Increased needle passes for comparable diagnostic yield in endoscopic ultrasound-guided tissue acquisition for pancreatic stiff lesions measured by elastography.

BACKGROUND/OBJECTIVES: Pancreatic cancer is characterized by tissue stiffness due to the high concentration of cancer-associated fibroblasts and extracellular matrix. Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is performed to diagnose pancreatic cancer but yields false-negative results attributed to inadequate specimens. EUS-elastography is a real-time assessment method to pancreatic tissue stiffness. This study aims to investigate the correlation between diagnostic yield and the number of needle passes based on the stiffness measured by elastography. METHODS: Patients who underwent EUS-TA for pancreatic solid mass were retrospectively reviewed and included in this study. The number of needle passes during EUS-TA was determined based on macroscopic on-site evaluation. Tissue stiffness measurements were taken using EUS-elastography. The primary study outcome was the diagnostic yield. The secondary outcome included the number of needle passes required for a diagnosis. RESULTS: A total of 652 patients were included. The average stiffness differed depending on the location of the tumor, and high-stiffness group had more malignant lesions. Although the diagnostic yield was not significantly different between groups, the number of needle passes was significantly higher in the high-stiffness group (3.6 ± 1.0 vs. 3.2 ± 0.9, p < 0.001). CONCLUSIONS: The higher the stiffness of the pancreatic mass in EUS-elastography, the more needle passes are required to achieve a comparable diagnostic yield.

Diagnostic performance of EUS-guided elastography for differential diagnosis of gallbladder polyp.

BACKGROUND AND AIMS: It is difficult to differentiate between neoplastic and non-neoplastic gallbladder (GB) polyps before surgery. EUS-guided elastography (EUS-EG) is a noninvasive complementary diagnostic method. The utility of EUS-EG in the differential diagnosis of GB polyps has not been investigated. We investigated the diagnostic performance of EUS-EG for the differential diagnosis of GB polyps. METHODS: Patients with GB polyps were prospectively enrolled from June 2020 until November 2022. EUS-EG and semiquantitative evaluation of the strain ratio (SR) were performed for differential diagnosis of GB polyps. Fifty-three eligible patients were divided into 2 groups based on the final diagnosis after surgery. Patient demographics, EUS characteristics, and SR values were compared. A receiver-operating characteristic curve analysis was performed to determine the optimal cutoff SR value that discriminates between neoplastic and non-neoplastic GB polyps. RESULTS: The median SR value for neoplastic polyps (32.93 [interquartile range {IQR}, 22.37-69.02]) was significantly higher than for non-neoplastic polyps (5.40 [IQR, 2.36-14.44], P < .001). Significant differences were found in SR values between non-neoplastic, benign neoplastic (23.38 [IQR, 13.62-39.04]), and malignant polyps (49.25 [IQR, 27.90-82.00]). The optimal cutoff SR value to differentiate between neoplastic and non-neoplastic polyps was 18.4. In multivariable logistic regression, SR value >18.4 (odds ratio, 33.604; 95% confidence interval, 2.588-436.292) was an independent predictor of neoplastic polyps. CONCLUSIONS: EUS-EG and SR values can be used as a supplementary method for evaluating GB polyps. (Clinical trial registration number: NCT04416763.).

Using Infrared Photothermal Heterodyne Imaging to Characterize Micro- and Nanoplastics in Complex Environmental Matrices.

A key challenge for addressing micro- and nanoplastics (MNPs) in the environment is being able to characterize their chemical properties, morphologies, and quantities in complex matrices. Current techniques, such as Fourier transform infrared spectroscopy, provide these broad characterizations but are unsuitable for studying MNPs in spectrally congested or complex chemical environments. Here, we introduce a new, super-resolution infrared absorption technique to characterize MNPs, called infrared photothermal heterodyne imaging (IR-PHI). IR-PHI has a spatial resolution of ∼300 nm and can determine the chemical identity, morphology, and quantity of MNPs in a single analysis with high sensitivity. Specimens are supported on CaF2 coverslips under ambient conditions from where we (1) quantify MNPs from nylon tea bags after steeping in ultrapure water at 25 and 95 °C, (2) identify MNP chemical or morphological changes after steeping at 95 °C, and (3) chemically identify MNPs in sieved road dust. In all cases, no special sample preparation was required. MNPs released from nylon tea bags at 25 °C were fiber-like and had characteristic IR frequencies corresponding to thermally extruded nylon. At 95 °C, degradation of the nylon chemical structure was observed via the disappearance of amide group IR frequencies, indicating chain scission of the nylon backbone. This degradation was also observed through morphological changes, where MNPs altered shape from fiber-like to quasi-spherical. In road dust, IR-PHI analysis reveals the presence of numerous aggregate and single-particle (<3 µm) MNPs composed of rubber and nylon.

Catalytic Hydrogel Membrane Reactor for Treatment of Aqueous Contaminants.

