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Background: A potent and sustained T cell response will likely be a requisite component of an effective HIV cure. Chimeric antigen receptor (CAR) T cells, whereby autologous T cells are engineered with specific antigen-targeting and functional attributes, have been effectively employed against a number of chemotherapy-refractive cancers. However, a highly effective CAR T cell against HIV has yet to be developed, which could represent a powerful approach to target the HIV reservoir. Methods: Bone marrow, liver, thymus (BLT) humanized mice were used to iteratively test CAR T cell efficacy against both acute and disseminated HIV infection. A CD4 ectodomain-expressing CAR was used to target HIV Env-expressing cells. We compared CAR T cells expressing the 4-1BB and CD28 co-stimulatory domains either individually, in a tandem '3rd generation' construct, or as a novel Dual CAR T cell simultaneously expressing independent 4-1BB and CD28 co-stimulated CARs. A CXCR4-C34 fusion inhibitor was co-expressed to protect CAR T cells from HIV infection. Results: HIV-specific CAR T cells expressing 4-1BB or CD28 costimulatory domains exhibited either enhanced proliferation and survival or enhanced effector function respectively, and the 3rd generation tandem construct took on the phenotype of the CD28 membrane proximal domain; all constructs had negligible impact on HIV pathogenesis in vivo. In contrast, Dual CAR T cells simultaneously expressing independent 4-1BB and CD28 costimulated CARs exhibited the proliferation and survival of 4-1BB and the effector function of CD28 and prevented HIV-induced CD4+ T cell loss despite persistent viremia. Importantly, protection of the Dual CAR T cells from HIV infection through expression of the C34-CXCR4 fusion inhibitor significantly increased their efficacy resulting in reductions in acute phase viremia, accelerated viral suppression in combination with ART, and reduced viral burden in lymphoid tissues. Conclusions: These data describe a novel CD4-based Dual CAR approach, harnessing the favorable attributes of both 4-1BB and CD28 costimulation. When protected from HIV infection, these Dual CAR T cells were capable of mitigating HIV pathogenesis in the context of a robust and fully disseminated HIV infection in vivo, while reducing tissue viral burden, a goal of HIV cure strategies., OA20.02 D. Claiborne (1); C. Maldini (2); K. Okawa (3); T. Chen (1); D. Dopkin (2); X. Shan (2); K. Power (1); R. Trifonova (1); K. Krupp (1); M. Phelps [...]

"Groove pancreatitis", a form of segmental pancreatitis affecting the head of the pancreas, is localized within the "groove" between pancreas head, duodenum, and common bile duct. Differentiation between groove pancreatitis and pancreatic head carcinoma is often difficult. We report a case of groove pancreatitis in which a hypoechoic mass between the duodenal wall and pancreas was clearly imaged, and narrowing of the second portion of the duodenum and bile duct stenosis were also found. The diagnosis was confirmed by surgery (pylorus-preserving pancreato duodenectomy). The patient was relieved from abdominal pain post operation. Up to the present, the patient has been good condition. We review the clinicopathologic and radiologic features of groove pancreatitis in the Japanese literature and discuss the possible role of Santorini's duct in its pathogenesis. We consider that impacted protein plugs in Santorini's duct are a pathogenic factor in the development of groove pancreatitis. Therefore, the findings of Santorini's duct on endoscopic retrograde pancreatography are very important in the diagnosis of groove pancreatitis. Groove pancreatitis presents various clinical features, such as biliary stenosis, duodenal stenosis, and pancreatic mass, and often masquerades as pancreatic head carcinoma. This condition should be kept in mind in the differential diagnosis of pancreatic head carcinoma. [ABSTRACT FROM AUTHOR]

Abstract Background It is known that thiazolidinediones are involved in regulating the expression of various genes, including the vascular endothelial growth factor (VEGF) gene via peroxisome proliferator-activated receptor γ (PPARγ); VEGF is a prognostic biomarker for non-small-cell lung cancer (NSCLC). Methods In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells. Results In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARγ antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition. Conclusions Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC.

