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Abstract Resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) leads to ineffective chemotherapy and, consequently, delayed treatment, thereby contributing to poor prognosis. Glycolysis is an important intrinsic reason for gemcitabine resistance as it competitively inhibits gemcitabine activity by promoting deoxycytidine triphosphate accumulation in PDAC. However, biomarkers are lacking to determine which patients can benefit significantly from glycolysis inhibition under the treatment of gemcitabine activity, and a comprehensive understanding of the molecular mechanisms that promote glycolysis in PDAC will contribute to the development of a strategy to sensitize gemcitabine chemotherapy. In this study, we aimed to identify a biomarker that can robustly indicate the intrinsic resistance of PDAC to gemcitabine and guide chemotherapy sensitization strategies. After establishing gemcitabine-resistant cell lines in our laboratory and collecting pancreatic cancer and adjacent normal tissues from gemcitabine-treated patients, we observed that circRNA hsa_circ_0008383 (namely cNEK6) was highly expressed in the peripheral blood and tumor tissues of patients and xenografts with gemcitabine-resistant PDAC. cNEK6 enhanced resistance to gemcitabine by promoting glycolysis in PDAC. Specifically, cNEK6 prevented K48 ubiquitination of small ribonucleoprotein peptide A from the BTRC, a ubiquitin E3 ligase; thus, the accumulated SNRPA stopped PP2Ac translation by binding to its G-quadruplexes in 5′ UTR of mRNA. mTORC1 pathway was aberrantly phosphorylated and activated owing to the absence of PP2Ac. The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy.

Abstract The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance’s core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.

Abstract Introduction Glioblastoma (GBM) poses a significant challenge in oncology, with median survival times barely extending beyond a year due to resistance to standard therapies like temozolomide (TMZ). This study introduces a novel therapeutic strategy combining progesterone (Prog) and abiraterone (Abi) aimed at enhancing GBM treatment efficacy by modulating the tumor microenvironment and augmenting NK cell-mediated immunity. Methods We employed in vitro and in vivo GBM models to assess the effects of Prog and Abi on cell viability, proliferation, apoptosis, and the immune microenvironment. Techniques included cell viability assays, Glo-caspase 3/7 apoptosis assays, RNA-seq and qPCR for gene expression, Seahorse analysis for mitochondrial function, HPLC-MS for metabolomics analysis, and immune analysis by flow cytometry to quantify NK cell infiltration. Results Prog significantly reduced the IC50 of Abi in TMZ-resistant GBM cell, suggesting the enhanced cytotoxicity. Treatment induced greater apoptosis than either agent alone, suppressed tumor growth, and prolonged survival in mouse models. Notably, there was an increase in CD3−/CD19−/CD56+/NK1.1+ NK cell infiltration in treated tumors, indicating a shift towards an anti-tumor immune microenvironment. The combination therapy also resulted in a reduction of MGMT expression and a suppression of mitochondrial respiration and glycolysis in GBM cells. Conclusion The combination of Prog and Abi represents a promising therapeutic approach for GBM, showing potential in suppressing tumor growth, extending survival, and modulating the immune microenvironment. These findings warrant further exploration into the clinical applicability of this strategy to improve outcomes for GBM patients.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 ‘don’t eat me’ signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial–mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.

Abstract Background and Aim The model for end‐stage liver disease (MELD) was updated to MELDNa and recently to MELD3.0 to predict survival of cirrhotic patients. We validated the prognostic performance of MELD3.0 and compared with MELDNa and MELD amongst cirrhotic inpatients. Methods Demographical, clinical, biochemical, and survival data of cirrhotic inpatients in Singapore General Hospital (SGH) from 01 January 2018 to 31 December 2018, were studied retrospectively. Patients were followed up from first admission in 2018 until death or until 01 April 2023. Area under the receiver operating characteristic curves (AUROC) were computed for the discriminative effects of MELD3.0, MELDNa, and MELD to predict 30‐, 90‐, and 365‐day mortalities. AUROC was compared with DeLong's test. The cutoff MELD3.0 score for patients at high risk of 30‐day mortality was determined using Youden's Index. Survival curves of patients with MELD3.0 score above and below the cutoff were estimated with Kaplan–Meier method and compared with log‐rank analysis. Results Totally 862 patients were included (median age 71.0 years [interquartile range, IQR: 64.0–79.0], 65.4% males, 75.8% Chinese). Proportion of patients with Child‐Turcotte‐Pugh classes A/B/C were 55.5%/35.5%/9.0%. Median MELD3.0/MELDNa/MELD scores were 12.2 (IQR: 8.7–18.3)/11.0 (IQR: 8.0–17.5)/10.3 (IQR: 7.8–15.0). Median time of follow‐up was 51.9 months (IQR: 8.5–59.6). The proportion of 30‐/90‐/365‐day mortalities was 5.7%/13.2%/26.9%. AUROC of MELD3.0/MELDNa/MELD in predicting 30‐, 90‐, and 365‐day mortalities, respectively, were 0.823/0.793/0.783, 0.754/0.724/0.707, 0.682/0.654/0.644 (P 19 (sensitivity = 67.4%, specificity = 82.4%). Patients with MELD3.0 > 19, compared with patients with MELD3.0 ≤ 19, had shorter median time to death (98.0 days [IQR: 28.8–398.0] vs 390.0 days [IQR: 134.3–927.5]), and higher proportion of 30‐day mortality (68.8% vs 43.0%) (P 19 predicts higher 30‐day mortality.

