Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: A large real-life worldwide population.

BACKGROUND: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes. METHODS: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS). RESULTS: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine. CONCLUSION: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.

A Surface Acoustic Wave-Based PM 1.0 Fine Dust Detection System Using Full Digital Time-Interleaved Counters.

This paper proposed a fine dust detection system using time-interleaved counters in which surface acoustic wave (SAW) sensors changed the resonance point characteristic. When fine dust was applied to the SAW sensor, the resonance point decreased. The SAW oscillator made of the SAW sensor and radio frequency (RF) amplifier generated an oscillation frequency that was the same as the resonance frequency. The oscillation frequency was transferred to digital data by a 20-bit asynchronous counter. This system has two channels: a sensing channel and a reference channel. Each channel has a SAW oscillator and a 20-bit asynchronous counter. The difference of the two channel counter results is the frequency difference. Through this, it is possible to know whether fine dust adheres to the SAW sensor. The proposed circuit achieved 0.95 ppm frequency resolution when it was operated at a frequency of 460 MHz. This circuit was implemented in a TSMC 130 nm CMOS process.

Phase Transitions and Thermoelectric Properties of Charge-Compensated ZnxCu12-xSb4Se13.

In this study, we investigated the phase transitions and thermoelectric properties of charge-compensated hakite (ZnxCu12-xSb4Se13) as a function of Zn content. Based on X-ray diffraction and a differential scanning calorimetric phase analysis, secondary phases (permingeatite and bytizite) transformed into hakite depending on the Zn content, while Zn2Cu10Sb4Se13 existed solely as hakite. Nondegenerate semiconductor behavior was observed, exhibiting increasing electrical conductivity with a rising temperature. With an increase in Zn content, the presence of mixed phases of hakite and permingeatite led to enhanced electrical conductivity. However, Zn2Cu10Sb4Se13 with a single hakite phase exhibited the lowest electrical conductivity. The Seebeck coefficient exhibited positive values, indicating that even after charge compensation (electron supply) by Zn, p-type semiconductor characteristics were maintained. With the occurrence of an intrinsic transition within the measured temperature range, the Seebeck coefficient decreased as the temperature increased; at a certain temperature, Zn2Cu10Sb4Se13 exhibited the highest value. Thermal conductivity showed a low temperature dependence, obtaining low values below 0.65 Wm-1K-1. A power factor of 0.22 mWm-1K-2 and dimensionless figure of merit of 0.31 were achieved at 623 K for ZnCu11Sb4Se13.

CWAS-Plus: estimating category-wide association of rare noncoding variation from whole-genome sequencing data with cell-type-specific functional data.

Variants in cis-regulatory elements link the noncoding genome to human pathology; however, detailed analytic tools for understanding the association between cell-level brain pathology and noncoding variants are lacking. CWAS-Plus, adapted from a Python package for category-wide association testing (CWAS), enhances noncoding variant analysis by integrating both whole-genome sequencing (WGS) and user-provided functional data. With simplified parameter settings and an efficient multiple testing correction method, CWAS-Plus conducts the CWAS workflow 50 times faster than CWAS, making it more accessible and user-friendly for researchers. Here, we used a single-nuclei assay for transposase-accessible chromatin with sequencing to facilitate CWAS-guided noncoding variant analysis at cell-type-specific enhancers and promoters. Examining autism spectrum disorder WGS data (n = 7280), CWAS-Plus identified noncoding de novo variant associations in transcription factor binding sites within conserved loci. Independently, in Alzheimer's disease WGS data (n = 1087), CWAS-Plus detected rare noncoding variant associations in microglia-specific regulatory elements. These findings highlight CWAS-Plus's utility in genomic disorders and scalability for processing large-scale WGS data and in multiple-testing corrections. CWAS-Plus and its user manual are available at https://github.com/joonan-lab/cwas/ and https://cwas-plus.readthedocs.io/en/latest/, respectively.