Background: The natural history of branch-duct intraductal papillary mucinous cystic neoplasms (BD-IPMNs) in the pancreas remains unclear. This study aimed to answer this clinical question by focusing on the development of concomitant pancreatic ductal adenocarcinomas (cPDAC)., Methods: The Japan Pancreas Society conducted a prospective multicenter surveillance study of BD-IPMN every six months for five years. The primary endpoints were progression of BD-IPMN, progression to high-grade dysplasia/invasive carcinoma (HGD/IC), and cPDAC. Factors predicting the progression of BD-IPMN to HGD/IC and development of cPDAC were also assessed as secondary endpoints., Results: Among the 2104 non-operated patients, 348 (16.5 %) showed progression of primary BD-IPMN. Cumulative incidences of BD-IPMN with HGD/IC and cPDAC during the 5.17-year surveillance period were 1.90 % and 2.11 %, respectively, and standard incidence ratios of BD-IPMN with HGD/IC and cPDAC were 5.28 and 5.73, respectively. Of 38 cPDACs diagnosed during surveillance, 25 (65.8 %) were resectable. The significant predictive characteristics of BD-IPMN for progression to HGD/IC were larger cyst size (p = 0.03), larger main pancreatic duct size (p < 0.01), and mural nodules (p = 0.02). Significant predictive characteristics for the development of cPDAC were male sex (p = 0.03) and older age (p = 0.02), while the size of IPMN was not significant., Conclusion: Careful attention should be given to "dual carcinogenesis" during BD-IPMN surveillance, indicating the progression of BD-IPMN to HGD/IC and development of cPDAC distinct from BD-IPMN, although the establishment of risk factors that predict cPDAC development remains a challenge (UMIN000007349)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The superior colliculus (SC) receives inputs from various brain regions in a layer- and radial subregion-specific manner, but whether the SC exhibits subregion-specific dynamics remains unclear. To address this issue, we recorded the spiking activity of single SC neurons while photoactivating cortical areas in awake head-fixed Thy1-ChR2 rats. We classified 309 neurons that responded significantly into 8 clusters according to the response dynamics. Among them, neurons with monophasic excitatory responses (7-12 ms latency) that returned to baseline within 20 ms were commonly observed in the optic and intermediate gray layers of centromedial and centrolateral SC. In contrast, neurons with complex polyphasic responses were commonly observed in the deep layers of the anterolateral SC. Cross-correlation analysis suggested that the complex pattern could be only partly explained by an internal circuit of the deep gray layer. Our results indicate that medial to centrolateral SC neurons simply relay cortical activity, whereas neurons in the deep layers of the anterolateral SC dynamically integrate inputs from the cortex, SNr, CN, and local circuits. These findings suggest a spatial gradient in SC integration, with a division of labor between simple relay circuits and those integrating complex dynamics., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection., Summary Background Data: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown., Methods: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated., Results: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways., Conclusion: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs., Competing Interests: Disclosures: All authors disclose no personal and financial conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Broadly neutralizing antibodies (bNAbs) have shown great promise for prevention and treatment of HIV infection. Breadth of bNAb neutralization, measured in vitro across panels of diverse viral isolates, is often used as a predictor of clinical potential. However, recent prevention studies demonstrate that the clinical efficacy of a broad and potent bNAb (VRC01) is undermined by neutralization resistance of circulating strains. Using HIV-infected humanized mice, we find that therapeutic efficacy of bNAbs delivered as Vectored ImmunoTherapy (VIT) is a function of both the fitness cost and resistance benefit of mutations that emerge during viral escape, which we term 'escapability'. Applying this mechanistic framework, we find that the sequence of the envelope V5-loop alters the resistance benefits of mutants that arise during escape, thereby impacting the therapeutic efficacy of VIT-mediated viral suppression. We also find that an emtricitabine-based antiretroviral drug regimen dramatically enhances the efficacy of VIT, by reducing the fitness of mutants along the escape path. Our findings demonstrate that bNAb escapability is a key determinant to consider in the rational design of antibody regimens with maximal efficacy and illustrates a tractable means of minimizing viral escape from existing bNAbs., Competing Interests: DECLARATION OF INTERESTS A.B.B. is a founder of Cure Systems LLC.

