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Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecular mechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC). We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial–mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation. These results suggest that the IL6–CXCR7 axis may provide a promising target for the treatment of ESCC.

High-intensity, short-pulse lasers are crucial for generating energetic electrons that produce high-energy-density (HED) states in matter, offering potential applications in igniting dense fusion fuels for fast ignition laser fusion. High-density targets heated by these electrons exhibit spatially non-uniform and highly transient conditions, which have been challenging to characterize due to limitations in diagnostics that provide simultaneous high spatial and temporal resolution. Here, we employ an X-ray Free Electron Laser (XFEL) to achieve spatiotemporally resolved measurements at sub-micron and femtosecond scales on a solid-density copper foil heated by laser-driven fast electrons. Our X-ray transmission imaging reveals the formation of a solid-density hot plasma localized to the laser spot size, surrounded by Fermi degenerate, warm dense matter within a picosecond, and the energy relaxation occurring within the hot plasma over tens of picoseconds. These results validate 2D particle-in-cell simulations incorporating atomic processes and provide insights into the energy transfer mechanisms beyond current simulation capabilities. This work significantly advances our understanding of rapid fast electron heating and energy relaxation in solid-density matter, serving as a key stepping stone towards efficient high-density plasma heating and furthering the fields of HED science and inertial fusion energy research using intense, short-pulse lasers. Intense, short-pulse laser irradiation generates energetic electrons that heat targets to extreme conditions relevant to laser fusion. Here, authors used an X-ray Free Electron Laser to perform spatiotemporal measurements in solid-density copper foil with sub-micron and femtosecond resolutions.

PurposePolysorbates are commonly added to protein formulations and serve an important function as stabilizers. This paper reviews recent literature detailing some of the issues seen with the use of polysorbate 80 and polysorbate 20 in protein formulations. Based on this knowledge, a development strategy is proposed that leads to a control strategy for polysorbates in protein formulations.MethodsA consortium of Biopharmaceutical scientists working in the area of protein formulations, shared experiences with polysorbates as stabilizers in their formulations.ResultsBased on the authors experiences and recent published literature, a recommendation is put forth for a development strategy which will lead into the appropriate control strategy for these excipients.ConclusionsAn appropriate control strategy may comprise one or more elements of raw material, in-process and manufacturing controls. Additionally, understanding the role, if any, polysorbates play during stability will require knowledge of the criticality of the excipient, based upon its impact on CQAs due to variations in concentration and degradation level.

Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO–sGC pathway by praliciguat in both healthy and fibrotic livers. In preclinical models of NASH, praliciguat treatment was associated with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH.

Experimental investigation of electron-ion coupling and electron heat capacity of copper in warm and dense states are presented. From time-resolved x-ray absorption spectroscopy, the temporal evolution of electron temperature is obtained for non-equilibrium warm dense copper heated by an intense femtosecond laser pulse. Electron heat capacity and electron-ion coupling are inferred from the initial electron temperature and its decrease over 10 ps. Data are compared with various theoretical models.

Emerging evidence has shown that cancer stem cells (CSCs) are the cellular determinants to promote cancer invasion and metastasis. However, the mechanism underlying CSC invasion remains unknown. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression, and their expressions are often dysregulated in cancers. In the present study, we demonstrated that two functionally related microRNAs, miR-20a and -106a (miR-20a/106a), were capable of enhancing the invasiveness of CD133 + glioma stem cells (GSCs) isolated from both glioblastoma cell line U87 and primary human glioma specimens. We found that the level of miR-20a/106a in GSCs was significantly higher than that in the committed CD133 − glioma cells, and correlated with the invasive capability of GSCs. By bioinformatic analysis, we identified tissue inhibitor of metalloproteinases-2 ( TIMP-2 ) as one of the miR-20a/106a-targeted genes. TIMP-2 level correlated inversely with miR-20/106 expression. Directly targeting by miR-20a/106a on 3′-untranslation region (3′-UTR) of TIMP-2 mRNA was confirmed by 3′-UTR dual-luciferase reporter assay. Knockdown of miR-20a/106a in GSCs increased endogenous TIMP-2 protein abundance, thereby inhibiting GSC invasion. We also found that Nordy, a synthetic lipoxygenase inhibitor, inhibited GSC invasiveness by elevating the expression of TIMP-2 via downregulation of miR-20a/106a. Our results indicate that miR-20a/106a has a key role in GSC invasion and may serve as targets for treatment of glioblastoma.

