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Purpose: Biliary tract cancers (BTCs), which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant BTC models which recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in BTCs to create a resource for modeling precision oncology., Experimental Design: PDXs were derived from BTC collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole exome sequencing and RNASeq. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease=partial response; >20% increase in tumor volume=progressive disease, and any non-PR/PD was considered stable disease., Results: Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, IDH1, ERRB2, PIK3CA, PTEN and KRAS. RNAseq demonstrated fusions and expression of antibody drug conjugate targets including TROP2, HER2 and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically., Conclusions: Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

Objective: Hepatocellular carcinoma (HCC) is a highly lethal cancer with significant mortality, primarily attributed to metastasis. Although Protocadherin Gamma Subfamily A, 9 (PCDHGA9) has been identified as a tumor suppressor gene in cancer metastasis, its role in HCC remains ambiguous. This study clarifies the role of PCDHGA9 in HCC by examining its expression, clinical significance, and molecular activities. Methods: Tissue microarray immunofluorescence analysis evaluated the expression of PCDHGA9 and its clinical relevance. In vitro experiments involved manipulating PCDHGA9 levels in SK-HEP-1 cells to assess migration through wound-healing and transwell assays. In vivo , shPCDHGA9 cell injections were utilized to observe effects on tumor growth and metastasis. Protein analysis and Western Blot validated epithelial-mesenchymal transition (EMT)-related proteins. Subsequent to TGF-β treatment, cell proliferation and apoptosis were quantified using cell counting kit-8 and flow cytometry, respectively, followed by investigation of TGF-β effects on PCDHGA9 N6-methyladenosine (m6A) modification via Methylated RNA immunoprecipitation, RT-qPCR, and Western blot analysis. Results: Downregulation of PCDHGA9 expression in HCC tissues is correlated with poor prognosis. In vitro experiments demonstrated that modulating PCDHGA9 expression influenced HCC cell migration. In vivo , PCDHGA9 knockdown is correlated with increased metastasis. Furthermore, TGF-β stimulation promoted cell proliferation and inhibited apoptosis. Mechanistically, TGF-β-mediated m6A modification led to PCDHGA9 decay, promoting EMT in HCC cells. Conclusion: PCDHGA9 serves as a potential tumor suppressor in HCC by inhibiting EMT. During this process, TGF-β is observed to exert regulatory control over m6A modifications of PCDHGA9.

Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified Yap1 in cancer cells and Cox2 in stromal fibroblasts as two key nodes in this signaling circuit. Co-targeting Yap1 in cancer cells and Cox2 in stroma sensitized PDAC to Gemcitabine treatment and dramatically prolonged survival of mice bearing late-stage PDAC, whereas simultaneously inhibiting Yap1 and Cox2 only in cancer cells was ineffective. Mechanistically, chemotherapy triggers non-canonical Yap1 activation by nemo-like kinase in 14-3-3ζ-overexpressing PDAC cells and increases secretion of CXCL2/5, which bind to CXCR2 on fibroblasts to induce Cox2 and PGE2 expression, which reciprocally facilitate PDAC cell survival. Finally, analyses of PDAC patient data revealed that patients who received Statins, which inhibit Yap1 signaling, and Cox2 inhibitors (including Aspirin) while receiving Gemcitabine displayed markedly prolonged survival compared to others. The robust anti-tumor efficacy of Statins and Aspirin, which co-target the chemo-induced adaptive circuit in the tumor cells and stroma, signifies a unique therapeutic strategy for PDAC., (© 2024. The Author(s).)

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.

As a double-stranded RNA-editing enzyme and an interferon-stimulated gene, double-stranded RNA-specific adenosine deaminase (ADAR1) suppresses interferon signaling and contributes to immunotherapy resistance. Suppression of ADAR1 overcomes immunotherapy resistance in preclinical models, but has not yet been translated to clinical settings. By conducting a screening of a subset of the FDA-approved drugs, we found that all-trans retinoic acid (ATRA, also known as tretinoin) caused ADAR1 protein degradation through ubiquitin-proteasome pathways and concomitantly increased PD-L1 expression in pancreatic and breast cancers. In addition, the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment and unleashed antitumor immunity and thereby impeded tumor growth in pancreatic cancer mouse models. In a pilot clinical trial, a higher dose of ATRA plus the anti-PD-1 antibody nivolumab prolonged median overall survival in patients with chemotherapy-resistant pancreatic cancer compared to a lower dose of the same regimen. In this study, ATRA was the first drug to be found to cause ADAR1 degradation. We propose translation of a promising 2-pronged antitumor strategy using ATRA and nivolumab to convert immunologically "cold" into "hot" tumors susceptible to immune checkpoint blockade.

