Dopamine D2 receptors in discrimination learning and spine enlargement.

Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3-5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.

Transient Receptor Potential Channel Vanilloid 1 Contributes to Facial Mechanical Hypersensitivity in a Mouse Model of Atopic Asthma.

Sensitive skin, a common pathophysiological feature of allergic diseases, is defined as an unpleasant sensation in response to stimuli that normally should not provoke such sensations. However, the relationship between allergic inflammation and hypersensitive skin in the trigeminal system remains to be elucidated. To explore whether bronchial allergic inflammation affects facial skin and primary sensory neurons, we used an ovalbumin (OVA)-induced asthma mouse model. Significant mechanical hypersensitivity was observed in the facial skin of mice with pulmonary inflammation induced by OVA sensitization compared to mice treated with adjuvant or vehicle as controls. The skin of OVA-treated mice showed an increased number of nerve fibers, especially rich intraepithelial nerves, compared to controls. Transient receptor potential channel vanilloid 1 (TRPV1)-immunoreactive nerves were enriched in the skin of OVA-treated mice. Moreover, epithelial TRPV1 expression was higher in OVA-treated mice than in controls. Trigeminal ganglia of OVA-treated mice displayed larger numbers of activated microglia/macrophages and satellite glia. In addition, more TRPV1 immunoreactive neurons were found in the trigeminal ganglia of OVA-treated mice than in controls. Mechanical hypersensitivity was suppressed in OVA-treated Trpv1-deficient mice, while topical skin application of a TRPV1 antagonist before behavioral testing reduced the reaction induced by mechanical stimulation. Our findings reveal that mice with allergic inflammation of the bronchi had mechanical hypersensitivity in the facial skin that may have resulted from TRPV1-mediated neuronal plasticity and glial activation in the trigeminal ganglion.

Integrated genetic and epigenetic analysis of cancer-related genes in non-ampullary duodenal adenomas and intramucosal adenocarcinomas.

The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One hundred and seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal-type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric-type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal- and gastric-type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear ß-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal-type adenomas and intramucosal adenocarcinomas may indicate that the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Efficacy of Endoscopic Evaluation of Acute Radiation Esophagitis during Chemoradiotherapy with Proton Beam Therapy Boost for Esophageal Cancer.

BACKGROUND/AIM: To evaluate the utility of endoscopy for assessing radiation esophagitis during chemoradiotherapy (CRT) with proton beam therapy (PBT) boost for esophageal cancer. METHODS: Between December 2012 and December 2016, 38 patients with esophageal cancer were treated with CRT with PBT boost. To evaluate radiation esophagitis, endoscopy was performed after administration of CRT with standard PBT boost (total dose 50-60 Gy relative biological effectiveness [RBE]). Radiation esophagitis was evaluated and classified into 5 newly developed endoscopic grades (Fukui Acute Radiation Esophagitis [FARE] grade). The additional PBT boost was then adjusted and delivered (2-20 Gy [RBE]) to a maximum total dose of 74.4 Gy (RBE) based on the degree of radiation esophagitis, probability of residual tumor, and patient's general condition. To evaluate the utility of endoscopic examination, the incidences of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) were determined at the time of endoscopic examination after CRT with standard PBT boost (50-60 Gy [RBE]) and at the completion of treatment (60-74.4 Gy [RBE]), as well as during the 90 days from the beginning of treatment. RESULTS: There was a significant correlation between FARE grade and CTCAE esophagitis grade (ρ = 0.48; p = 0.03). Moreover, endoscopy detected severe esophagitis in an asymptomatic patient. Radiation dose escalation was achieved without severe acute adverse events. There was no significant difference between the incidence of acute toxicity at the time of the CRT with standard PBT boost (50-60 Gy [RBE]) and the higher dose at the completion of treatment (60-74.4 Gy [RBE]), which suggests this dose escalation strategy is safe. CONCLUSION: Endoscopic evaluation of radiation esophagitis using FARE grades was safely performed and useful for adjusting added radiation to ensure the safety of escalations in CRT with PBT boost for esophageal cancer.

Predicting successful/unsuccessful extrapolation for in vivo total clearance of model compounds with a variety of hepatic intrinsic metabolism and protein bindings in humans from pharmacokinetic data using chimeric mice with humanised liver.