Background: Tumoural infiltration of T lymphocytes is determined by local patterns of specific chemokine expression. In this report, we examined the roles of CCL4 and CCL20 in the accumulation of CD8 + cytotoxic T lymphocytes (CTLs) and regulatory T (T reg ) lymphocytes in oesophageal squamous cell carcinoma (ESCC), and determined the correlations between chemokine expressions and ESCC patients’ survival. Methods: Reverse transcriptase–PCR and immunohistochemistry (IHC) staining were performed to examine the expressions of interested genes. Flow cytometry was adopted to check the expressions of CCL4- and CCL6-specific receptors, CCR5 and CCR6, on CTLs and T reg cells. In addition, transwell assay was carried on. Results: The CCL4 expression was significantly correlated with the expression of CTL markers ( CD8 and Granzyme B ), whereas CCL20 was positively correlated with T reg markers ( FoxP3 and IL-10 ). Consistently, CCR5 was found to be mainly expressed on CD8 + T lymphocytes, while CCR6 showed prevalence on T reg lymphocytes and the frequencies of CCR5 + CD8 + CTLs and CCR6 + T reg cells were higher in TIL compared with PBMC. Respectively, CCL4 and CCL20 recruited CD8 + and regulatory T cells in vitro . Importantly, high levels of CCL4 in the lesions of ESCC patients predicted prolonged survival. Furthermore, CCL4 high /CCL20 low group demonstrated better overall survival, whereas CCL4 low /CCL20 low and CCL4 low /CCL20 high groups showed the worst overall survival. Conclusions: Our data showed that CCL4 and CCL20 recruit functionally different T lymphocyte subsets into oesophageal carcinoma, indicating CCL4 and CCL20 are potential predictors of ESCC patients’ survival.

At low flow rates, centrifugal compressors often experience aerodynamic instabilities, posing a crucial concern for gas turbine engineers. This study focused on a standard centrifugal compressor and investigated its aerodynamic behavior through numerical simulations in both steady and unsteady full-annulus states. Additionally, it analyzed diffuser stability by evaluating the signals associated with rotating stall. Results indicated that, as the flow rate decreases and the flow shifts downstream in the full-cycle model, the non-uniformity of the Mach number in the circumferential direction near the blockage region increases from 8.13% to 25.52%. Under the design condition, the circumferential non-uniformity rises from 15.18% to 24.12%. When the compressor becomes unstable, the centrifugal impeller exhibits rotational instabilities with a disturbance frequency of 1304.61 Hz, corresponding to 23.95% of the blade passing frequency. The conclusions of this study provide fresh insights into unsteady flow characteristics in centrifugal compressors and offer practical guidelines for enhancing the operational stability of microturbine units.

Background Chronic low back pain (CLBP) prevalence has steadily increased over the last two decades. Manual therapy (MT) is recommended within a multimodal management approach to improve pain and disability although evidence investigating the patients’ experience of MT is scarce. Objective To explore expectations and perceptions of MT techniques in people with CLBP. Methods A qualitative study embedded sequential to an experimental trial using semi-structured interviews (SSI) explored participants’ experiences of thrust, non-thrust and sham technique. Purposive sampling enabled variance in age and CLBP duration. An evidence informed topic guide was used. Data were analysed using thematic analysis (TA). Respondent validation and peer debriefing enhanced trustworthiness. The Consolidating Criteria for Reporting Qualitative Studies (COREQ) reported methodological rigour. Findings Ten participants (50% male) with a mean age of 29.1 years (Standard Deviation (SD): 7.9, range: 19–43), a mean pain intensity of 4.5 on a Numeric Rating Scale (NRS) 0–10 (SD: 1.5, range: 2–7), a mean Oswestry Disability Score (ODI) of 9 (SD: 4.6, range: 2–17) and a mean Tampa Scale of Kinesiophobia (TSK) score of 38.6 (SD: 4.8, range: 30–45) participated. Four themes were identified: understanding of pain; forming expectations; perception of care; re-evaluation of body awareness and management. Understanding of CLBP is formed by an individuals’ pain perception and exchange with social environment. This, combined with communication with physiotherapist influenced expectations regarding the MT technique. Conclusion Expectations for MT were formed by an individual’s social environment and previous experience. A treatment technique is perceived as positive if its characteristics are aligned with the individual’s understanding of pain and if care is delivered in an informative and reassuring manner.

Thermal conductivity is one of the most crucial physical properties of matter when it comes to understanding heat transport, hydrodynamic evolution, and energy balance in systems ranging from astrophysical objects to fusion plasmas. In the warm dense matter regime, experimental data are very scarce so that many theoretical models remain untested. Here we present the first thermal conductivity measurements of aluminum at 0.5–2.7 g/cc and 2–10 eV, using a recently developed platform of differential heating. A temperature gradient is induced in a Au/Al dual-layer target by proton heating, and subsequent heat flow from the hotter Au to the Al rear surface is detected by two simultaneous time-resolved diagnostics. A systematic data set allows for constraining both thermal conductivity and equation-of-state models. Simulations using Purgatorio model or Sesame S27314 for Al thermal conductivity and LEOS for Au/Al release equation-of-state show good agreement with data after 15 ps. Discrepancy still exists at early time 0–15 ps, likely due to non-equilibrium conditions.