Cobalt-Doped Ceria Sensitizer Effects on Metal Oxide Nanofibers: Heightened Surface Reactivity for High-Performing Chemiresistive Sensors.

Chemiresistive gas sensors based on semiconducting metal oxides typically rely on noble metal catalysts to enhance their sensitivity and selectivity. However, noble metal catalysts have several drawbacks for practical utilization, including their high cost, their propensity for spontaneous agglomeration, and poisoning effects with certain types of gases. As such, in the interest of commercializing the chemiresistive gas sensor technology, we propose an alternative design for a noble-metal-free sensing material through the case study of Co-doped ceria (Co-CeO2) catalysts embedded in a SnO2 matrix. In this investigation, we utilized electrospinning and subsequent calcination to prepare Co-CeO2 catalyst nanoparticles integrated with SnO2 nanofibers (NFs) with uniform particle distribution and particle size regulation down to the sub-2 nm regime. The resulting Co-CeO2@SnO2 NFs exhibited superior gas sensing characteristics toward isoprene (C5H8) gas, a significant biomarker for monitoring the onset of various diseases through breath diagnostics. In particular, we identified that the Co-CeO2 catalysts, owing to the transition metal doping, facilitated the spillover of chemisorbed oxygen species to the SnO2 sensing body. This resulting in the sensor having a 27.4-fold higher response toward 5 ppm of C5H8 (compared to pristine SnO2), exceptionally high selectivity, and a low detection limit of 100 ppb. The sensor also exhibited high stability for prolonged response-recovery cycles, attesting to the strong anchoring of Co-CeO2 catalysts in the SnO2 matrix. Based on our findings, the transition metal-doped metal oxide catalysts, such as Co-CeO2, demonstrate strong potential to completely replace noble metal catalysts, thereby advancing the development of the commercially viable chemiresistive gas sensors free from noble metals, capable of detecting target gases at sub-ppm levels.

Clinical and Radiological Outcomes in C2 Recapping Laminoplasty for the Pathologies in the Upper Cervical Spine.

OBJECTIVE: To evaluate C2 muscle preservation effect and the radiological and clinical outcomes after C2 recapping laminoplasty. METHODS: Fourteen consecutive patients who underwent C2 recapping laminoplasty around C1-2 level were enrolled. To evaluate muscle preservation effect, the authors conducted a morphological measurement of extensor muscles between the operated and nonoperated side. Two surgeons measured the cross-sectional area (CSA) of obliquus capitis inferior (OCI) and semispinalis cervicis (SSC) muscle before and after surgery to determine atrophy rates (ARs). Additionally, we examined range of motion (ROM), sagittal vertical axis (SVA), neck visual analogue scale (VAS), Neck Disability Index (NDI), and Japanese Orthopaedic Association (JOA) score to assess potential changes in alignment and consequent clinical outcomes following posterior cervical surgery. RESULTS: We measured the CSA of OCI and SSC before surgery, and at 6 and 12 months postoperatively. Based on these measurements, the AR of the nonoperated SSC was 0.1% ± 8.5%, the AR of the operated OCI was 2.0% ± 7.2%, and the AR of the nonoperated OCI was -0.7% ± 5.1% at the 12 months after surgery. However, the AR of the operated side's SSC was 11.2% ± 12.5%, which is a relatively higher value than other measurements. Despite the atrophic change of SSC on the operated side, there were no prominent changes observed in SVA, C0-2 ROM, and C2-7 ROM between preoperative and 12 months postoperative measurements, which were 11.8 ± 10.9 mm, 16.3° ± 5.9°, and 48.7° ± 7.7° preoperatively, and 14.1 ± 11.6 mm, 16.1° ± 7.2°, and 44.0° ± 10.3° at 12 months postoperative, respectively. Improvement was also noted in VAS, NDI, and JOA scores after surgery with JOA recovery rate of 77.3% ± 29.6%. CONCLUSION: C2 recapping laminoplasty could be a useful tool for addressing pathologies around the upper cervical spine, potentially mitigating muscle atrophy and reducing postoperative neck pain, while maintaining sagittal alignment and ROM.