A general and practical K 2 CO 3 -promoted [3+2] annulation between trifluoroacetaldehyde N -triftosylhydrazone (TFHZ-Tfs) and 4-nitroisoxazoles has been developed to access structurally diverse trifluoromethylpyrazolo[3,4- d ]isoxazoles. Mechanistically, CF 3 CHN 2 is formed in situ by TFHZ-Tfs decomposition and involves a formal [3+2] dearomative cycloaddition with 4-nitroisoxazoles, followed by aromatization via the elimination of the nitro group. Furthermore, this protocol is metal-free, scalable, mild, and operationally safe, with a broad substrate scope and high functional group compatibility.

Organoborons have recently received much attention, while a biocatalytic platform for the synthesis of chiral organoborons is limited only to Rma cytochrome c . In this study, we exploited the other heme protein, neuroglobin (Ngb), and engineered a quadruple mutant, A15C/H64G/V68F/F28M Ngb, by redesigning the heme active site using the structural information on A15C Ngb and molecular docking studies. The enzyme was shown to be efficient in catalyzing carbene transfer B-H insertion reactions between pyridine/quinoline boranes and benzyl 2-diazopropanoates and their derivatives (29 examples). The designed cavity in the heme distal site favors the binding of large volume substrates such as those containing a quinoline, naphthyl, or biphenyl group. As further determined by the X-ray crystallography of 6c , the chiral products are in the R -configuration, with up to 98:2 e.r. Furthermore, both the whole cell and cell lysate containing the enzyme are reactive toward the B-H insertion reactions. This study presents a convenient biocatalytic platform that may be generally applicable for the synthesis of functional chiral organoborons.

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods : We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023-2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes ( BRCA1/2 , PALB2 , and ATM ) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME) contributing to its therapeutic resistance. Following our previous studies, we report that mast cells infiltrating the PDAC TME foster this immunosuppression and desmoplasia. Mast cell infiltration correlated with human PDAC progression, and genetic or pharmacological mast cell depletion reduced tumor growth and desmoplasia while enhancing survival in mouse PDAC models. Mechanistically, mast cell-derived IL-10 promoted PDAC progression. Strikingly, combining an agonistic anti-OX40 immunotherapy with mast cell blockade synergistically elicited durable anti-tumor immunity, marked by increased infiltration of CD8 + T effector cells expressing granzyme B and dramatic survival benefit unachievable with either approach alone. An OX40-associated gene signature correlated with improved survival in human PDAC, supporting therapeutic translation. Our findings establish mast cells as promoters of the suppressive PDAC TME and rational targets for combination immunotherapy. Targeting this mast cell-mediated resistance mechanism could overcome immunotherapy failure in PDAC., Competing Interests: The authors disclose no potential conflicts of interest., (© 2024 The Author(s).)

The development of efficient Pd single-atom catalysts for CO oxidation, crucial for environmental protection and fundamental studies, has been hindered by their limited reactivity and thermal stability. Here, we report a thermally stable TiO 2 -supported Pd single-atom catalyst that exhibits enhanced intrinsic CO oxidation activity by tunning the local coordination of Pd atoms via H 2 treatment. Our comprehensive characterization reveals that H 2 -treated Pd single atoms have reduced nearest Pd-O coordination and form short-distanced Pd-Ti coordination, effectively stabilizing Pd as isolated atoms even at high temperatures. During CO oxidation, partial replacement of the Pd-Ti coordination by O or CO occurs. This unique Pd local environment facilitates CO adsorption and promotes the activity of the surrounding oxygen species, leading to superior catalytic performance. Remarkably, the turnover frequency of the H 2 -treated Pd single-atom catalyst at 120 °C surpasses that of the O 2 -treated Pd single-atom catalyst and the most effective Pd/Pt single-atom catalysts by an order of magnitude. These findings open up new possibilities for the design of high-performance single-atom catalysts for crucial industrial and environmental applications.