1. Immunodeficient chimeric mice with humanised liver have been useful in predicting total clearance values of drugs in humans. However, their usefulness may currently be limited for specific compounds with interspecies differences.2. In vivo total clearance and in vitro hepatic intrinsic clearance values of 16 model compounds were determined in control/humanised-liver mice and in mouse and human hepatocytes, respectively, for extrapolating the total clearance values of compounds in humans.3. The predictability of in vivo total clearance values of 11 model compounds in humans was adequate using pharmacokinetic data from humanised-liver mice. The predictability of total clearance values using humanised-liver mice was better than conventional allometric scaling for compounds with large interspecies differences in in vitro hepatic intrinsic clearance or plasma unbound fractions.4. There were trends that total clearance values in control and humanised-liver mice were similar to or higher than reported hepatic blood flow rates in normal mice among four compounds with poor predictability. Diazepam, with the poorest predictability, showed 38-fold-higher hepatic intrinsic clearance in mice than in humans.5. These results could lead to guidelines describing that compounds may be suited or unsuited to extrapolating total clearance values in humans from pharmacokinetics in humanised-liver mice.

Analysis of the prognostic value of BMI and the difference in its impact according to age and sex in DLBCL patients.

Studies that have evaluated the prognostic value of body mass index (BMI) in patients with diffuse large B-cell lymphoma have recently been reported. However, the impact of BMI on survival outcomes remains controversial. We retrospectively analyzed the data of 406 diffuse large B-cell lymphoma patients treated with R-CHOP or R-CHOP-like regimens. The number (%) of patients that were categorized into 1 of 4 groups according to BMI were underweight (<18.5 kg/m2 ), 58 (14.3%); normal weight (≥18.5 to <25 kg/m2 ), 262 (64.5%); overweight (≥25 to <30 kg/m2 ), 75 (18.5%); and obese (≥30.0 kg/m2 ), 11 (2.7%). While the prognosis of overweight patients was good, being similar to that of normal weight, underweight, and obese patients had a worse prognosis (5-y overall survival [OS] was 57.9%, 74.3%, 73.4%, and 40.9% for underweight, normal weight, overweight, and obese patients, respectively; P = .004). In multivariate analysis, underweight and obesity were independent prognostic factors for OS compared with normal weight (hazard ratios 2.90 and 5.17, respectively). In elderly female patients (≥70 y), patients with a low BMI (<25 kg/m2 ) had significantly inferior OS than those with a high BMI (≥25 kg/m2 ) (5-y OS, 61.5% vs 85.7%; P = .039). In contrast, in young female patients (<70 years), patients with a low BMI had significantly better OS than those with a high BMI (5-y OS, 88.6% vs 46.4%; P < .001). In male patients, there were no differences in the effect of BMI on OS between young and elderly patients. In this study, we demonstrated that being underweight and obese were independent prognostic factors compared with being normal weight. In female patients, BMI had a different impact on the prognosis of young and elderly patients, whereas in male patients, there was no difference in the effect of BMI on prognosis according to age.

Beta-2 microglobulin as a significant prognostic factor and a new risk model for patients with diffuse large B-cell lymphoma.

Previous reports have evaluated the prognostic value of serum beta-2 microglobulin (B2MG) level in patients with non-Hodgkin lymphoma. However, its role in predicting clinical outcome of patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been extensively investigated. Here, we evaluated the prognostic value of B2MG and proposed a new prognostic model including B2MG for patients with DLBCL. A total of 274 patients with newly diagnosed de novo DLBCL were retrospectively analyzed. We defined the best cutoff value as 3.2 mg/L by using a receiver operating characteristic curve. Patients with a B2MG level ≥3.2 mg/L had significantly lower overall survival (OS) and progression-free survival than those with a B2MG level <3.2 mg/L (3-year OS, 50.9% vs. 89.4%, p < 0.001; 3-year progression-free survival, 45.3% vs. 79.7%, p < 0.001). Multivariate analysis showed that B2MG, age, performance status, and Ann Arbor stage were independent prognostic factors for OS. We developed a new prognostic model consisting of these four significant factors. We stratified patients into four-risk groups: low (L, 0 factor), low-intermediate (LI, 1-2 factors), high-intermediate (HI, 3 factors), high (H, 4 factors). This new prognostic model showed better risk discrimination compared with the National Comprehensive Cancer Network-International Prognostic Index (5-year OS: 100% and 23.4% vs. 100% and 27.1%, in L and H risk groups, respectively). Our study suggested that B2MG level is a significant prognostic factor in patients with DLBCL. A new prognostic index composed of age, performance status, stage, and B2MG could stratify the outcomes of patients with DLBCL effectively and appears to be a valuable risk model for these patients. Copyright © 2016 John Wiley & Sons, Ltd.