Poly(phenylalanine) and poly(3,4-dihydroxy-L-phenylalanine): Promising biomedical materials for building stimuli-responsive nanocarriers.

Cancer is a serious threat to human health because of its high annual mortality rate. It has attracted significant attention in healthcare, and identifying effective strategies for the treatment and relief of cancer pain requires urgency. Drug delivery systems (DDSs) offer the advantages of excellent efficacy, low cost, and low toxicity for targeting drugs to tumor sites. In recent decades, copolymer carriers based on poly(phenylalanine) (PPhe) and poly(3,4-dihydroxy-L-phenylalanine) (PDopa) have been extensively investigated owing to their good biocompatibility, biodegradability, and controllable stimulus responsiveness, which have resulted in DDSs with loading and targeted delivery capabilities. In this review, we introduce the synthesis of PPhe and PDopa, highlighting the latest proposed synthetic routes and comparing the differences in drug delivery between PPhe and PDopa. Subsequently, we summarize the various applications of PPhe and PDopa in nanoscale-targeted DDSs, providing a comprehensive analysis of the drug release behavior based on different stimulus-responsive carriers using these two materials. In the end, we discuss the challenges and prospects of polypeptide-based DDSs in the field of cancer therapy, aiming to promote their further development to meet the growing demands for treatment.

In vivo neural regeneration via AAV-NeuroD1 gene delivery to astrocytes in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIBI) is a significant contributor to neonatal mortality and long-term neurodevelopmental disability, characterized by massive neuronal loss and reactive astrogliosis. Current therapeutic approaches for neonatal HIBI have been limited to general supportive therapy because of the lack of methods to compensate for irreversible neuronal loss. This study aimed to establish a feasible regenerative therapy for neonatal HIBI utilizing in vivo direct neuronal reprogramming technology. METHODS: Neonatal HIBI was induced in ICR mice at postnatal day 7 by permanent right common carotid artery occlusion and exposure to hypoxia with 8% oxygen and 92% nitrogen for 90 min. Three days after the injury, NeuroD1 was delivered to reactive astrocytes of the injury site using the astrocyte-tropic adeno-associated viral (AAV) vector AAVShH19. AAVShH19 was engineered with the Cre-FLEX system for long-term tracking of infected cells. RESULTS: AAVShH19-mediated ectopic NeuroD1 expression effectively converted astrocytes into GABAergic neurons, and the converted cells exhibited electrophysiological properties and synaptic transmitters. Additionally, we found that NeuroD1-mediated in vivo direct neuronal reprogramming protected injured host neurons and altered the host environment, i.e., decreased the numbers of activated microglia, reactive astrocytes, and toxic A1-type astrocytes, and decreased the expression of pro-inflammatory factors. Furthermore, NeuroD1-treated mice exhibited significantly improved motor functions. CONCLUSIONS: This study demonstrates that NeuroD1-mediated in vivo direct neuronal reprogramming technology through AAV gene delivery can be a novel regenerative therapy for neonatal HIBI.

Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids.

BACKGROUND: The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies. METHODS: This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety. RESULTS: Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26 mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms. CONCLUSION: TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.

Identifying the source rookery of green turtles (Chelonia mydas) found in feeding grounds around the Korean Peninsula.