Abstract Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient‐derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF‐κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC.

Abstract Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR‐199a‐5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co‐loading of siRNA against cPKM (si‐cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co‐loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si‐cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.

In order to improve the light extraction efficiency (LEE) of a plane AlGaAs-based LED (Device A), three different surface periodic micron-scale arrays, micron pillar (Device B), micron truncated cone (Device C) and micron cone (Device D), are prepared by the conventional ultra-violet (UV) lithography. The morphology of the three devices B–D is characterized by a scanning electron microscopy (SEM). The periodic array structures improve the photon escape probabilities. In comparison to the Device A, the light output powers (LOPs) of the Devices B–D increase 54.0%, 145.5% and 157.2% at an injection current of 500 mA, respectively. Moreover, we use the Monte Carlo ray-tracing method to simulate the LEE of the four devices. The energy distribution of the Devices B-D is more concentrated in the middle region in contrast with the Device A.

Agenesis and hypoplasia affecting multiple flexor tendons within the same hand represent an exceedingly uncommon occurrence, with no previous studies addressing this condition. This report details a 4-year-old girl with agenesis of the right third and fourth fingers, who sought consultation due to the inability to flex her seemingly unaffected second and fifth fingers. Ultrasound examination revealed substantial thinning of the flexor tendons in the second to fifth digits, with a notable absence of attachment to the middle phalanx. In addition to flexor tendon hypoplasia, hypoplasia of the third and fourth middle phalanges was observed. Hand deformities featuring both finger agenesis and flexor tendon hypoplasia across multiple fingers were exceptionally rare. In such instances, ultrasound, in conjunction with radiography, emerges as the recommended initial imaging tool for comprehensive evaluation of both the phalangeal bones and flexor tendons.

Abstract Glioblastoma (GBM) is the most aggressive brain tumor and relapses after chemo- or radiotherapy in a short time. The anticancer drug temozolamide (TMZ) is commonly used for GBM treatment, but glioma stem-like cells (GSCs) often lead to drug resistance and therapeutic failure. To date, the mechanism of GSC formation in TMZ-treated GBM remains largely unknown. CCAAT/Enhancer-binding protein delta (CEBPD) is an inflammation-responsive transcription factor and is proposed to be oncogenic in the context of drug resistance, prompting us to clarify its role in TMZ-resistant GBM. In this study, we first found that the CEBPD protein levels in GBM patients were significantly increased and further contributed to TMZ resistance by promoting GSC formation. Accordingly, the protein levels of stemness transcription factors, namely, SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG, and ATP-binding cassette subfamily A member 1 (ABCA1), were increased in GSCs and TMZ-treated GBM cells. Increased binding of CEBPD to promoter regions was observed in GSCs, indicating the direct regulation of these GSC-related genes by CEBPD. In addition, an ABCA1 inhibitor increased the caspase 3/7 activity of TMZ-treated GSCs, suggesting that TMZ efflux is controlled by ABCA1 activity and that the expression levels of the ABCA1 gene are an indicator of the efficiency of TMZ treatment. Together, we revealed the mechanism of CEBPD-mediated GSC drug resistance and proposed ABCA1 inhibition as a potential strategy for the treatment of TMZ-resistant GBM.