Sensitive cytometry based system for enumeration, capture and analysis of gene mutations of circulating tumor cells.

Methods for the enumeration and molecular characterization of circulating tumor cells (CTC) have been actively investigated. However, such methods are still technically challenging. We have developed a novel epithelial cell adhesion molecule independent CTC enumeration system integrated with a sorting system using a microfluidics chip. We compared the number of CTC detected using our system with those detected using the CellSearch system in 46 patients with various cancers. We also evaluated epidermal growth factor receptor (EGFR) and PIK3CA mutations of captured CTC in a study of 4 lung cancer and 4 breast cancer patients. The percentage of samples with detected CTC was significantly higher with our system (65.2%) than with CellSearch (28.3%). The number of detected CTC per patient using our system was statistically higher than that using CellSearch (median 5, 0; P = 0.000172, Wilcoxon test). In the mutation analysis study, the number of detected CTC per patient was low (median for lung, 4.5; median for breast, 5.5); however, it was easy to detect EGFR and PIK3CA mutations in the CTC of 2 lung and 1 breast cancer patient, respectively, using a commercially available kit. Our system is more sensitive than CellSearch in CTC enumeration of various cancers and is also capable of detecting EGFR and PIK3CA mutations in the CTC of lung and breast cancer patients, respectively.

Central nervous system relapse in patients with diffuse large B cell lymphoma: analysis of the risk factors and proposal of a new prognostic model.

Central nervous system (CNS) relapse in patients with diffuse large B cell lymphoma (DLBCL) is an uncommon event, and the outcome of patients with CNS relapse is poor. However, no reliable prediction models for CNS relapse have been developed. We retrospectively analyzed consecutive de novo DLBCL patients referred to our department between September 2004 and August 2015 and treated with R-CHOP or R-CHOP-like regimens. Of 413 patients analyzed in this study, a total of 27 patients (6.5 %) eventually developed CNS relapse. The 5-year probability of CNS relapse was 8.4 %. The median time from diagnosis of DLBCL to CNS relapse was 15 months, and the median survival after CNS relapse was 7 months. In univariate analysis, the risk factors significantly associated with CNS relapse were Ann Arbor stage 3 or 4, albumin level <3.2 mg/L, number of extranodal sites >1, and involvement of retroperitoneal lymph node. We developed a new prognostic model consisting of these four factors. The 5-year probability of CNS relapse was significantly higher in patients with at least three of these four factors than in those with two or fewer factors (26.4 vs. 3.0 %, P < 0.001). Using this model, we evaluated the incidence and the risk factors of CNS relapse in DLBCL patients. The new risk model consisting of the four factors demonstrated good risk stratification for CNS relapse, and could help to identify high-risk patients for whom CNS prophylaxis is warranted.

A novel flow cytometry-based cell capture platform for the detection, capture and molecular characterization of rare tumor cells in blood.