Determining the genetic diversity and source rookeries of sea turtles collected from feeding grounds can facilitate effective conservation initiatives. To ascertain the genetic composition and source rookery, we examined a partial sequence of the mitochondrial control region (CR, 796 bp) of 40 green turtles (Chelonia mydas) collected from feeding grounds around the Korean Peninsula between 2014 and 2022. We conducted genetic and mixed-stock analyses (MSA) and identified 10 CR haplotypes previously reported in Japanese populations. In the haplotype network, six, three, and one haplotype(s) grouped with the Japan, Indo-Pacific, and Central South Pacific clades, respectively. The primary rookeries of the green turtles were two distantly remote sites, Ogasawara (OGA) and Central Ryukyu Island (CRI), approximately 1,300 km apart from each other. Comparing three parameters (season, maturity, and specific feeding ground), we noted that OGA was mainly associated with summer and the Jeju Sea, whereas CRI was with fall and the East (Japan) Sea ground. The maturity did not show a distinct pattern. Our results indicate that green turtles in the feeding grounds around the Korean Peninsula originate mainly from the Japan MU and have genetic origins in the Japan, Indo-Pacific, and Central South Pacific clades. Our results provide crucial insights into rookeries and MUs, which are the focus of conservation efforts of the Republic of Korea and potential parties to collaborate for green turtle conservation.

Versatile Hyper-Cross-Linked Polymers Derived from Waste Polystyrene: Synthesis, Properties, and Intentional Recycling.

Waste polystyrene contributes considerably to environmental pollution due to its persistent nature, prompting a widespread consensus on the urgent need for viable recycling solutions. Owing to the aromatic groups structure of polystyrene, hyper-cross-linked polymers can be synthesized through the Friedel-Crafts cross-linking reaction using Lewis acids as catalysts. In addition, hyper-cross-linked polystyrene and its carbonaceous counterparts can be used in several important applications, which helps in their efficient recycling. This review systematically explores methods for preparing multifunctional hyper-cross-linked polymers from waste polystyrene and their applications in sustainable recycling. We have comprehensively outlined various synthetic approaches for these polymers and investigated their physical and chemical properties. These multifunctional polymers not only exhibit structural flexibility but also demonstrate diversity in performance, making them suitable for various applications. Through a systematic examination of synthetic methods, we showcase the cutting-edge positions of these materials in the field of hyper-cross-linked polymers. Additionally, we provide in-depth insights into the potential applications of these hyper-cross-linked polymers in intentional recycling, highlighting their important contributions to environmental protection and sustainable development. This research provides valuable references to the fields of sustainable materials science and waste management, encouraging further exploration of innovative approaches for the utilization of discarded polystyrene.

The Extracts from Two Antarctic Fish Species, Trematomus newnesi and Trematomus bernacchii, Enhance JEG-3 Cell Migration and Invasion via MMP9 Activation Through Akt/Protein Phosphatase1/ß-Catenin Pathway.

SCOPE: This study investigates the impact of extracts derived from Antarctic fish species, Trematomus newnesi and Trematomus bernacchii, on the migration of human placental trophoblast JEG-3 cells, which is a crucial aspect of successful pregnancy. METHODS AND RESULTS: The extracts, obtained from the muscles of these fish, significantly enhance the migration and invasion of JEG-3 cells in in vitro wound healing, Transwell, and collagen invasion assays. These effects are accompanied by an increase in matrix metalloproteinase (MMP) 9 activity, as demonstrated by zymography. Furthermore, the extracts activated Akt and protein phosphatase 1, resulting in the dephosphorylation of ß-catenin at Ser33/37/Thr41, as confirmed by western blot analysis. Consequently, MMP9 is upregulated, while metallopeptidase inhibitor 1/3 is downregulated, as verified by western blot and qRT-PCR analyses. Finally, utilizing ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, followed by matching with the Global Natural Product Social Molecular Networking library, the study annotates the compound responsible for the observed migratory activity as taurocholic acid. Importantly, the study confirms that taurocholic acid enhances cell migration in JEG-3 cells. CONCLUSION: The results of this study emphasize the potential of Antarctic fish extracts in promoting extravillous trophoblast migration and invasion, which are critical for successful pregnancy.

Time-restricted feeding protects against cisplatin-induced acute kidney injury in mice.