SNNs are gaining popularity in AI research as a low-power alternative in deep learning due to their sparse properties and biological interpretability. Using SNNs for dense prediction tasks is becoming an important research area. In this paper, we firstly proposed a novel modification on the conventional Spiking U-Net architecture by adjusting the firing positions of neurons. The modified network model, named Analog Spiking U-Net (AS U-Net), is capable of incorporating the Convolutional Block Attention Module (CBAM) into the domain of SNNs. This is the first successful implementation of CBAM in SNNs, which has the potential to improve SNN model's segmentation performance while decreasing information loss. Then, the proposed AS U-Net (with CBAM&ViT) is trained by direct encoding on a comprehensive dataset obtained by merging several diabetic retinal vessel segmentation datasets. Based on the experimental results, the provided SNN model achieves the highest segmentation accuracy in retinal vessel segmentation for diabetes mellitus, surpassing other SNN-based models and most ANN-based related models. In addition, under the same structure, our model demonstrates comparable performance to the ANN model. And then, the novel model achieves state-of-the-art(SOTA) results in comparative experiments when both accuracy and energy consumption are considered (Fig. 1). At the same time, the ablative analysis of CBAM further confirms its feasibility and effectiveness in SNNs, which means that a novel approach could be provided for subsequent deployment and hardware chip application. In the end, we conduct extensive generalization experiments on the same type of segmentation task (ISBI and ISIC), the more complex multi-segmentation task (Synapse), and a series of image generation tasks (MNIST, Day2night, Maps, Facades) in order to visually demonstrate the generality of the proposed method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Adequate sampling is essential to an accurate pathologic evaluation of pancreatectomy specimens resected for pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT). However, limited data are available for the association between the sampling and survival in these patients. We examined the association of the entire submission of the tumor (ESOT) and the entire submission of the pancreas (ESOP) with disease-free survival (DFS) and overall survival (OS), as well as their correlations with clinicopathologic features, for 627 patients with PDAC who received NAT and pancreaticoduodenectomy. We demonstrated that both ESOT and ESOP were associated with lower ypT, less frequent perineural invasion, and better tumor response ( p < 0.05). ESOP was also associated with a smaller tumor size ( p < 0.001), more lymph nodes ( p < 0.001), a lower ypN stage ( p < 0.001), better differentiation ( p = 0.02), and less frequent lymphovascular invasion ( p = 0.009). However, since ESOP and ESOT were primarily conducted for cases with no grossly identifiable tumor or minimal residual carcinoma in initial sections, potential bias cannot be excluded. Both ESOT and ESOP were associated with less frequent recurrence/metastasis and better DFS and OS ( p < 0.05) in the overall study population. ESOP was associated with better DFS and better OS in patients with ypT0/ypT1 or ypN0 tumors and better OS in patients with complete or near-complete response ( p < 0.05). ESOT was associated with better OS in patients with ypT0/ypT1 or ypN0 tumors ( p < 0.05). Both ESOT and ESOP were independent prognostic factors for OS according to multivariate survival analyses. Therefore, accurate pathologic evaluation using ESOP and ESOT is associated with the prognosis in PDAC patients with complete or near-complete pathologic response and ypT0/ypT1 tumor after NAT.

Pancreatic cancer is associated with an oncogenic KRAS mutation in approximately 90% of cases. However, a non-negligible proportion of pancreatic cancer cases harbor wild-type KRAS (KRAS-WT). This study establishes genetically engineered mouse models that develop spontaneous pancreatic cancer in the context of KRAS-WT. The Trp53 loxP/loxP ;Smad4 loxP/loxP ;Pdx1-Cre (PPSSC) mouse model harbors KRAS-WT and loss of Trp53/Smad4. The Trp53 loxP/loxP ;Tgfbr2 loxP/loxP ;Pdx1-Cre (PPTTC) mouse model harbors KRAS-WT and loss of Trp53/Tgfbr2. We identify that either Trp53/Smad4 loss or Trp53/Tgfbr2 loss can induce spontaneous pancreatic tumor formation in the absence of an oncogenic KRAS mutation. The Trp53/Smad4 loss and Trp53/Tgfbr2 loss mouse models exhibit distinct pancreatic tumor histological features, as compared to oncogenic KRAS-driven mouse models. Furthermore, KRAS-WT pancreatic tumors with Trp53/Smad4 loss reveal unique histological features of pancreatic adenosquamous carcinoma (PASC). Single-cell RNA sequencing (scRNA-seq) analysis reveals the distinct tumor immune microenvironment landscape of KRAS-WT (PPSSC) pancreatic tumors as compared with that of oncogenic KRAS-driven pancreatic tumors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no relevant financial interest in the products or companies described in this article.

Neoadjuvant therapy (NAT) has become routine in patients with borderline resectable pancreatic cancer. Pathologists examine pancreatic cancer resection specimens to evaluate the effect of NAT. However, an automated scoring system to objectively quantify residual pancreatic cancer (RPC) is currently lacking. Herein, we developed and validated the first automated segmentation model using artificial intelligence techniques to objectively quantify RPC. Digitized histopathological tissue slides were included from resected pancreatic cancer specimens from 14 centers in 7 countries in Europe, North America, Australia, and Asia. Four different scanner types were used: Philips (56%), Hamamatsu (27%), 3DHistech (10%), and Leica (7%). Regions of interest were annotated and classified as cancer, non-neoplastic pancreatic ducts, and others. A U-Net model was trained to detect RPC. Validation consisted of by-scanner internal-external cross-validation. Overall, 528 unique hematoxylin and eosin (H & E) slides from 528 patients were included. In the individual Philips, Hamamatsu, 3DHistech, and Leica scanner cross-validations, mean F1 scores of 0.81 (95% CI, 0.77-0.84), 0.80 (0.78-0.83), 0.76 (0.65-0.78), and 0.71 (0.65-0.78) were achieved, respectively. In the meta-analysis of the cross-validations, the mean F1 score was 0.78 (0.71-0.84). A final model was trained on the entire data set. This ISGPP model is the first segmentation model using artificial intelligence techniques to objectively quantify RPC following NAT. The internally-externally cross-validated model in this study demonstrated robust performance in detecting RPC in specimens. The ISGPP model, now made publically available, enables automated RPC segmentation and forms the basis for objective NAT response evaluation in pancreatic cancer., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS. By leveraging both pancreatic and colorectal cancer models, we found that surface SDC1 expression was initially diminished upon mKRAS inhibition, but recovered in tumor cells that bypass mKRAS dependency. Functional studies showed that these tumors depended on SDC1 for survival, further establishing SDC1 as a driver for the acquired resistance to mKRAS inhibition. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing mKRAS dependency to sustain nutrient salvage machinery and tumor maintenance. Specifically, YAP1 activation mediated the recovery of SDC1 localization on cell surface that sustained macropinocytosis and enhanced the activation of multiple RTKs, promoting resistance to KRAS-targeted therapy. Overall, our study has provided the rationale for targeting the YAP-SDC1 axis to overcome resistance to mKRAS inhibition, thereby revealing new therapeutic opportunities for improving the clinical outcome of patients with KRAS-mutated cancers.