BACKGROUND: Personalized cancer treatment relies on the accurate detection of actionable genomic aberrations in tumor cells. Circulating tumor cells (CTCs) could provide an alternative genetic resource for diagnosis; however, the technical difficulties in isolating and analyzing rare CTCs have limited progress to date. In this preclinical study, we aimed to develop an improved capture system for molecular characterization of CTCs based on a novel cell sorting technology. METHODS: We developed a cell capture platform using On-chip Sort (On-Chip Biotechnologies), a novel bench-top cell sorter equipped with a disposable microfluidic chip. Spike-in experiments comprising a series of lung cancer cell lines with varying epithelial cell adhesion molecule (EpCAM) expression levels were conducted to assess the capture and purification efficiency of the platform. Samples were negatively enriched using anti-CD45-coated magnetic beads to remove white blood cells, followed by sample fixation and labeling. The enriched and labeled samples were then sorted by On-chip Sort based on cytokeratin, vimentin, and CD45 expression. Captured cells were immediately subjected to whole genome amplification followed by mutation analysis using deep targeted sequencing, and copy number analysis using quantitative polymerase chain reaction (qPCR). RESULTS: Spike-in experiments revealed an excellent overall mean capture rate of 70.9%. A 100% success rate in the detection of EGFR, KRAS and BRAF mutations from captured cells was achieved using pyrosequencing and deep sequencing. The mutant variant detection rates were markedly higher than those obtained with the CellSearch profile kit. qPCR analysis of amplified DNA demonstrated reproducible detection of copy number changes of the EGFR in captured tumor cells. CONCLUSIONS: Using a novel cell sorter, we established an efficient and convenient platform for the capture of CTCs. Results of a proof-of-principle preclinical study indicated that this platform has potential for the molecular characterization of captured CTCs from patients.

Multicolor detection of rare tumor cells in blood using a novel flow cytometry-based system.

The presence and number of circulating tumor cells (CTCs) in the blood of patients with solid tumors are predictive of their clinical outcomes. To date, the CellSearch system is the only US Food and Drug Administration-approved CTC enumeration system for advanced breast, prostate, and colon cancers. However, sensitivity issues due to epithelial cellular adhesion molecule (EpCAM)-based enrichment and limited capability for subsequent molecular analysis must be addressed before CTCs can be used as predictive markers in the clinical setting. We have developed a multicolor CTC detection system using cross-contamination-free flow cytometry, which permits the enumeration and characterization of CTCs for multiple molecular analyses. Tumor cell lines with different expression levels of EpCAM were spiked into peripheral blood obtained from healthy donors. Spike-in samples were negatively enriched using anti-CD45-coated magnetic beads to remove white blood cells, and this was followed by fixation and labeling with CD45-Alexa Fluor 700, EpCAM-phycoerythrin, cytokeratin (CK)-fluorescein isothiocyanate antibodies, and/or 7-aminoactinomycin D for nuclei staining. Excellent detection (slope = 0.760-0.888) and a linear performance (R(2) = 0.994-0.998) were noted between the observed and expected numbers of tumor cells, independent of EpCAM expression. The detection rate was markedly higher than that obtained using the CellSearch system, suggesting the superior sensitivity of our system in detecting EpCAM- tumor cells. Additionally, the incorporation of an epithelial-mesenchymal transition (EMT) marker allowed us to detect EpCAM-/CK- cells and EMT-induced tumor cells. Taken together, our multicolor CTC detection system may be highly efficient in detecting previously unrecognized populations of CTCs.

Association between genomic alterations and metastatic behavior of colorectal cancer identified by array-based comparative genomic hybridization.

Colorectal cancers (CRCs) exhibit multiple genetic alterations, including allelic imbalances (copy number alterations, CNAs) at various chromosomal loci. In addition to genetic aberrations, DNA methylation also plays important roles in the development of CRC. To better understand the clinical relevance of these genetic and epigenetic abnormalities in CRC, we performed an integrative analysis of copy number changes on a genome-wide scale and assessed mutations of TP53, KRAS, BRAF, and PIK3CA and DNA methylation of six marker genes in single glands isolated from 39 primary tumors. Array-based comparative genomic hybridization (array-CGH) analysis revealed that genomic losses commonly occurred at 3q26.1, 4q13.2, 6q21.32, 7q34, 8p12-23.3, 15qcen and 18, while gains were commonly found at 1q21.3-23.1, 7p22.3-q34, 13q12.11-14.11, and 20. The total numbers and lengths of the CNAs were significantly associated with the aberrant DNA methylation and Dukes' stages. Moreover, hierarchical clustering analysis of the array-CGH data suggested that tumors could be categorized into four subgroups. Tumors with frequent DNA methylation were most strongly enriched in subgroups with infrequent CNAs. Importantly, Dukes' D tumors were enriched in the subgroup showing the greatest genomic losses, whereas Dukes' C tumors were enriched in the subgroup with the greatest genomic gains. Our data suggest an inverse relationship between chromosomal instability and aberrant methylation and a positive association between genomic losses and distant metastasis and between genomic gains and lymph node metastasis in CRC. Therefore, DNA copy number profiles may be predictive of the metastatic behavior of CRCs.