Heterogeneous hydrogenation catalysis is a promising approach for treating oxidized contaminants in drinking water, but scale-up has been limited by the challenge of immobilization of the catalyst while maintaining efficient mass transport and reaction kinetics. We describe a new process that addresses this issue: the catalytic hydrogel membrane (CHM) reactor. The CHM consists of a gas-permeable hollow-fiber membrane coated with an alginate-based hydrogel containing catalyst nanoparticles. The CHM benefits from counter-diffusional transport within the hydrogel, where H2 diffuses from the interior of the membrane and contaminant species (e.g., NO2-, O2) diffuse from the bulk aqueous solution. The reduction of O2 and NO2- were investigated using CHMs with varying palladium catalyst densities, and mass transport of reactive species in the catalytic hydrogel was characterized using microsensors. The thickness of the "reactive zone" within the hydrogel affected the reaction rate and byproduct selectivity, and it was dependent on catalyst density. In a continuously mixed flow reactor test using groundwater, the CHM activity was stable for a 3 day period. Outcomes of this study illustrate the potential of the CHM as a scalable process in the treatment of aqueous contaminants.

HIF-2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells.

Recent reports suggest that hypoxia inducible factor-2α (HIF-2α) is a key regulator of osteoarthritis cartilage destruction. However, the precise role of HIF-2α in the inflammatory response and osteoclast differentiation remains unclear. The purpose of this study was to investigate the effect of HIF-2α on inflammatory cytokines, extracellular matrix (ECM) destruction enzymes, and osteoclastic differentiation in nicotine and lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (PDLCs). HIF-2α was upregulated in chronically inflamed PDLCs of periodontitis patients, and in nicotine- and LPS-exposed PDLC in dose- and time-dependent manners. HIF-2α inhibitor and HIF-2α siRNA attenuated the nicotine- and LPS- induced production of NO and PGE2 , upregulation of iNOS, COX-2, pro-inflammatory cytokines (IL-1ß, TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-11, and IL-17), and matrix metalloproteinases (MMPs; MMP-1, -8, -13, -2 and -9), and reversed the effect on TIMPs (TIMP-1 and -2) in PDLCs. The conditioned medium produced by nicotine and LPS-treated PDLCs increased the number of TRAP-stained osteoclasts, TRAP activity and osteoclast-specific genes, which has been blocked by HIF-2α inhibition and silencing. HIF-2α inhibitor and HIF-2α siRNA inhibited the effects of nicotine and LPS on the activation of Akt, JAK2 and STAT3, ERK and JNK MAPK, nuclear factor-κB, c-Jun, and c-Fos. Taken together, this study is the first to demonstrate that HIF-2α inhibition exhibits anti-inflammatory activity through the inhibition of inflammatory cytokines and impairment of ECM destruction, as well as blocking of osteoclastic differentiation in a nicotine- and periodontopathogen-stimulated PDLCs model. Thus, HIF-2α inhibition may be a novel molecular target for therapeutic approaches in periodontitis.

Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.

Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.

The impact of biofilms and dissolved organic matter on the transport of nanoparticles in field-scale streams.

The fate and transport of nanoparticles (NPs) in streams is critical for understanding their overall environmental impact. Using a unique field-scale stream at the Notre Dame-Linked Experimental Ecosystem Facility, we investigated the impact of biofilms and the presence of dissolved organic matter (DOM) on the transport of titanium dioxide (TiO2) NPs. Experimental breakthrough curves were analyzed using temporal moments and fit using a mobile-immobile model. The presence of biofilms in the stream severely reduced the transport of the TiO2 NPs, but this was mitigated by the presence of DOM. Under minimal biofilm conditions, the presence of DOM increased the mass recovery of TiO2 from 4.2% to 32% for samples taken 50 m downstream. For thriving biofilm conditions only 0.5% of the TiO2 mass was recovered (50 m), but the presence of DOM improved the mass recovery TiO2 to 36%. The model was suitable for predicting early, peak, tail, and truncation time portions of the breakthrough curves, which attests to its ability to capture a range of processes in the mobile and immobile domains of the stream. The model outcomes supported the hypothesis that DOM changed the interaction of NP-biofilm from an irreversible to a reversible process. Collectively, these outcomes stress the importance of considering biogeological complexity when predicting the transport of NPs in streams.

Activity and stability of the catalytic hydrogel membrane reactor for treating oxidized contaminants.

The catalytic hydrogel membrane reactor (CHMR) is an interfacial membrane process that uses nano-sized catalysts for the hydrogenation of oxidized contaminants in drinking water. In this study, the CHMR was operated as a continuous-flow reactor using nitrite (NO2-) as a model contaminant and palladium (Pd) as a model catalyst. Using the overall bulk reaction rate for NO2- reduction as a metric for catalytic activity, we evaluated the effect of the hydrogen gas (H2) delivery method to the CHMR, the initial H2 and NO2- concentrations, Pd density in the hydrogel, and the presence of Pd-deactivating species. The chemical stability of the catalytic hydrogel was evaluated in the presence of aqueous cations (H+, Na+, Ca2+) and a mixture of ions in a hard groundwater. Delivering H2 to the CHMR lumens using a vented operation mode, where the reactor is sealed and the lumens are periodically flushed to the atmosphere, allowed for a combination of a high H2 consumption efficiency and catalytic activity. The overall reaction rate of NO2- was dependent on relative concentrations of H2 and NO2- at catalytic sites, which was governed by both the chemical reaction and mass transport rates. The intrinsic catalytic reaction rate was combined with a counter-diffusional mass transport component in a 1-D computational model to describe the CHMR. Common Pd-deactivating species [sulfite, bisulfide, natural organic matter] hindered the reaction rate, but the hydrogel afforded some protection from deactivation compared to a batch suspension. No chemical degradation of the hydrogel structure was observed for a model water (pH > 4, Na+, Ca2+) and a hard groundwater after 21 days of exposure, attesting to its stability under natural water conditions.