Compared with conventional InGaN Quantum Wells (QWs), staggered InGaN QWs offer improved optical and electronic properties. This work studied the carrier concentration, band structure, overlap of hole and electron wave functions, and polarization field of three-layer staggered QWs in the blue spectral region and analyzed them in detail theoretically to explore the source and the dominant mechanism for improvement. Although theoretical studies indicate that the polarization field in QWs of staggered InGaN QWs is larger, the carrier confinement effect is stronger, and the carrier distribution is more uniform. Therefore, three-layer staggered QWs can improve overlapping of the hole and electron wave functions and then enhance the recombination rate so as to increase the optical output power and electroluminescence intensity. Moreover, the performance of the staggered structure C with the lowest indium content at the center of the well is better than that of the step-staggered structure B.

Abstract Background The small population of glioma stem-like cells (GSCs) contributes to tumor initiation, malignancy, and recurrence in glioblastoma. However, the maintenance of GSC properties in the tumor microenvironment remains unclear. In glioma, non-neoplastic cells create an inflammatory environment and subsequently mediate tumor progression and maintenance. Transcriptional factor CCAAT/enhancer-binding protein delta (CEBPD) is suggested to regulate various genes responsive to inflammatory cytokines, thus prompting us to investigate its role in regulating GSCs stemness after inflammatory stimulation. Methods Stemness properties were analyzed by using spheroid formation. Oncomine and TCGA bioinformatic databases were used to analyze gene expression. Western blotting, quantitative real-time polymerase chain reaction, luciferase reporter assay, and chromatin immunoprecipitation assay were used to analyze proteins and gene transcript levels. The glioma tissue microarrays were used for CEBPD and PDGFA expression by immunohistochemistry staining. Results We first found that IL-1β promotes glioma spheroid formation and is associated with elevated CEBPD expression. Using microarray analysis, platelet-derived growth factor subunit A (PDGFA) was confirmed as a CEBPD-regulated gene that mediates IL-1β-enhanced GSCs self-renewal. Further analysis of the genomic database and tissue array revealed that the expression levels between CEBPD and PDGFA were coincident in glioma patient samples. Conclusion This is the first report showing the activation of PDGFA expression by CEBPD through IL-1β treatment and a novel CEBPD function in maintaining the self-renewal feature of GSCs.

Background/purpose: Hepatic encephalopathy (HE), a major neuropsychiatric complication in advanced liver disease, is associated with poor prognosis. Sarcopenia, characterized by a decline in muscle mass, strength, and physical performance, is prevalent in liver cirrhosis. This study aims to explore whether sarcopenia is associated with HE in cirrhotic patients. Methods: PubMed and EMBASE were searched for relevant cohort and case-control studies investigating the association between sarcopenia and HE up to July 2018. Data of patients' characteristics, definition of low muscle mass, and protocols of grading/diagnosing HE were retrieved. The primary outcome was estimated by a pooled odds ratio (OR) and its 95% confidence interval (CI), using a random effect model. Results: The meta-analysis enrolled 6 studies, comprising 1795 patients. Sarcopenia was positively associated with the presence of HE (OR 2.74 with a 95% CI, 1.87 to 4.01). The association was less likely to be influenced by differences in research designs, focused study outcomes, muscle mass measurements, and protocols of grading/diagnosing HE. There was lack of evidence supporting higher serum ammonia levels in patients with sarcopenia. Conclusion: In patients with liver cirrhosis, there is a significant association between sarcopenia and HE. A greater number of prospective studies are necessary to clarify whether the association remains even after adjusting relevant confounders and to suggest effective prevention of HE in patients with coexisting sarcopenia. Keywords: Liver, Malnutrition, Skeletal muscle, Neurology, Ammonia

Laser exhibition technology has been widely used in the virtual environment of exhibitions and shows, as well as in the physical conference and exhibition centers. However, the speckle issue due to the high coherence of laser sources has caused harmful impacts on image quality, which is one of the obstacles to exhibition effects. In this paper, we design a compact Nd:YAG/PPMgLN laser module at 561.5 nm and use two different types of big-core multi-mode fibers to lower the spatial coherence. According to our experiment, the speckle contrasts relating to these two types reduce to 7.9% and 4.1%, respectively. The results of this paper contribute to improving the application effects of key optical components in the exhibitions. Only in this way can we provide technical supports and service guarantee for the development of the exhibition activities, and an immersive interactive experience for the audiences.