Heat stress, which occurs when temperatures exceed the optimal range for growth, challenges the maintenance of crop yield because it disrupts plant homeostasis at the cellular and developmental levels. Chemical priming, which can activate the response to environmental stress using chemical compounds, is a promising method of maintaining plant growth under stressful conditions. Recently, we found that the non-proteogenic amino acid N-acetylglutamic acid (NAG) confers tolerance to oxidative stress through the activation of genes related to scavenging reactive oxygen species in plants. However, it has been unknown whether NAG alleviates environmental stress except oxidative stress. Here, we revealed that the response to heat stress was enhanced by exogenous treatment with NAG in plants. NAG alleviated the reduction in chlorophyll content induced by heat stress in Arabidopsis thaliana . Gene expression analysis showed that NAG activates the transcription factor HSFA2 , which is regarded as a master regulator of the transcriptional cascade in response to heat stress. NAG induces histone H4 acetylation, an active histone modification, at the HSFA2 locus, suggesting that NAG could activate the expression of HSFA2 based on epigenetic modifications such as histone acetylation. Additionally, we found that Oryza sativa treated with NAG showed tolerance to heat stress. These results suggest that NAG could be used for chemical priming in the maintenance of plant growth under heat-stress conditions., Competing Interests: Conflict of interestT.H., S.T., and K.O. were employed by the Kirin Holdings Company, Ltd. The authors declare no conflict of interest., (© 2024 Japanese Society for Plant Biotechnology.)

Background: Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC., Methods: This retrospective multi-institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC., Results: Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19-9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un-matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS ( p  = 0.001), DSS ( p  = 0.001), and RFS ( p  = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p  < 0.001)., Conclusion: Postoperative AT might benefit selected patients with invasive IPMC, especially those at high risk of poor survival. NAT might improve the survivability of BR invasive IPMC. Any treatment for recurrence after surgery for invasive IPMC might improve survival., Competing Interests: Author SH was supported by grants from the Japan Pancreas Society. Author MU was supported by grants from Taiho Pharma, however, the funding source had no role in the design, practice, or analysis of this study. Author SS was supported by grants from Nihon Servier, Amino‐Up co, however, the funding source had no role in the design, practice, or analysis of this study. Authors HN, KH, and HY are editorial board members of Annals of Gastroenterological Surgery. Authors SH, IE, and AH are associate editors of Annals of Gastroenterological Surgery., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Oxidative stress causes cellular damage and genomic instability through the accumulation of reactive oxygen species (ROS) in plants, resulting in reduced crop production. Chemical priming, which can enhance plant tolerance to environmental stress using functional chemical compounds, is expected to improve agricultural yield in various plants without genetic engineering. In the present study, we revealed that non-proteogenic amino acid N-acetylglutamic acid (NAG) can alleviate oxidative stress damage in Arabidopsis thaliana (Arabidopsis) and Oryza sativa (rice). Exogenous treatment with NAG prevented chlorophyll reduction induced by oxidative stress. The expression levels of ZAT10 and ZAT12 , which are regarded as master transcriptional regulators in response to oxidative stress, increased following NAG treatment. Additionally, Arabidopsis plants treated with NAG showed enhanced levels of histone H4 acetylation at ZAT10 and ZAT12 with the induction of histone acetyltransferase s HAC1 and HAC12 . The results suggest that NAG could enhance tolerance to oxidative stress through epigenetic modifications and contribute to the improvement of crop production in a wide variety of plants under environmental stress., Competing Interests: TH, ST, and KO were employed by the Kirin Holdings Company, Ltd. This study received funding from Kirin Holdings Company Ltd. The funder had the following involvement with the study: the decision to publish., (Copyright © 2023 Hirakawa, Tanno and Ohara.)

Background: Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6 months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC., Methods: In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180 ± 30 days and a longer duration group that included patients who received treatment for >210 days., Results: The median duration of S-1 chemotherapy was 167 days, with a mean ± standard deviation of 200 ± 193 days. After excluding patients who had a recurrence within 210 days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n = 1473) and the longer duration group (n = 975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p = .6186; 5-year OS: 52.8% vs. 53.4%, respectively; p = .5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis., Conclusions: The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6 months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment., (© 2022 American Cancer Society.)