Real-time simulation of hyperelastic membranes like cloth still faces a lot of challenges, such as hyperplasticity modeling and contact handling. In this study, we propose projective peridynamics that uses a local-global strategy to enable fast and robust simulation of hyperelastic membranes with contact. In the global step, we propose a semi-implicit strategy to linearize the governing equation for hyperelastic materials that are modeled with peridynamics. By decomposing the first Piola-Kirchhoff stress tensor into a positive and a negative part, successive substitutions can be taken to solve the nonlinear problems. Convergence is guaranteed by further addressing the overshooting problem. Since our global step solve requires no energy summation and dot product operations over the entire problem, it fits into GPU implementation perfectly. In the local step, we further present a GPU-friendly gradient descent method to prevent interpenetration by solving an optimization problem independently. Putting the global and local solves together, experiments show that our method is robust and efficient in simulating complex models of membranes involving hyperelastic materials and contact.

A series of amides, including α-bromo hydroxamates, N -alkoxyamides, and N -aryloxyamides, were subjected to phosphine-catalyzed ring-opening O -selective addition with cyclopropenones, producing various special α,β -unsaturated esters containing oxime ether motif, in moderate to excellent yields, with high regioselectivity, and exclusive O -selectivity. The methodology is highly atom-economical, with simple operation procedures, and compatible with a wide substrate scope (more than 44 examples).

Background: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset., Materials and Methods: The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed., Results: Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis to Br-M detection was 24 months; median OS from Br-M diagnosis was 3 months. At Br-M diagnosis, 82% (n = 36) of patients had elevated CA19-9. Lung was the most common preexisting metastatic location (71%) with Br-M, followed by liver (66%). Br-M were most frequently observed in the frontal lobe (34%, n = 15), cerebellar region (23%, n = 10), and leptomeninges (18%, n = 8). KRAS mutations were detected in 94.1% (n = 16) of patients who had molecular data available (n = 17) with KRASG12V being the most frequent subtype 47% (n = 8); KRASG12D in 29% (n = 5); KRASG12R in 18% (n = 3). Patients who underwent Br-M surgical resection (n = 5) had median OS of 8.6 months, while median OS following stereotactic radiosurgery only (n = 11) or whole-brain radiation only (n = 20) was 3.3 and 2.8 months, respectively., Conclusion: Br-M is a late PDAC complication, resulting in an extremely poor prognosis especially in leptomeningeal disease. KRAS was mutated in 94.1% of the patients and the KRASG12V subtype was prevalent., (© The Author(s) 2024. Published by Oxford University Press.)

Chloroaluminate ionic liquids selectively transform (waste) polyolefins into gasoline-range alkanes through tandem cracking-alkylation at temperatures below 100 °C. Further improvement of this process necessitates a deep understanding of the nature of the catalytically active species and the correlated performance in the catalyzing critical reactions for the tandem polyolefin deconstruction with isoalkanes at low temperatures. Here, we address this requirement by determining the nuclearity of the chloroaluminate ions and their interactions with reaction intermediates, combining in situ 27 Al magic-angle spinning nuclear magnetic resonance spectroscopy, in situ Raman spectroscopy, Al K-edge X-ray absorption near edge structure spectroscopy, and catalytic activity measurement. Cracking and alkylation are facilitated by carbenium ions initiated by AlCl 3 -tert-butyl chloride (TBC) adducts, which are formed by the dissociation of Al 2 Cl 7 - in the presence of TBC. The carbenium ions activate the alkane polymer strands and advance the alkylation cycle through multiple hydride transfer reactions. In situ 1 H NMR and operando infrared spectroscopy demonstrate that the cracking and alkylation processes occur synchronously; alkenes formed during cracking are rapidly incorporated into the carbenium ion-mediated alkylation cycle. The conclusions are further supported by ab initio molecular dynamics simulations coupled with an enhanced sampling method, and model experiments using n-hexadecane as a feed., (© 2024. Battelle Memorial Institute and The Authors.)