Excessive reactive oxygen species (ROS) can form an oxidative stress and an associated neuroinflammation. However, the contribution of astrocytes to ROS formation, the cause of the resistance of astrocytes to oxidative stress, and the consequences on neurons remain largely uninvestigated. The transcription factor CCAAT/enhancer-binding protein delta (CEBPD) is highly expressed in astrocytes and has been suggested to contribute to the progress of Alzheimer's disease (AD). In this study, we found that ROS formation and expression of p47phox and p67phox, subunits of NADPH oxidase, were increased in AppTg mice but attenuated in AppTg/Cebpd-/- mice. Cebpd can up-regulate p47phox and p67phox transcription via a direct binding on their promoters, which results in an increase in intracellular oxidative stress. In addition, Cebpd also up-regulated Cu/Zn superoxide dismutase (Sod1) in astrocytes. Inactivation of Sod1 increased the sensitization to oxidative stress, which provides a reason for the resistance of astrocytes in an oxidative stress environment. Taken together, the study first revealed and dissected the involvement of astrocytic Cebpd in the promotion of oxidative stress and the contribution of CEBPD to the resistance of astrocytes in an oxidative stress environment. Keywords: ROS, Astrocyte, CEBPD, SOD1 and neuroinflammation

We present an experimental method for evaluating interfacial force per width and predicting internal stress in mid-infrared band-pass filters (MIR-BPF). The interfacial force per width between the two kinds of thin-film materials was obtained by experimental measurement values, and the residual stress of the multilayer thin films was predicted by the modified Ennos formula. A dual electron beam evaporation system combined with ion-assisted deposition was used to fabricate mid-infrared band-pass filters. The interfacial forces per width for Ge/SiO2 and SiO2/Ge were 124.9 N/m and 127.6 N/m, respectively. The difference between the measured stress and predicted stress in the 23-layer MIR-BPF was below 0.059 GPa. The residual stresses of the four-layer film, as well as the 20-layer and 23-layer mid-infrared band-pass filter, were predicted by adding the interface stress to the modified Ennos formula. In the four-layer film, the difference between the predicted value and the measured stress of the HL (high–low refractive index) and LH (low–high refractive index) stacks were −0.384 GPa for (HL)2 and −0.436 GPa for (LH)2, respectively. The predicted stress and the measured stress of the 20-layer mid-infrared filter were −0.316 GPa and −0.250 GPa. The predicted stress and the measured stress of the 23-layer mid-infrared filter were −0.257 GPa and −0.198 GPa, respectively.

This study presents the effect of oxygen flow rate on the optical, electrical, and mechanical properties of indium tin oxide (ITO) thin films prepared by the DC magnetron sputtering technique. The oxygen flow rate was varied from 10 to 50 sccm. The ITO thin films deposition under different oxygen flow rates exhibits different properties. We used an optical spectrometer to measure the optical transmittance and a four-point probe instrument to determine the resistivity. A home-made Twyman-Green interferometer was used to evaluate residual stress and a microscopic interferometer was used to measure the surface roughness of ITO thin films. The experimental results show that the average optical transmittance is larger than 85% in visible range; the electrical resistivity has a minimum 6.85×10-4 ohm-cm for the oxygen flow of 10 sccm. The residual stress is varied from −0.15 GPa to −0.34 GPa in the range of 10–50 sccm. The root-mean-square (rms) surface roughness is changed from 2.64 nm to 2.74 nm as the oxygen flow rate increases. The results show that the oxygen flow rate has significant influence on the electrical resistivity, residual stress, and surface roughness of the ITO thin film.

This paper presents a high sensitivity liquid refractive index (RI) sensor based on lossy mode resonance (LMR) effect. The D-shaped fibers coated with nanosized titanium dioxide (TiO2) thin film as a sensing head were submerged into different refractive index solutions. The variations in the optical spectrum of the proposed RI sensor with different refractive index solutions were measured. The LMR resonance peaks were used to determine the wavelength shifts with different refractive index solutions. The results show that the optical spectrum peaks shifted towards the longer wavelength side with increasing the refractive index. For the proposed fiber sensing head with a polishing residual thickness of 72 μm, the maximum shift of the absorption peak was 264 nm. The sensitivity of the proposed RI sensor was 4122 nm/RIU for the refractive index range from 1.333 to 1.398.

In the crystal structure of the title compound, C8H6Br2O2, the carboxyl groups are involved in pairs of O—H...O hydrogen bonds, which link the molecules into inversion dimers.

In the title compound, C8H6Br4, intramolecular C—H...Br hydrogen bonds generate two S(6) rings. The two geminal bromine-atom substituents point to opposite sides of the aromatic ring system. In the crystal, molecules are linked by intermolecular π–π interactions with centroid–centroid distances of 3.727 (9) and 3.858 (9) Å.