Ductile P-Type AgCu(Se,S,Te) Thermoelectric Materials.

Ductile inorganic thermoelectric (TE) materials open a new approach to develop high-performance flexible TE devices. N-type Ag2(S,Se,Te) and p-type AgCu(Se,S,Te) pseudoternary solid solutions are two typical categories of ductile inorganic TE materials reported so far. Comparing with the Ag2(S,Se,Te) pseudoternary solid solutions, the phase composition, crystal structure, and physical properties of AgCu(Se,S,Te) pseudoternary solid solutions are more complex, but their relationships are still ambiguous now. In this work, via systematically investigating the phase composition, crystal structure, mechanical, and TE properties of about 60 AgCu(Se,S,Te) pseudoternary solid solutions, the comprehensive composition-structure-property phase diagrams of the AgCuSe-AgCuS-AgCuTe pseudoternary system is constructed. By mapping the complex phases, the "ductile-brittle" and "n-p" transition boundaries are determined and the composition ranges with high TE performance and inherent ductility are illustrated. On this basis, high performance p-type ductile TE materials are obtained, with a maximum zT of 0.81 at 340 K. Finally, flexible in-plane TE devices are prepared by using the AgCu(Se,S,Te)-based ductile TE materials, showing high output performance that is superior to those of organic and inorganic-organic hybrid flexible devices.

Mechanism insights into the histopathological changes of polypropylene microplastics induced gut and liver in zebrafish.

Microplastics (MPs), emerging as significant pollutants, have been consistently detected in aquatic environments, with the Yangtze River experiencing a particularly severe level of microplastic pollution, exceeding all other watersheds in China. Polypropylene (PP), the plastic most abundantly found in the middle and lower reaches of the Yangtze River Basin, has less comprehensive research results into its toxic effects. Consequently, the present investigation employed zebrafish as a model organism to delve into the toxicological impacts of polypropylene microplastics (PP-MPs) with a diameter of 5 µm across varying concentrations (300 mg/L and 600 mg/L). Using histopathological, microbiota profiling, and transcriptomic approaches, we systematically evaluated the impact of PP-MPs exposure on the intestine and liver of zebrafish. Histopathological analysis revealed that exposure to PP-MPs resulted in thinner intestinal walls, damaged intestinal mucosa, and hepatic cellular damage. Intestinal microbiota profiling demonstrated that, the richness, uniformity, diversity, and homogeneity of gut microbes significantly increased after the PP-MPs exposure at high concentration. These alterations were accompanied by shifts in the relative abundance of microbiota associated with intestinal pathologies, suggesting a profound impact on the intestinal microbial community structure. Concurrently, hepatic transcriptome analysis and RT-qPCR indicated that the downregulation of pathways and genes associated with cell proliferation regulation and DNA damage repair mechanisms contributed to hepatic cellular damage, ultimately exerting adverse effects on the liver. Correlation analysis between the intestinal microbiota and liver transcriptome profiles further highlighted significant associations between intestinal microbiota and the downregulated hepatic pathways. Collectively, these results provide novel insights into the subacute toxicological mechanisms of PP-MPs in aquatic organisms and highlight the need for further research on the ecological and health risks associated with PP-MPs pollution.

Identification of PSMD11 as a novel cuproptosis- and immune-related prognostic biomarker promoting lung adenocarcinoma progression.