An efficient phosphine-catalyzed dearomative [3+2] annulation of 4-nitroisoxazoles with allenoates or Morita-Baylis-Hillman carbonates has been established for the convenient synthesis of bicyclic isoxazoline derivatives. This reaction approach showed a broad substrate scope, high functional group compatibility, and excellent regioselectivity and diastereoselectivity. Furthermore, the success at the gram-scale and synthetic applications of the obtained compound 3a demonstrate the great potential of this methodology for practical applications in organic synthesis.

Background & Aims: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease., Methods: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor., Results: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression., Conclusions: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA., Impact and Implications: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive., Methods: We generated a novel transgenic mouse model (LSL-Kras G12D/+ ;Trp53 loxP/loxP ;Pdx1-Cre;Lgals3 -/- [KPPC;Lgals3 -/- ]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated the therapeutic efficacy of GAL3 inhibition in combination with immunotherapy., Results: Genetic deletion of GAL3 significantly inhibited the spontaneous pancreatic tumor progression and prolonged the survival of KPPC;Lgals3 -/- mice. Single-cell analysis revealed that genetic deletion of GAL3 altered the phenotypes of immune cells, cancer cells, and other cell populations. GAL3 deletion significantly enriched the antitumor myeloid cell subpopulation with high major histocompatibility complex class II expression. We also identified that GAL3 depletion resulted in CXCL12 upregulation, which could act as a potential compensating mechanism on GAL3 deficiency. Combined inhibition of the CXCL12-CXCR4 axis and GAL3 enhanced the efficacy of anti-PD-1 immunotherapy, leading to significantly inhibited PDAC progression. In addition, deletion of GAL3 also inhibited the basal/mesenchymal-like phenotype of pancreatic cancer cells., Conclusions: GAL3 promotes PDAC progression and immunosuppression via both cancer cell-intrinsic and immune-related mechanisms. Combined treatment targeting GAL3, CXCL12-CXCR4 axis, and PD-1 represents a novel therapeutic strategy for PDAC., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 + T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8 + T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.

In order to prevent uranium pollution and recovery uranium resources, it was necessary to find a highly efficient adsorbent for radioactive wastewater treatment. Herein, U(VI) imprinted polyethyleneimine (PEI) incorporated chitosan/layered hydrotalcite composite foam (IPCL) was synthesized by combining ion-imprinting and freeze-drying techniques. IPCL has a high amino/imino content and an ultralight macroporous structure, making it capable of efficiently adsorbing U(VI) and easy to separate; Especially after ion-imprinting, vacancies matching the size of uranyl ions were formed, significantly improving U(VI) selectivity. The adsorption isotherms and adsorption kinetics were in accordance with the Freundlich model and PSO model respectively, indicating that heterogeneous adsorption of U(VI) by the adsorbents. The adsorption capacity of IPCL-2 for U(VI) reached 278.8. mg/g (under the conditions of optimal pH 5.0, temperature of 298 K, contact time of 2 h, and adsorbent dosage of 0.2 g/L), which is almost double of that for the non-imprinted foam (PCL-2, 138.2 mg/g), indicating that IPCL-2 can intelligently recognize U(VI). The heterogeneous adsorption mechanism of U(VI) by IPCL-2 involves complexation, ion-exchange and isomorphic substitution. The adsorption of U(VI) by IPCL-2 is spontaneous and endothermic. IPCL-2 has excellent adsorption performance for U(VI), and is a promising adsorbent for radioactive pollution control., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras G12D -driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism., (© 2024. The Author(s).)

Background: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented., Methods: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed., Results: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen., Conclusions: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

While wet waste hydrothermal liquefaction technology has a high biofuel yield, a significant amount of the carbon and nitrogen in the feedstock reports to the aqueous-phase product. Pretreatment of this stream before sending to a conventional wastewater plant is essential or at the very least, advisable. In this work, techno-economic and life-cycle assessments were conducted for the state-of-technology baseline and four aqueous-phase product treatment and monetization options based on experimental data. These options can cut minimum fuel selling prices by up to 13 % and life-cycle greenhouse gas emissions by up to 39 % compared to the baseline. These findings highlight the substantial influence of aqueous produce treatment strategies on the entire wet waste hydrothermal liquefaction process, demonstrating the potential for optimizing economic viability and environmental impact through further research and development of milder treatment methods and diversified by-product valorization pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients., (© 2024 Zou et al.)