Recent advances in the treatment of oral ulcerative mucositis from clinical and basic perspectives.

BACKGROUND: Oral ulcerative mucositis (OUM) is common in patients with cancer, particularly in those undergoing chemoradiation therapy. The effective management of OUM is crucial for continuous cancer care and patient well-being. Recent studies have advanced our understanding of the causes, leading to clinical trials toward novel treatments. This review focuses on the contemporary therapeutic landscape, and provides the latest insights into the mechanisms of mucosal healing and pain. HIGHLIGHTS: Management strategies for oral ulcerative mucositis in patients with cancer include maintaining good oral hygiene, reducing mucosal irritation against radiation, and using various topical analgesic treatments, including herbal medicines. However, the current management practices have limitations that necessitate the development of more efficacious and novel treatments. Molecular research on transient receptor potential (TRP) channels in the oral mucosa is crucial for understanding the mechanisms of wound healing and pain in patients with OUM. Targeting TRP subfamily V member 3 (V3) and TRPV4 can enhance wound healing through re-epithelialization. The suppression of TRPV1, TRPA1, and TRPV4 may be effective in alleviating OUM-induced pain. CONCLUSION: Research advancements have improved our understanding and potentially led to novel treatments that offer symptomatic relief. This progress highlights the importance of collaborations between clinical researchers and scientists in the development of innovative therapies.

Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype.

The concept of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) is widely accepted, although the timing of its occurrence and its interaction with other genetic defects are not fully understood. Our aim in this study was to unravel the molecular development of CIMP cancers by dissecting their genetic and epigenetic signatures in precancerous and malignant colorectal lesions. We characterized the methylation profile and BRAF/KRAS mutation status in 368 colorectal tissue samples, including precancerous and malignant lesions. In addition, genome-wide copy number aberrations, methylation profiles, and mutations of BRAF, KRAS, TP53, and PIK3CA pathway genes were examined in 84 colorectal lesions. Genome-wide methylation analysis of CpG islands and selected marker genes revealed that CRC precursor lesions are in three methylation subgroups: CIMP-high, CIMP-low, and CIMP-negative. Interestingly, a subset of CIMP-positive malignant lesions exhibited frequent copy number gains on chromosomes 7 and 19 and genetic defects in the AKT/PIK3CA pathway genes. Analysis of mixed lesions containing both precancerous and malignant components revealed that most aberrant methylation is acquired at the precursor stage, whereas copy number aberrations are acquired during the progression from precursor to malignant lesion. Our integrative genomic and epigenetic analysis suggests early onset of CIMP during CRC development and indicates a previously unknown CRC development pathway in which epigenetic instability associates with genomic alterations.

Fat-water interface on susceptibility-weighted imaging and gradient-echo imaging: comparison of phantoms to intracranial lipomas.

OBJECTIVE: In a clinical setting, lipoma can sometime show low signal intensity on susceptibility-weighted imaging (SWI) mimicking hemorrhage. The purpose of this study was to evaluate the fat-water interface chemical-shift artifacts between SWI and T2*-weighted imaging with a phantom study and evaluate SWI in lipoma cases. MATERIALS AND METHODS: SWI, magnitude, high-pass filtered phase, and T2*-weighted imaging of a lard-water phantom were evaluated in the in-phase, out-of phase, and standard partially out-of-phase TE settings used for clinical 3-T SWI (19.7, 20.9, and 20.0 ms, respectively) to identify the most prominent fat-water interface low signal. SWI of five cases of CNS lipoma were retrospectively evaluated by two neuroradiologists. RESULTS: TE at 19.7 ms (in-phase) showed the minimum fat-water interface low signal in the phase-encoding direction on magnitude, high-pass filtered phase, and SWI. TE at 20.9 ms (out-of-phase) showed the maximum fat-water interface in the phase-encoding direction on magnitude, high-pass filtered phase, and SWI. TE at 20.0 ms (partially out-of-phase) showed more fat-water interface low signal on SWI than on T2*-weighted imaging, especially in the phase-encoding direction. All lipomas in the five patients showed high signal intensity with surrounding peripheral dark rim on SWI. CONCLUSION: Fat-water interface is more prominent on the standard TE setting used for clinical SWI (20.0 ms) than that of T2*-weighted imaging and shows a characteristic surrounding peripheral low-signal-intensity rim in lipoma. Knowing the fat-water appearance on SWI is important to avoid misinterpreting intracranial lipomas as hemorrhages.