BACKGROUND: Time-restricted feeding (TRF), devoid of calorie restriction, is acknowledged for promoting metabolic health and mitigating various chronic metabolic diseases. While TRF exhibits widespread benefits across multiple tissues, there is limited exploration into its impact on kidney function. In this study, our aim was to investigate the potential ameliorative effects of TRF on kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI). METHODS: Cisplatin-induced AKI was induced through intraperitoneal injection of cisplatin into C57BL/6 male mice. Mice undergoing TRF were provided unrestricted access to standard chow daily but were confined to an 8-hour feeding window during the dark cycle for 2 weeks before cisplatin injection. The mice were categorized into four groups: control, TRF, cisplatin, and TRF + cisplatin. RESULTS: The tubular damage score and serum creatinine levels were significantly lower in the TRF + cisplatin group compared to the cisplatin group. The TRF + cisplatin group exhibited reduced expression of phosphorylated nuclear factor kappa B, inflammatory cytokines, and F4/80-positive macrophages compared to the cisplatin group. Furthermore, oxidative stress markers for DNA, protein, and lipid were markedly decreased in the TRF + cisplatin group compared to the cisplatin group. TUNEL-positive tubular cells, cleaved caspase-3 expression, and the Bax/Bcl-2 ratio in the TRF + cisplatin group were lower than those in the cisplatin group. CONCLUSION: TRF, without calorie restriction, effectively mitigated kidney damage by suppressing inflammatory reactions, oxidative stress, and tubular apoptosis in a mouse model of cisplatin-induced AKI. TRF holds promise as a novel dietary intervention for preventing cisplatin-induced AKI.

A new order parameter model for the improper ferroelastic phase transitions in KMnF3 single crystal.

This paper proposes a new order parameter model which satisfactorily explains complicated symmetry changes, the temperature-pressure (T-P) phase diagram and elastic anomalies observed experimentally with the improper ferroelastic phase transitions in multiferroic KMnF3 single crystal. First, it is shown that the order parameter model is transformed according to the four-dimensional reducible representation of the wavevector star channel group. Second, based on the order parameter model and the singularity theory, the sixth-order structurally stable Landau potential model is constructed. Finally, the theoretical T-P phase diagram is plotted and the elastic anomalies possible for each of the phase transitions are discussed.

The complete mitochondrial genome of Trematomus hansoni Boulenger, 1902 (Perciformes, Nototheniidae).

The striped notothen Trematomus hansoni is an Antarctic fish species belonging to the family Nototheniidae (cod icefishes) that is distributed throughout the Southern Ocean. In this study, the complete mitochondrial genome of T. hansoni was sequenced using an Illumina MiSeq platform. The circular mitochondrial genome is 19,218 bp long and contains 13 protein-coding genes, 23 tRNA genes, two rRNA genes, and one control region. Notably, there are two trnG-UCC genes and the second gene, located between trnE-UUC and trnI-GAU, has no D-arm structure. The base composition is 56.18% of A + T and 43.82% of G + C. The phylogenetic analysis supports that T. hansoni is grouped into a single clade with T. bernacchii. This study will be a valuable resource for further research on the phylogeny and evolution of the genus Trematomus.

Free essential amino acid feeding improves endurance during resistance training via DRP1-dependent mitochondrial remodelling.