Transforming polyolefin waste into liquid alkanes through tandem cracking-alkylation reactions catalyzed by Lewis-acid chlorides offers an efficient route for single-step plastic upcycling. Lewis acids in dichloromethane establish a polar environment that stabilizes carbenium ion intermediates and catalyzes hydride transfer, enabling breaking of polyethylene C-C bonds and forming C-C bonds in alkylation. Here, we show that efficient and selective deconstruction of low-density polyethylene (LDPE) to liquid alkanes is achieved with anhydrous aluminum chloride (AlCl3) and gallium chloride (GaCl3). Already at 60 °C, complete LDPE conversion was achieved, while maintaining the selectivity for gasoline-range liquid alkanes over 70%. AlCl3 showed an exceptional conversion rate of 5000 gLDPEmolcat-1h-1, surpassing other Lewis acid catalysts by two orders of magnitude. Through kinetic and mechanistic studies, we show that the rates of LDPE conversion do not correlate directly with the intrinsic strength of the Lewis acids or steric constraints that may limit the polymer to access the Lewis acid sites. Instead, the rates for the tandem processes of cracking and alkylation are primarily governed by the rates of initiation of carbenium ions and the subsequent intermolecular hydride transfer. Both jointly control the relative rates of cracking and alkylation, thereby determining the overall conversion and selectivity., (© 2024 Wiley-VCH GmbH.)

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 patients with PDAC (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p < 0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRAS G12R had a similar OS (median 34 months), while patients with KRAS Q61 and KRAS G12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p = 0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p < 0.001], respectively). There was enrichment of KRAS G12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p = 0.001) and enrichment of KRAS G12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p = 0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor® dataset, n = 408)., (© 2024. The Author(s).)

Using myoglobin (Mb) as a model protein, we herein developed a facial approach to modifying the heme active site. A cavity was first generated in the heme distal site by F46 C mutation, and the thiol group of Cys46 was then used for covalently linked to exogenous ligands, 1H-1,2,4-triazole-3-thiol and 1-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione. The engineered proteins, termed F46C-triazole Mb and F46C-phenol Mb, respectively, were characterized by X-ray crystallography, spectroscopic and stopped-flow kinetic studies. The results showed that both the heme coordination state and the protein function such as H 2 O 2 activation and peroxidase activity could be efficiently regulated, which suggests that this approach might be generally applied to the design of functional heme proteins., (© 2023 Wiley-VCH GmbH.)

Phosphatidylinositol 4-kinases (PI4Ks) could phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P) and maintain its metabolic balance and location. PI4P, the most abundant monophosphate inositol in eukaryotic cells, is a precursor of higher phosphoinositols and an essential substrate for the PLC/PKC and PI3K/Akt signaling pathways. PI4Ks regulate vesicle transport, signal transduction, cytokinesis, and cell unity, and are involved in various physiological and pathological processes, including infection and growth of parasites such as Plasmodium and Cryptosporidium, replication and survival of RNA viruses, and the development of tumors and nervous system diseases. The development of novel drugs targeting PI4Ks and PI4P has been the focus of the research and clinical application of drugs, especially in recent years. In particular, PI4K inhibitors have made great progress in the treatment of malaria and cryptosporidiosis. We describe the biological characteristics of PI4Ks; summarize the physiological functions and effector proteins of PI4P; and analyze the structural basis of selective PI4K inhibitors for the treatment of human diseases in this review. Herein, this review mainly summarizes the developments in the structure and enzyme activity of PI4K inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The search for effective and low-risk treatment methods for colorectal cancer (CRC) is a pressing concern, given the inherent risks and adverse reactions associated with traditional therapies. Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment, offering advantages such as non-radiation, non-invasiveness, and targeted treatment. Consequently, the development of nanoparticles with high stability, biocompatibility, and photothermal effects has become a significant research focus within the field of PTT., Methods: In this study, TiO 2 -Ti 3 C 2 nanocomposites were synthesized and characterized, and their photothermal conversion efficiency in the near-infrared region II (NIR-II) was determined. Then studied the in vivo and in vitro photothermal activity and anti-tumor effect of TiO 2 -Ti 3 C 2 in human colorectal cancer cell lines and nude mice subcutaneous tumor model., Results: The results showed that TiO 2 -Ti 3 C 2 nanocomposites have strong absorption ability in the NIR-II, and have high photothermal conversion efficiency under 1064 nm (0.5 W/cm 2 , 6 min) laser stimulation. In addition, in vitro experiments showed that TiO 2 -Ti 3 C 2 nanocomposites significantly inhibited the invasion, migration, and proliferation of colorectal cancer cells, and induced cell apoptosis; in vivo, experiments showed that TiO 2 -Ti 3 C 2 nanocomposites-mediated PTT had good biocompatibility and efficient targeted inhibition of tumor growth., Conclusion: In conclusion, TiO 2 -Ti 3 C 2 nanocomposites can be used as NIR-II absorption materials in PTT to suppress the invasion, migration, and proliferation of colorectal cancer cells, induce colorectal cancer cell apoptosis, and thus inhibit the development of CRC. Therefore, TiO 2 -Ti 3 C 2 nanocomposites can be used as potential anti-tumor drugs for photothermal ablation of colorectal cancer cells., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wang et al.)

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers., (© 2024. The Author(s).)

Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA-approved drug, effectively attenuated cyst formation in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation., Competing Interests: Declaration of interests A Singapore patent application no.10202303337R has been filed on November 24, 2023 for this work. C.R.E. and J.C.I.B. are employees of Altos Labs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and promote fascial adipogenesis, and this effect is related to the structure of heparin. Regarding the structural and physiological properties of the negatively charged polymers, hexasulfonated suramin, a centuries-old medicine that is still used for treating African trypanosomiasis and onchocerciasis, is assumed to be a heparin-related analog or heparinoid. This investigation aims to elucidate the influence of suramin on the adipogenesis., Methods: To assess the influence exerted by suramin on adipogenic differentiation of primary white adipocytes in rats, this exploration was conducted both in vitro and in vivo. Moreover, it was attempted to explore the role played by the sulfonic acid groups present in suramin in mediating this adipogenic process., Results: Suramin demonstrated a dose- and time-dependent propensity to stimulate the adipogenic differentiation of rat preadipocytes isolated from the superficial fascia tissue and from adult adipose tissue. This stimulation was concomitant with a notable upregulation in expression levels of pivotal adipogenic factors as the adipocyte differentiation process unfolded. Intraperitoneal injection of suramin into rats slightly increased adipogenesis in the superficial fascia and in the epididymal and inguinal fat depots. PPADS, NF023, and NF449 are suramin analogs respectively containing 2, 6, and 8 sulfonic acid groups, among which the last two moderately promoted lipid droplet formation and adipocyte differentiation. The number and position of sulfonate groups may be related to the adipogenic effect of suramin., Conclusions: Suramin emerges as a noteworthy pharmaceutical agent with the unique capability to significantly induce adipocyte differentiation, thereby fostering adipogenesis., (© 2023. The Author(s).)

Significant efforts have been made in the design of artificial metalloenzymes. Myoglobin (Mb), an O 2 carrier, has been engineered to exhibit different functions. Herein, we applied a series of engineered Mb mutants with peroxidase activity for biosynthesis of clofazimine (CFZ), a potential drug with a broad-spectrum antiviral activity, by integration with chemical synthesis. Two of those mutants, F43Y Mb and F43Y/T67R Mb, have been shown to efficiently catalyze the oxidative coupling of 2- N -(4-chlorophenyl) benzene-1,2-diamine ( N -4-CPBDA) in the presence of H 2 O 2 , with 97% yields. The overall catalytic efficiency ( k cat / K m ) is 46-fold and 82-fold higher than that of WT Mb, respectively. By further combination of this reaction with chemical synthesis, the production of CFZ was accomplished with an isolated yield of 72%. These results showed that engineered Mbs containing the Tyr-heme cross-link (F43Y Mb and F43Y/T67R Mb) exhibit enhanced activity in the oxidative coupling reaction. This study also indicates that the combination of biocatalysis and chemical synthesis avoids the need for the separation of intermediate products, which offers a convenient approach for the total synthesis of the biological compound CFZ.

Simulating liquid-textile interaction has received great attention in computer graphics recently. Most existing methods take textiles as particles or parameterized meshes. Although these methods can generate visually pleasing results, they cannot simulate water content at a microscopic level due to the lack of geometrically modeling of textile's anisotropic structure. In this paper, we develop a method for yarn-level simulation of hygroscopicity of textiles and evaluate it using various quantitative metrics. We model textiles in a fiber-yarn-fabric multi-scale manner and consider the dynamic coupled physical mechanisms of liquid spreading, including wetting, wicking, moisture sorption/desorption, and transient moisture-heat transfer in textiles. Our method can accurately simulate liquid spreading on textiles with different fiber materials and geometrical structures with consideration of air temperatures and humidity conditions. It visualizes the hygroscopicity of textiles to demonstrate their moisture management ability. We conduct qualitative and quantitative experiments to validate our method and explore various factors to analyze their influence on liquid spreading and hygroscopicity of textiles.

Biomass was upgraded to fuel blendstocks via catalytic fast pyrolysis (CFP) followed by hydrotreating using three approaches: ex situ CFP with a zeolite catalyst (HZSM-5), ex situ CFP with a hydrodeoxygenation catalyst (Pt/TiO 2 ) and cofed hydrogen, and in situ CFP with a low-cost mixed metal oxide catalyst (red mud). Each approach was evaluated using a common pine feedstock and the same hydrotreating procedure. The oxygen contents in the CFP oils ranged from 17 to 28 wt % on a dry basis, and the carbon efficiencies for the CFP processes were in the range of 28-38%. The residual oxygen was reduced to <1 wt % during hydrotreating, which was operated for 104-140 h for each CFP oil without plugging issues. The hydrotreating carbon efficiencies were 81-93%. The CFP pathway with the hydrodeoxygenation catalyst gave the highest overall carbon efficiency from biomass to fuel blendstocks (34%) but, at the same time, also the highest cumulative hydrogen consumption during CFP and hydrotreating. The zeolite pathway produced the largest fraction boiling in the gasoline range and the highest estimated octane number due to the high aromatic content in that CFP oil. The in situ red mud pathway produced the largest fraction of diesel-range products with the highest derived cetane number. However, advances in the CFP and hydrotreating process are required to improve the fuel blendstock properties for all pathways., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

We report herein a general and effective system achieving cyclization of β-trifluoromethyl enones with amidines in the presence of 1,3-diiodo-5,5-dimethylhydantoin (DIH), which affords a range of trifluoromethylated 2-imidazolines in synthetically useful yields with good diastereoselectivities (up to 95% yield, up to 98:2 dr) and good functional group tolerance. Furthermore, the one-pot synthesis of trifluoromethylated imidazoles via sequential cyclization and oxidation is demonstrated. More significantly, the reaction mechanism was verified by ESI-MS studies of possible intermediates, and a reasonable reaction mechanism was proposed.