Hepatic portal venous gas in pancreatic solitary metastasis from an esophageal squamous cell carcinoma.

BACKGROUND: Hepatic portal venous gas (HPVG) is a rare entity commonly associated with intestinal necrosis and fatal outcome, and various underlying diseases have been reported. Pancreatic solitary metastasis without local extension is also rare in esophageal squamous cell carcinoma. METHODS: This report describes an interesting and unusual case of HPVG arising from pancreatic tumor. Autopsy revealed pathogenesis of HPVG and synchronous tumors of the esophagus and pancreas. RESULTS: A 73-year-old man developed synchronous double tumor in the esophagus and pancreas several months before acute abdomen and his death, which were generated by HPVG. Autopsy revealed that HPVG was caused by gastric wall infarction owing to expansion of an isolated pancreatic metastasis from esophageal squamous cell carcinoma. CONCLUSIONS: This is the first case of HPVG that was derived from pancreatic tumor infiltration. If he had been diagnosed with solitary pancreatic metastasis from esophageal squamous cell carcinoma in the first time, he might have an option for chemotherapy, which could let him live longer.

Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination.

Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort (n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4+ T cells including CXCR3+ circulating follicular helper T cells and the TH1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific TH1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8+ T cell responses. Thus, an inefficient CD4+ T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4+ T cell response following the first dose is key to improving vaccine efficacy in older adults.

A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma.

OBJECTIVES: Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic diagnosis is often difficult. Our aim was to clarify which endoscopic findings are specific to SSAs. METHODS: The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing. RESULTS: Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns. CONCLUSIONS: Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance.

Diagnosis of moyamoya disease using 3-T MRI and MRA: value of cisternal moyamoya vessels.

INTRODUCTION: The purpose of this study was to propose new magnetic resonance (MR) criteria of diagnosing moyamoya disease (MMD) from cisternal moyamoya vessels (MMVs) on 3-T magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) and compare the diagnostic accuracy of the existing MR criteria and the proposed MR criteria. METHODS: Participants comprised 20 consecutive patients with MMD (4 males, 16 females) diagnosed clinically using conventional angiography and 20 controls (13 male and 7 female arteriosclerosis patients). In these participants, 3-T MRI/MRA was evaluated by the existing MR criteria, which use MMVs in the basal ganglia, and the proposed MR criteria, which use cisternal MMVs, and then these two criteria were statistically compared by McNemar's test. RESULTS: Diagnostic accuracy was 62.5% with the existing MR criteria and 97.5% with the proposed MR criteria. The proposed MR criteria was more sensitive (1.00) than the existing MR criteria (0.45), but less specific (0.95) than the existing MR criteria (1.00). CONCLUSION: The proposed MR criteria using cisternal MMVs showed significantly higher diagnostic accuracy than the existing MR criteria. We believe that our proposed MR criteria will be beneficial for diagnosing MMD.

A behavioural correlate of the synaptic eligibility trace in the nucleus accumbens.

Reward reinforces the association between a preceding sensorimotor event and its outcome. Reinforcement learning (RL) theory and recent brain slice studies explain the delayed reward action such that synaptic activities triggered by sensorimotor events leave a synaptic eligibility trace for 1 s. The trace produces a sensitive period for reward-related dopamine to induce synaptic plasticity in the nucleus accumbens (NAc). However, the contribution of the synaptic eligibility trace to behaviour remains unclear. Here we examined a reward-sensitive period to brief pure tones with an accurate measurement of an effective timing of water reward in head-fixed Pavlovian conditioning, which depended on the plasticity-related signaling in the NAc. We found that the reward-sensitive period was within 1 s after the pure tone presentation and optogenetically-induced presynaptic activities at the NAc, showing that the short reward-sensitive period was in conformity with the synaptic eligibility trace in the NAc. These findings support the application of the synaptic eligibility trace to construct biologically plausible RL models.