BACKGROUND: Loss of muscle strength and endurance with aging or in various conditions negatively affects quality of life. Resistance exercise training (RET) is the most powerful means to improve muscle mass and strength, but it does not generally lead to improvements in endurance capacity. Free essential amino acids (EAAs) act as precursors and stimuli for synthesis of both mitochondrial and myofibrillar proteins that could potentially confer endurance and strength gains. Thus, we hypothesized that daily consumption of a dietary supplement of nine free EAAs with RET improves endurance in addition to the strength gains by RET. METHODS: Male C57BL6J mice (9 weeks old) were assigned to control (CON), EAA, RET (ladder climbing, 3 times a week), or combined treatment of EAA and RET (EAA + RET) groups. Physical functions focusing on strength or endurance were assessed before and after the interventions. Several analyses were performed to gain better insight into the mechanisms by which muscle function was improved. We determined cumulative rates of myofibrillar and mitochondrial protein synthesis using 2H2O labelling and mass spectrometry; assessed ex vivo contractile properties and in vitro mitochondrial function, evaluated neuromuscular junction (NMJ) stability, and assessed implicated molecular singling pathways. Furthermore, whole-body and muscle insulin sensitivity along with glucose metabolism, were evaluated using a hyperinsulinaemic-euglycaemic clamp. RESULTS: EAA + RET increased muscle mass (10%, P < 0.05) and strength (6%, P < 0.05) more than RET alone, due to an enhanced rate of integrated muscle protein synthesis (19%, P < 0.05) with concomitant activation of Akt1/mTORC1 signalling. Muscle quality (muscle strength normalized to mass) was improved by RET (i.e., RET and EAA + RET) compared with sedentary groups (10%, P < 0.05), which was associated with increased AchR cluster size and MuSK activation (P < 0.05). EAA + RET also increased endurance capacity more than RET alone (26%, P < 0.05) by increasing both mitochondrial protein synthesis (53%, P < 0.05) and DRP1 activation (P < 0.05). Maximal respiratory capacity increased (P < 0.05) through activation of the mTORC1-DRP1 signalling axis. These favourable effects were accompanied by an improvement in basal glucose metabolism (i.e., blood glucose concentrations and endogenous glucose production vs. CON, P < 0.05). CONCLUSIONS: Combined treatment with balanced free EAAs and RET may effectively promote endurance capacity as well as muscle strength through increased muscle protein synthesis, improved NMJ stability, and enhanced mitochondrial dynamics via mTORC1-DRP1 axis activation, ultimately leading to improved basal glucose metabolism.

N-glycosylation by Mgat5 imposes a targetable constraint on immune-mediated tumor clearance.

The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V (encoded by Mgat5 or GnT-V), which catalyzes the addition of ß1,6-linked N-acetylglucosamine to form complex N-glycans, has been linked to tumor growth and metastasis across tumor types. Using a panel of murine pancreatic ductal adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that Mgat5 is required for tumor growth in vivo but not in vitro. Loss of Mgat5 results in tumor clearance that is dependent on T cells and dendritic cells, with NK cells playing an early role. Analysis of extrinsic cell death pathways revealed Mgat5-deficient cells have increased sensitivity to cell death mediated by the TNF superfamily, a property that was shared with other non-PDAC Mgat5-deficient cell lines. Finally, Mgat5 knockout in an immunotherapy-resistant PDAC line significantly decreased tumor growth and increased survival upon immune checkpoint blockade. These findings demonstrate a role for N-glycosylation in regulating the sensitivity of cancer cells to T cell killing through classical cell death pathways.

Multiplexed Imaging Mass Cytometry Analysis Characterizes the Vascular Niche in Pancreatic Cancer.

Oncogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) are driven by complex interactions between the neoplastic component and the tumor microenvironment, which includes immune, stromal, and parenchymal cells. In particular, most PDACs are characterized by a hypovascular and hypoxic environment that alters tumor cell behavior and limits the efficacy of chemotherapy and immunotherapy. Characterization of the spatial features of the vascular niche could advance our understanding of inter- and intratumoral heterogeneity in PDAC. In this study, we investigated the vascular microenvironment of PDAC by applying imaging mass cytometry using a 26-antibody panel on 35 regions of interest across 9 patients, capturing more than 140,000 single cells. The approach distinguished major cell types, including multiple populations of lymphoid and myeloid cells, endocrine cells, ductal cells, stromal cells, and endothelial cells. Evaluation of cellular neighborhoods identified 10 distinct spatial domains, including multiple immune and tumor-enriched environments as well as the vascular niche. Focused analysis revealed differential interactions between immune populations and the vasculature and identified distinct spatial domains wherein tumor cell proliferation occurs. Importantly, the vascular niche was closely associated with a population of CD44-expressing macrophages enriched for a proangiogenic gene signature. Taken together, this study provides insights into the spatial heterogeneity of PDAC and suggests a role for CD44-expressing macrophages in shaping the vascular niche. Significance: Imaging mass cytometry revealed that pancreatic ductal cancers are composed of 10 distinct cellular neighborhoods, including a vascular niche enriched for macrophages expressing high levels of CD44 and a proangiogenic gene signature.