BACKGROUND: Due to the unfavorable prognosis associated with lung adenocarcinoma (LUAD), the development of targeted therapies and immunotherapies is essential. Cuproptosis, an emerging form of regulated cell death, is implicated in mitochondrial metabolism and is induced by copper ions. This study aimed to explore the prognostic value of cuproptosis- and immune-related genes (CIRGs) in LUAD. METHODS: We used The Cancer Genome Atlas database to develop a prognostic prediction model for LUAD patients based on eight CIRGs. Using Cox regression analysis, we determined that the CIRG signature is a reliable, independent prognostic factor. We further identified PSMD11 as a critical CIRG and performed immunohistochemistry to study the protein expression levels of PSMD11 in LUAD tissues. We also investigated the impact of PSMD11 on the biological behavior of lung cancer cell lines. RESULTS: We found that patients with low PSMD11 expression levels displayed an improved prognosis compared with those with high PSMD11 expression levels. Overexpression of PSMD11 enhanced proliferation, migration, invasion, and tumor growth of lung carcinoma cell line A549, while PSMD11 knockdown diminished proliferation, migration, invasion, and tumor growth of lung carcinoma cell line PC9. Additionally, we discovered that PSMD11 expression was positively correlated with the infiltration of myeloid-derived suppressor cells and the increased expression of immunosuppressive molecules. CONCLUSION: These findings suggest that PSMD11 may serve as a valuable prognostic biomarker and therapeutic target for LUAD.

[Comparison of effectiveness of three surgical methods in treatment of Pauwels type â ¢ femoral neck fracture in young and middle-aged patients].

Objective: To compare the effectiveness of three surgical methods in the treatment of Pauwels type Ⅲ femoral neck fracture in young and middle-aged patients, in order to provide reference for clinical selection of appropriate surgical methods. Methods: The clinical data of 103 patients with Pauwels type Ⅲ femoral neck fracture who met the selection criteria between June 2018 and December 2021 were retrospectively analyzed. The fractures were fixed with hollow screws in an inverted triangular shape (37 cases, hollow screw group), hollow screws in an inverted triangular shape combined with eccentric shaft screw (34 cases, eccentric shaft screw group), and hollow screws in an inverted triangular shape combined with medial support plate (32 cases, support plate group). There was no significant difference in age, gender, cause of injury, body mass index, time from injury to operation, side of the fracture, and Garden classification, whether they were in traction preoperatively, and other baseline data between groups ( P>0.05). The operation time, intraoperative blood loss, the number of fluoroscopy, the length of hospital stay, early postoperative complication and postoperative weight-bearing time of the three groups were recorded. Harris score was used to evaluate joint function at 6 and 12 months after operation, and the difference between the two time points (change value) was calculated for comparison between groups. X-ray films were reviewed to evaluate the quality of fracture reduction (Garden index) and healing, as well as the occurrence of internal fixation failure and femoral head necrosis. Results: The patients of the three groups were successfully completed. Compared with the hollow screw group and the eccentric shaft screw group, the operation time and intraoperative blood loss of the support plate group significantly increased, the number of fluoroscopy reduced, and the quality of fracture reduction was better, the differences were significant ( P<0.05). The operation time, intraoperative blood loss, and the number of fluoroscopy of the hollow screw group were less than those of the eccentric shaft screw group, the differences were significant ( P<0.05). There was no significant difference in the length of hospital stay between groups ( P>0.05). All patients in the three groups were followed up 21-52 months, with an average follow-up time of 36.0 months, and there was no significant difference between groups ( P>0.05). The incisions of all patients healed by first intention. Imaging reexamination showed that there was no significant difference in the incidence of fracture nonunion between groups ( P>0.05). The fracture healing, partial weight-bearing, and full weight-bearing were significantly earlier in the eccentric shaft screw group and the support plate group than in the hollow screw group ( P<0.05). There was no significant difference in change value of Harris score, the incidence of postoperative deep venous thrombosis and femoral head necrosis between groups ( P>0.05); however, the incidence of internal fixation failure in the support plate group and the eccentric shaft screw group was significantly lower than that in the hollow screw group ( P<0.05). The incidence of postoperative lateral thigh irritation in the support plate group was significantly lower than that in the hollow screw group ( P<0.05); there was no significant difference between the eccentric shaft screw group and the other two groups ( P>0.05). The overall incidences of postoperative complications in the eccentric shaft screw group and the support plate group were significantly lower than that in the hollow screw group ( P<0.05). Conclusion: For young and middle-aged patients with Pauwels type Ⅲ femoral neck fracture, compared with simple hollow screw fixation in an inverted triangular shape, combined with medial support plate or eccentric shaft screw internal fixation can shorten the fracture healing time, reduce the incidences of postoperative complication, more conducive to early functional exercise of the affected limb; at the same time, the operation time and blood loss of combined eccentric shaft screw internal fixation are less than those of combined medial support plate internal fixation, so the hollow screw in an inverted triangular shape combined with eccentric shaft screw fixation may be a better choice.

