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.

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.

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.

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.

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.

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.

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.

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.

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.

[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.

[A case of hepatocellular carcinoma with gall bladder metastasis].

A 74-year-old male was admitted to Osaka University Hospital for advanced hepatocellular carcinoma in April 2007. CT and MRI scan showed the tumor was located mainly in posterior segment and had portal vein tumor thrombus, and the wall of gall bladder was edematous and thick, but seemed not to be close to the main tumor. We performed an extended posterior segmentectomy, tumor thrombectomy and cholecystectomy. Pathological examination showed that poorly differentiated hepatocellular carcinoma cells, which were same as the main tumor, existed in lamina propria and muscle layer of gall bladder, and invaded the submucosal vessels. So we diagnosed it as gall bladder metastasis from hepatocellular carcinoma.

[A case of synchronous triple cancer involving advanced hepatocellular carcinoma].

We report herein a case of advanced hepatocellular carcinoma (HCC) with gastric cancer and rectal cancer. A 68-year-old man was diagnosed with advanced HCC and gastric cancer. At first, he was planned to be treated by trans-catheter arterial chemoembolization (TACE). After TACE, he was diagnosed with rectal cancer by following abdominal computed tomography (CT) and colonoscopy. Then, he was diagnosed with synchronous triple cancer. To avoid bleeding and obstruction, a resection of rectal cancer was performed secondly. After the surgery, he was treated by TACE for three times. HCC was well-controlled, but there remained a small active HCC lesion. Gastric cancer had little progressed, but was still resectable. Finally, we performed a partial hepatectomy and a distal gastrectomy simultaneously. Both of cancer stage and progression-related multimodal treatment is necessary in synchronous cancer.

Motility of the pouch correlates with quality of life after total gastrectomy.

BACKGROUND: Jejunal pouch reconstruction is used to provide reservoir function after total gastrectomy, but controversy remains regarding pouch functions and quality of life (QOL). In this study, pouch motility was studied in conjunction with postoperative QOL. METHODS: Pouch motility of 23 patients with jejunal pouch interposition after total gastrectomy was examined by manometry under fasting conditions and by an emptying test using dual-scintigraphy under postprandial conditions. Residual food was graded by endoscopic examinations. QOL was evaluated using the Gastrointestinal Quality of Life Index, and a stasis- or dumping-related symptom score. RESULTS: The pouch showed interdigestive contractile activity. Bursts of contractile activity occurred frequently and were long-lasting compared with the migrating motor complex phase III of the control jejunum. The percentage of time of contractile bursts correlated with postprandial pouch emptying (liquid: R(2) = 0.229, P < .03; solid: R(2) = 0.243, P < .02). Patients with little or no residual food had more percentage of time of contractile bursts than those with moderate residual food (P < .01). The percentage of time of contractile bursts was correlated with the Gastrointestinal Quality of Life Index score (R(2) = 0.262, P < .02), stasis-related symptoms (R(2) = 0.279, P < .01), and dumping-related symptoms (R(2) = 0.218, P < .03). CONCLUSIONS: An interposed jejunum pouch showed bursts of contractile activity that affected postoperative gastrointestinal function and patient QOL.

Dai-kenchu-to, a Chinese herbal medicine, improves stasis of patients with total gastrectomy and jejunal pouch interposition.

BACKGROUND: Intestinal motility after gastric surgery frequently is disturbed and results in postoperative intestinal symptoms and poor quality of life (QOL). The purpose of this study was to examine the effects of Dai-kenchu-to on intestinal motility and postoperative QOL of patients. METHODS: Seventeen patients who underwent total gastrectomy with jejunal pouch interposition for gastric cancer in the Department of Surgery of Osaka University Medical Hospital were enrolled. The patients were assigned randomly to the cross-over study with or without 15 g/d of Dai-kenchu-to. Questionnaires and emptying tests using (111)In-labeled liquid and (99m)Tc-labeled solid test meal were performed at the end of each treatment period. A manometric study was performed in 6 patients to measure contractile activity with or without Dai-kenchu-to. RESULTS: Stasis-related symptoms were reduced significantly by Dai-kenchu-to (P = .032). In the emptying test, Dai-kenchu-to accelerated emptying of both liquid (P < .01) and solid (P = .015) meals from the pouch. The pouch showed bursts of contractions, which were increased significantly by oral intake of Dai-kenchu-to (P = .028). CONCLUSIONS: Dai-kenchu-to increased intestinal motility and decreased postoperative symptoms of patients with total gastrectomy with jejunal pouch interposition.