Objective: Frozen-section evaluation of the pancreatic margin is challenging. We aimed to determine interobserver variability among gastrointestinal pathologists for the assessment of frozen sections of pancreatic margins with marked chronic pancreatitis and to determine the challenging histological features in discrepant cases., Methods: We identified 45 patients who underwent pancreas resection for pancreatic ductal adenocarcinoma and showed marked chronic pancreatitis at pancreatic margin. Deidentified first levels of frozen-sections of the pancreatic margins from all cases were independently reviewed by 5 experienced gastrointestinal pathologists for the presence of carcinoma and/or high-grade dysplasia., Results: Interobserver agreement among pathologists was calculated as kappa coefficients ([Formula: see text]). A consensus diagnosis for discordant cases was obtained after group review and discussion. Interobserver agreement for adenocarcinoma diagnosis was 87%, and there was "substantial agreement" (Fleiss [Formula: see text]=0.78, P <0.01) and "almost perfect agreement" (Brennan-Prediger [Formula: see text]=0.86, P <0.01). Using the final diagnosis based on frozen and permanent sections as the gold standard and the concordant read of at least 3 of 5 pathologists for comparison, the diagnosis of adenocarcinoma was made in frozen-sections of pancreas margins, with accuracy 98%, sensitivity 83%, specificity 100%, negative predictive value 97%, positive predictive value 100%, false negative rate 9%, and false positive rate 0%., Conclusions: We showed excellent interobserver agreement among gastrointestinal pathologists for diagnosis of adenocarcinoma on frozen sections of pancreatic margins with marked chronic pancreatitis. Missed adenocarcinoma at the margin was mainly caused by freezing or cautery artifacts or by overlooking a tiny focus of perineural invasion in a background of marked chronic pancreatitis. The evaluation of deeper levels led to perfect agreement., (© 2023 by the Association of Clinical Scientists, Inc.)

Aims: Acinar cystic transformation (ACT) of the pancreas is a rare pancreatic cystic lesion. Owing to its rarity, comprehensive histomolecular characterisation of this entity is still lacking. We aim to perform a systematic review on this controversial entity., Methods: We searched PubMed, SCOPUS and Embase through May 2023 to identify all studies on ACTs. Clinicopathological, immunohistochemical (IHC) and molecular data have been extracted and analysed., Results: Overall, there were 121 cases of ACTs in the literature. ACT had a female predominance (65.3% of patients), and a mean size of 4.8 cm. ACT was more often unifocal (71.9%) and multiloculate (61.2%). Histologically, the cysts were lined by an acinar epithelium, sometimes harbouring ductal-like areas (18.2%). In five cases (4.1%), an intralesional pancreatic intraepithelial neoplasia (PanIN) was reported. Preoperative diagnosis is challenging. After surgical resection, all patients were alive and disease free during follow-up except one patient who developed a second ACT after resection. By IHC, all lesions were positive for acinar markers; cytokeratin 7 and 8/18/19 were usually positive, and Ki-67 was invariably ≤3%. At the molecular level, three cases demonstrated genetic alterations: one showed multiple chromosomal gains, and other two harboured somatic mutations of KRAS and SMO genes (one mutation per case)., Conclusions: Globally considered, our findings demonstrated that ACT is a benign entity, without the need of surgical resection with the exception of symptomatic lesions. The rare occurrence of intracystic PanINs and driver mutations suggest considering follow-up if a preoperative diagnosis of ACT can be made., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Given the importance of cyclic frameworks in molecular scaffolds and drug discovery, it is intriguing to precisely forge and manipulate ring systems in synthetic chemistry. In this field, the intermolecular synthesis of densely substituted cyclobutanes with precise diastereocontrol under simple reaction conditions remains a challenge. Herein, a photoredox strategy for the difunctionalization of bicyclo[1.1.0]butanes (BCBs) under high regio- and syn -selectivity is disclosed. C-S σ-bond cleavage of partially unsaturated sulfur-containing bifunctional reagents in an overall strain-release-driven process enables the thio-alkynylation, -alkenylation, and -allylation of BCBs under mild conditions and demonstrates the generality of this protocol. Mechanistic studies suggest that the intermediacy of cyclic distonic radical cations might be key for the efficient scission of C-S σ-bonds and the origin of diastereoselectivity.