Involvement of Nrf2-mediated upregulation of heme oxygenase-1 in mollugin-induced growth inhibition and apoptosis in human oral cancer cells.

Although previous studies have shown that mollugin, a bioactive phytochemical isolated from Rubia cordifolia L. (Rubiaceae), exhibits antitumor effects, its biological activity in oral cancer has not been reported. We thus investigated the effects and putative mechanism of apoptosis induced by mollugin in human oral squamous cell carcinoma cells (OSCCs). Results show that mollugin induces cell death in a dose-dependent manner in primary and metastatic OSCCs. Mollugin-induced cell death involved apoptosis, characterized by the appearance of nuclear shrinkage, flow cytometric analysis of sub-G1 phase arrest, and annexin V-FITC and propidium iodide staining. Western blot analysis and RT-PCR revealed that mollugin suppressed activation of NF- κ B and NF- κ B-dependent gene products involved in antiapoptosis (Bcl-2 and Bcl-xl), invasion (MMP-9 and ICAM-1), and angiogenesis (FGF-2 and VEGF). Furthermore, mollugin induced the activation of p38, ERK, and JNK and the expression of heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2). Mollugin-induced growth inhibition and apoptosis of HO-1 were reversed by an HO-1 inhibitor and Nrf2 siRNA. Collectively, this is the first report to demonstrate the effectiveness of mollugin as a candidate for a chemotherapeutic agent in OSCCs via the upregulation of the HO-1 and Nrf2 pathways and the downregulation of NF- κ B.

Embryonic toxicity changes of organic nanomaterials in the presence of natural organic matter.

When elucidating the potential fate and bioavailability of nanomaterials (NMs) in an aquatic system, it is important to consider the interactions between NMs and natural organic matter (NOM). The present study compared the toxicities of carbon-based NMs, with disparate physicochemical properties, on Japanese medaka (Oryzias latipes) embryos after the addition of NOM. The measured embryonic toxicity parameters were mortality, malformation and hatching delay. Various physicochemical properties of water suspended fullerenes (nC(60)) and multi-walled carbon nanotubes (MWNTs) were modulated by organic exchange (Tol/nC(60)), stirring over time (Aqu/nC(60)) and acid treatment (f-MWNTs) followed by characterization. Tol/nC(60) produced relatively more hydrophobic surfaces and exhibited smaller closed spherical agglomerates than Aqu/nC(60). Acid-treated f-MWNTs displayed functionalized hydrophilic surfaces compared to raw MWNTs (r-MWNTs). The resultant embryonic toxicities, in the absence of NOM, were ranked in the order: f-MWNTs>Tol/nC(60)>Aqu/nC(60). As the NOM concentrations were increased, no changes in embryonic toxicities were observed on exposure of Aqu/nC(60) and r-MWNTs; whereas, the toxicities were reduced on exposure to Tol/nC(60) and f-MWNTs, due to a disappearance of hydrophobic primary spherical aggregates and partial coating, respectively. These data suggest that in the presence of NOM, the morphological differences of NMs, as well as their physicochemical properties, play a significant role in their reactions and subsequent medaka embryonic nanotoxicity.

Effect of preparation methods on toxicity of fullerene water suspensions to Japanese medaka embryos.

The physicochemical properties of fullerene water suspensions (nC(60)) and their subsequent toxicity were influenced by different preparation methods. The nC(60) suspensions were produced by three methods: toluene exchange (Tol/nC(60)), DMSO dissolving (DMSO/nC(60)), and stirring overtime (Aqu/nC(60)). The particle size, zeta potential, and nC(60) structure were strongly dependent on both the type of aggregates formed and the test medium addition. Specifically, Tol/nC(60) exhibited small and spherical closed aggregates, whereas DMSO/nC(60) and Aqu/nC(60) presented mesoscale aggregates of smaller spherical aggregates. These differences in the physicochemical properties of nC(60) determined the embryonic toxicity and oxidative stress of Japanese medaka (Oryzias latipes). The mortality and glutathione (GSH) induction of embryos were ranked in the order of Tol/nC(60)>DMSO/nC(60)>Aqu/nC(60), and the morphological malformations were in the order of DMSO/nC(60)>Tol/nC(60)>Aqu/nC(60). The mortality of Tol/nC(60) was attributed to its closely packed fullerene structure, which remained as largely underivatized C(60). The malformations of DMSO/nC(60) might have originated from the co-effect of organic solvent remaining in the fullerene colloid. To summarize, these findings clearly illustrated the need to consider the effect of preparation method on the physicochemical properties when assessing nC(60) toxicity.