and Proxies.

We compare two approaches to using information about the signs of structural shocks at specific dates within a structural vector autoregression (SVAR): imposing "narrative restrictions" (NR) on the shock signs in an otherwise set-identified SVAR; and casting the information about the shock signs as a discrete-valued "narrative proxy" (NP) to point-identify the impulse responses. The NP is likely to be "weak" given that the sign of the shock is typically known in a small number of periods, in which case the weak-proxy robust confidence intervals in Montiel Olea, Stock, and Watson are the natural approach to conducting inference. However, we show both theoretically and via Monte Carlo simulations that these confidence intervals have distorted coverage-which may be higher or lower than the nominal level-unless the sign of the shock is known in a large number of periods. Regarding the NR approach, we show that the prior-robust Bayesian credible intervals from Giacomini, Kitagawa, and Read deliver coverage exceeding the nominal level, but which converges toward the nominal level as the number of NR increases.

Epithelial Cell Transformation and Senescence as Indicators of Genome Aging: Current Advances and Unanswered Questions.

The recent advances in deciphering the human genome allow us to understand and evaluate the mechanisms of human genome age-associated transformations, which are largely unclear. Genome sequencing techniques assure comprehensive mapping of human genetics; however, understanding of gene functional interactions, specifically of time/age-dependent modifications, remain challenging. The age of the genome is defined by the sum of individual (inherited) and acquired genomic traits, based on internal and external factors that impact ontogenesis from the moment of egg fertilization and embryonic development. The biological part of genomic age opens a new perspective for intervention. The discovery of single cell-based mechanisms for genetic change indicates the possibility of influencing aging and associated disease burden, as well as metabolism. Cell populations with transformed genetic background were shown to serve as the origin of common diseases during extended life expectancy (superaging). Consequently, age-related cell transformation leads to cancer and cell degeneration (senescence). This article aims to describe current advances in the genomic mechanisms of senescence and its role in the spatiotemporal spread of epithelial clones and cell evolution.

Impact of One-Carbon Metabolism-Driving Epitranscriptome as a Therapeutic Target for Gastrointestinal Cancer.

One-carbon (1C) metabolism plays a key role in biological functions linked to the folate cycle. These include nucleotide synthesis; the methylation of DNA, RNA, and proteins in the methionine cycle; and transsulfuration to maintain the redox condition of cancer stem cells in the tumor microenvironment. Recent studies have indicated that small therapeutic compounds affect the mitochondrial folate cycle, epitranscriptome (RNA methylation), and reactive oxygen species reactions in cancer cells. The epitranscriptome controls cellular biochemical reactions, but is also a platform for cell-to-cell interaction and cell transformation. We present an update of recent advances in the study of 1C metabolism related to cancer and demonstrate the areas where further research is needed. We also discuss approaches to therapeutic drug discovery using animal models and propose further steps toward developing precision cancer medicine.

Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes.

Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine.

Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages.

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.

State-of-the-Art Technology of Model Organisms for Current Human Medicine.

Since the 1980s, molecular biology has been used to investigate medical field mechanisms that still require the use of crude biological materials in order to achieve their necessary goals. Transcription factor-induced pluripotent stem cells are used in regenerative medicine to screen drugs and to support lost tissues. However, these cells insufficiently reconstruct whole organs and require various intact cells, such as damaged livers and diabetic pancreases. For efficient gene transfer in medical use, virally mediated gene transfers are used, although immunogenic issues are investigated. To obtain efficient detective and diagnostic power in intractable diseases, biological tools such as roundworms and zebrafish have been found to be useful for high-throughput screening (HST) and diagnosis. Taken together, this biological approach will help to fill the gaps between medical needs and novel innovations in the field of medicine.

COVID-19 Drug Discovery Using Intensive Approaches.

Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.

Reduction of adverse effects by a mushroom product, active hexose correlated compound (AHCC) in patients with advanced cancer during chemotherapy--the significance of the levels of HHV-6 DNA in saliva as a surrogate biomarker during chemotherapy.

Chemotherapy improves the outcome of cancer treatment, but patients are sometimes forced to discontinue chemotherapy or drop out of a clinical trial due to adverse effects, such as gastrointestinal disturbances and suppression of bone marrow function. The objective of this study was to evaluate the safety and effectiveness of a mushroom product, active hexose correlated compound (AHCC), on chemotherapy-induced adverse effects and quality of life (QOL) in patients with cancer. Twenty-four patients with cancer received their first cycle of chemotherapy without AHCC and then received their second cycle with AHCC. During chemotherapy, we weekly evaluated adverse effects and QOL via a blood test, EORTC QLQ-C30 questionnaire, and DNA levels of herpes virus type 6 (HHV-6) in saliva. The DNA levels of HHV-6 were significantly increased after chemotherapy. Interestingly, administration of AHCC significantly decreased the levels of HHV-6 in saliva during chemotherapy and improved not only QOL scores in the EORTC QLQ-C30 questionnaire but also hematotoxicity and hepatotoxicity. These findings suggest that salivary HHV-6 levels may be a good biomarker of QOL in patients during chemotherapy, and that AHCC may have a beneficial effect on chemotherapy-associated adverse effects and QOL in patients with cancer undergoing chemotherapy.

Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer.

Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity-positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy.

Utility of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography in differential diagnosis of benign and malignant intraductal papillary-mucinous neoplasm of the pancreas.

Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas presents in various histopathological stages from benign to malignant lesions. The differentiation between benign and malignant IPMN is important in order to determine the treatment of the patients. However, pre-operative differentiation remains difficult. The aim of this study was to assess the utility of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in pre-operative differentiation of benign and malignant IPMN of the pancreas. In the present study we prospectively investigated 29 patients who underwent CT, FDG-PET, and surgery for IPMNs, followed by histopathological examination. The maximum standardized uptake value (SUVmax) was determined on FDG-PET, and differentiation of benign from malignant IPMN was tested using various SUVmax cut-off levels and various parameters derived from the CT. SUVmax was found to be significantly higher in malignant IPMNs (4.7+/-3.0) than that in benign IPMNs (1.8+/-0.3, P=0.0011). SUVmax values correlated with the histopathological types of IPMN (adenoma/borderline lesion/carcinoma in situ/invasive carcinoma) (Spearman rank correlation 0.865, P<0.0001). The specificity, sensitivity and accuracy values were best for SUVmax of 2.5 (100, 93, and 96%, respectively). The combination of mural nodule, detected on CT, and SUVmax of 2.5 offered the best diagnosis of malignant IPMN. These results suggest that FDG-PET is useful for differentiation of malignant IPMN of the pancreas, and that it should be performed in combination with other conventional imaging modalities.

Phase I trial of gemcitabine dose escalation with concurrent radiotherapy for patients with locally advanced pancreatic cancer.

AIM: The safety and efficacy, and the dose-limiting toxicity (DLT) of the chemotherapeutic agent gemcitabine administered in conjunction with radiotherapy in patients with locally advanced pancreatic cancer are not yet established. Here, we evaluated the safety and efficacy, DLT, and maximum tolerated dose of gemcitabine with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Tumor response and time to progression were also assessed. PATIENTS AND METHODS: Patients with previously untreated pancreatic cancer (n = 12) received gemcitabine intravenously on days 1, 8, and 15. Concurrent radiation therapy was initiated on day 1 (40 Gy in 2 Gy/day x 20 fractions, days 1-5, 8-12, 15-19, 22-26). Patients received limited-field irradiation with three-dimensional radiotherapy. Dose escalation included dose levels 1-3 (gemcitabine 400, 600, and 800 mg/m(2)). RESULTS: No patient developed DLT in this study. Of the 12 patients, there were 11 sustained responses, 0 partial responses, and 1 progressive disease. Two patients with a sustained response underwent surgery after re-evaluation. The median progression-free survival was 8 months, not including the patients that underwent surgery. CONCLUSION: Weekly gemcitabine at a dose of 800 mg/m(2) with concurrent radiation therapy in patients with locally advanced pancreatic cancer was well tolerated. and IAP.

[A case of complete response to S-1 therapy for multiple pulmonary recurrences of hepatocellular carcinoma after hepatic resection].

A 68-year-old man lost in unconscious and was diagnosed as ruptured hepatocellular carcinoma (HCC) in a local emergency hospital. He was treated by transcatheter arterial embolization, and further investigation revealed simultaneous cancer in rectum. He was referred to our institute, and admitted in June 2005. He underwent lateral segment and S8 partial resection of the liver, cholecystectomy, anterior resection of rectum, and D3 lymphadenectomy in August 2005. Multiple HCC recurrences in the remnant liver appeared in December 2005. He was subsequently treated with transcatheter chemoembolization four times. In May 2006, CT scan revealed multiple metastatic nodules in bilateral lungs with remarkably elevated serum AFP and PIVKA-II. The nodules were diagnosed as lung metastasis of the HCC. Because the lesions grew larger, S-1 was started in February 2007. Diagnostic imaging and tumor markers showed a marked improvement 2 months after S-1 administration, and no recurrence has been found since then. This case illustrates that S-1 may be an effective treatment for HCC with extrahepatic metastasis.

[A case of long-term survival for advanced gallbladder cancer].

A 50-year-old woman with epigastric uncomfortable feeling was referred to our hospital. We have diagnosed her as an advanced gallbladder cancer with direct liver invasion and lymph node metastasis of hepatoduodenal ligament by the image analysis, including enhanced abdominal CT, MRI and FDG-PET. Subsequently, we performed operation with cholecystectomy, hepatic segmentectomy of S4a/5, bile duct resection and D2 lymph node dissection, resulted in the curative operation. We additionally performed adjuvant chemotherapy with 6 courses of 800 mg/m2 of gemcitabine (GEM) on days 1, 8 and 15 for every 35 days. No recurrent signs were observed for 33 months after curative operation.