Obesity exacerbates ischemia-reperfusion injury and senescence in murine kidneys and perirenal adipose tissues.

Background: Obesity is a major worldwide health problem and can be related to cellular senescence. Along with the rise in obesity, the comorbidity of renal ischemia-reperfusion (IR) injury is increasing. Whether obesity accelerates the severity of IR injury and whether senescence contributes to these conditions remain unclear. We studied the degree of injury and cellular senescence in the IR kidneys and perirenal adipose tissues of high-fat-diet-induced obese mice. Methods: C57BL/6 mice fed standard chow or a high-fat diet for 16 weeks were randomized to renal IR or sham group (n = 6-10 each). Renal IR was performed by unilateral clamping of the right renal pedicle for 30 minutes. Six weeks after surgery, renal function, perirenal fat/renal senescence, and histology were evaluated ex vivo. Results: Obese mice showed more renal tubular damage and fibrosis in IR injury than control mice, even though the degree of ischemic insult was comparable. Renal expression of senescence and its secretory phenotype was upregulated in either IR injury or with a high-fat diet and was further increased in the IR kidneys of obese mice. Fat senescence and the expression of tumor necrosis factor alpha were also increased, especially in the perirenal depot of the IR kidneys, with a high-fat diet. Conclusion: A high-fat diet aggravates IR injury in murine kidneys, which is associated, at least in part, with perirenal fat senescence and inflammation. These observations support the exploration of therapeutic targets of the adipo-renal axis in injured obese kidneys.

Sarcopenia is independently associated with mortality and recovery from dialysis in critically ill patients with sepsis-induced acute kidney injury receiving continuous renal replacement therapy.

Background: Sarcopenia upon admission to the intensive care unit (ICU) consistently correlates with adverse outcomes, including heightened mortality, in critically ill patients. This study aims to investigate the independent association of sarcopenia with both mortality and recovery from dialysis in critically ill patients with sepsis-induced acute kidney injury (SIAKI) undergoing continuous renal replacement therapy (CRRT). Methods: This retrospective study included 618 patients with SIAKI who underwent CRRT in our ICU. All patients had abdominal computed tomography (CT) scans within 3 days preceding ICU admission. The cross-sectional area of skeletal muscles at the third lumbar vertebra was quantified, and the skeletal muscle index (SMI), a normalized measure of skeletal muscle mass, was computed. Using Korean-specific SMI cutoffs, patients were categorized into sarcopenic and non-sarcopenic groups. Results: Among the 618 patients, 301 expired within 28 days of ICU admission. Multivariable Cox regression analysis revealed that sarcopenia independently predicted 28-day mortality. Among survivors, sarcopenia was independently associated with recovery from dialysis within 28 days after ICU admission. Kaplan-Meier analysis illustrated that sarcopenic patients had a higher mortality rate and a lower rate of recovery from dialysis within 28 days after ICU admission compared to non-sarcopenic patients. Conclusion: This study underscores the independent association of sarcopenia, assessed via CT-derived SMI, with both mortality and recovery from dialysis in critically ill patients with SIAKI undergoing CRRT. The inclusion of sarcopenia assessment could serve as a valuable tool for physicians in effectively stratifying the risk of adverse outcomes in these patients.