[A long-term survival case of pancreatic cancer with hepatic metastasis after pancreaticoduodenectomy successfully treated by s-1 and gemcitabine combination chemotherapy].

Gemcitabine monotherapy is accepted as a standard first-line treatment for locally advanced unresectable or metastatic pancreatic cancer. On another front, S-1 and gemcitabine combination chemotherapy is challenging but promising. We report a long-term survival case of pancreatic cancer with hepatic metastasis after surgical resection treated by S-1 and gemcitabine combination chemotherapy. A 59-year-old woman was diagnosed as locoregionally advanced pancreas head cancer without metastatic disease. Pancreatoduodenectomy with regional lymph node dissection was performed after preoperative chemoradiotherapy. Pathological examination revealed a poorly differentiated adenocarcinoma. A solitary hepatic metastasis was detected by CT imaging one year after the surgery. The patient received 35 courses of S-1 and gemcitabine combination therapy. The metastatic tumor was disappeared, and serum CEA decreased to a normal level. S-1 and gemcitabine combination therapy is not only effective but also well tolerated and safe. This combination therapy should be considered one of selective choices for advanced or metastatic pancreatic cancer.

[A case of locally advanced pancreatic cancer with superior membrane artery invasion successfully resected after gemcitabine-based chemoradiotherapy].

A 69-year-old man with chief complaint of epigastralgia was diagnosed as locally advanced borderline unresectable pancreatic head cancer that involved superior membrane artery (SMA). Gemcitabine (GEM) -based chemoradiotherapy (CRT) was administered for consecutive 3 weeks in the following fashion: continuous twice-a-day accelerated radiotherapy (2 daily fractions of 1.5 Gy, 5 days a week, with a 6-hr minimal interval between fractions) with 3-time weekly intravenous infusions of GEM. Total radiation dose was 45 Gy and GEM was given on days 1, 8 and 15 at dose of 800 mg/m2. After the completion of CRT, the involvement of SMA remained. Next, additional systemic chemotherapy with GEM was performed for 3 weeks in the following fashion: weekly intravenous infusions of GEM at dose of 1,000 mg/m2. Finally, the main tumor and the invasion to SMA were reduced. Surgical resection with negative margins (R0 resection) was performed. Adjuvant chemotherapy with 6 courses of GEM was also performed. The patient has no recurrence, suggesting the efficacy of GEM-based CRT for locally advanced borderline unresectable pancreatic cancer.

Sclerosing epithelioid fibrosarcoma of the liver infiltrating the inferior vena cava.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and distinct variant of fibrosarcoma, composed of epithelioid tumor cells arranged in strands, nests, cords, or sheets embedded within a sclerotic collagenous matrix. We report a 39-year-old man with SEF of the liver, which infiltrated the inferior vena cava (IVC). The SEF of the liver was successfully resected, and the infiltrated IVC was also removed together with the liver tumor. Histopathological examination of the tumor showed typical histopathology of SEF. Immunohistochemically, the tumor was positive for vimentin. Recurrence was noted 7 mo after surgery. After chemotherapy, the recurrent tumor was resected surgically, and histopathological examination showed similar findings to those of the primary tumor. To our knowledge, this is the first report of SEF of the liver with tumor invasion of the IVC.

Comparison of postoperative morphological changes in remnant pancreas between pancreaticojejunostomy and pancreaticogastrostomy after pancreaticoduodenectomy.

OBJECTIVES: The aim of this study was to compare postoperative morphological changes in remnant pancreas between pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG) after pancreaticoduodenectomy (PD). METHODS: The study subjects were 28 patients with PJ and 14 with PG. The diameter of the main pancreatic duct (MPD) and pancreatic parenchymal thickness 2 years after PD were measured on computed tomography scans and compared between the 2 groups. RESULTS: The preoperative and postoperative MPD diameter was 5.2 mm (SD, 2.4 mm) and 4.2 mm (SD, 2.0 mm) in the PJ group (P = 0.0422) and 4.8 mm (SD, 3.2 mm) and 5.7 mm (SD, 1.8 mm) (P = 0.1494) in the PG group, respectively. In those patients with preoperatively normal-size MPD, MPD after surgery tended to become dilated relative to before surgery in the PJ group (P = 0.0931), and the MPD measured postoperatively was significantly larger than preoperatively in the PG group (P = 0.0009). A significant atrophy of the pancreatic parenchyma was noted postoperatively in both groups (P < 0.0001), but these changes were more severe in the PG group than the PJ group (P = 0.0018). CONCLUSIONS: Considering the above postoperative morphological changes, PJ seems to be preferable to PG after pancreaticoduodenectomy.