Enhancing the properties of soy protein isolate and dialdehyde starch films for food packaging applications through tannic acid crosslinking.

The utilization of naturally derived biodegradable polymers, including proteins, polysaccharides, and polyphenols, holds significant promise in addressing environmental concerns and reducing reliance on nonrenewable resources. This study aimed to develop films with enhanced UV resistance and antibacterial capabilities by covalently cross-linking soy protein isolate (SPI) with dialdehyde starch (DAS) through the incorporation of tannic acid (TA). The covalent crosslinking of TA with DAS and SPI was shown to establish a stable chemical cross-linking network. The tensile strength of the resulting SPI/DAS/15TA film exhibited a remarkable increase of 208.27 % compared to SPI alone and 52.99 % compared to SPI/DAS film. Notably, the UV absorption range of SPI/DAS/10TA films extended from 200 nm to 389 nm. This augmentation can be attributed to the oxidation of TA's phenolic hydroxyl groups to quinone under alkaline conditions, which then facilitated cross-linking with the SPI chain via Michael addition and Schiff base reactions. Furthermore, the film demonstrated robust antibacterial properties due to the incorporation of TA. Collectively, the observed properties highlight the significant potential of the SPI/DAS/10TA film for applications in food packaging, where its enhanced mechanical strength, UV resistance, and antibacterial characteristics can contribute to improved product preservation and safety.

Efficacy and Durability of Intravenous Ertapenem Therapy for Recalcitrant Hidradenitis Suppurativa.

Importance: Hidradenitis suppurativa (HS) is a debilitating follicular skin disorder in which bacterial colonization is typical. Oral antibiotic efficacy can be unreliable; however, selective intravenous antibiotics, specifically ertapenem, may provide favorable clinical outcomes. Objective: To explore optimal course duration, efficacy, and patient satisfaction associated with intravenous ertapenem for HS. Design, Setting, and Participants: This retrospective review of the medical records of 98 patients with HS between 2018 and 2022 measured and evaluated patient outcomes before and after treatment with intravenous ertapenem. Participants were followed up in a telephone survey assessing patient perspectives and satisfaction. All of those included in this study received medical care from the Albert Einstein College of Medicine's Montefiore HS Center. Exposures: Patients were treated with 1 g of ertapenem that was self-administered at home through a peripheral intravenous central catheter using an elastomeric pump for 12 to 16 weeks. Antiandrogens and immunomodulatory biologic therapies initiated prior to ertapenem were maintained throughout the treatment course. Main Outcomes and Measures: The primary outcomes, encompassing clinical severity (evaluated through the HS Physician Global Assessment score [a 6-point scale ranging from clear to very severe] and a numerical rating scale for pain [an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain]) and markers of inflammation (such as leukocytes, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6), were measured at baseline, the midcourse of intravenous ertapenem treatment, at the end of the course, and posttherapy. Bacterial abundance was also examined at these 4 points, and patient satisfaction was assessed during follow-up. Results: A total of 98 patients (mean [SD] age, 35.8 [13.0] years; 61 [62.2%] female) with HS were treated with intravenous ertapenem. The self-reported racial distribution included 3 individuals identifying as Asian (3.1%), 59 as Black/African American (60.2%), 13 as White (13.3%), and 23 as either other or unknown (23.5%). Additionally, 24 participants (24.5%) reported Spanish/Hispanic/Latino ethnicity. The mean (SD) treatment duration spanned 13.1 (4.0) weeks, with posttherapy follow-up occurring after 7.8 (3.6) weeks. From baseline to posttherapy follow-up, significant reductions were found in the mean (SD) HS Physician Global Assessment scores (3.9 [1.0] vs 2.7 [1.2]; P < .001) and the numerical rating scale for pain (4.2 [3.3] vs 1.8 [2.7]; P < .001), C-reactive protein (5.4 [11.4] vs 2.4 [2.0] mg/dL; P < .001), interleukin-6 (25.2 [21.1] vs 13.7 [13.9]; P < .001), and leukocytes (11.34 [3.9] vs 10.0 [3.4]; P < .001). At follow-up, 76 patients (78.0%) participated in the telephone survey, where 63 (80.3%) reported medium to high satisfaction; further, 69 (90.8%) would recommend ertapenem to other patients. Conclusions and Relevance: In this retrospective review of medical records and telephone survey, treating HS with intravenous ertapenem, administered for a mean of 13 weeks, was associated with improvement in clinical and inflammatory markers, as well as heightened patient satisfaction. Nonetheless, this approach should be monitored for the emergence of antimicrobial resistance given a longer than standard treatment course.

Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway.

INTRODUCTION: Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. METHOD: We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. RESULTS: 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91±1.76 vs. 40.47±3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8±2.7 vs. 28.5±5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6±9.5 vs. 93.5±13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0± 8.3 vs. 67.9±13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. CONCLUSION: Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.

Single-port endoscopic-sentinel lymph node biopsy combined with indocyanine green and carbon nanoparticles in breast cancer.

BACKGROUND: In order to explore the surgical safety and the reliability of axillary staging of single-port endoscopic-sentinel lymph node biopsy, we combined it with indocyanine green that was excited by near-infrared fluorescence endoscopy and carbon nanoparticles as a tracer and compared this method to conventional open sentinel lymph node biopsy. METHODS: This is a retrospective and observational study, there were 20 patients in each group and the total sample size was 60: Group 1, single-port endoscopic-sentinel lymph node biopsy combined with indocyanine green and carbon nanoparticles; Group 2, single-port endoscopic-sentinel lymph node biopsy with carbon nanoparticles only; Group 3, conventional sentinel lymph node biopsy with indocyanine green and carbon nanoparticles. Sentinel lymph node detection and upper extremity function were determined to measure the safety and efficacy of the novel single-port endoscopic-sentinel lymph node biopsy (SPE-SLNB) technique to the standard conventional sentinel lymph node biopsy technique. RESULTS: The detection rate of sentinel lymph nodes was 100% in Group 1, 100% in Group 2, and 95% in Group 3. There were no significant differences in upper arm function and pain scores between the three groups. CONCLUSION: The novel technique of combining indocyanine green and carbon nanoparticles with single-port endoscopic-sentinel lymph node biopsy achieved a similar detection rate and mean number of sentinel lymph nodes as conventional sentinel lymph node biopsy. Traditional open surgery requires two different incisions for breast surgery and SLNB. While the most important advantage of SPE-SLNB is that two procedures can be effectively performed through a single-port in the axilla Therefore, for patients who meet the indications, single-port endoscopic-sentinel lymph node biopsy is as safe and reliable as conventional sentinel lymph node biopsy but has the aesthetic advantage of only one incision.

Intelligent gold nanoparticles for malignant tumor treatment via spontaneous copper manipulation and on-demand photothermal therapy based on copper induced click chemistry.

The excessive copper in tumor cells is crucial for the growth and metastasis of malignant tumor. Herein, we fabricated a nanohybrid to capture, convert and utilize the overexpressed copper in tumor cells, which was expected to achieve copper dependent photothermal damage of primary tumor and copper-deficiency induced metastasis inhibition, generating accurate and effective tumor treatment. The nanohybrid consistsed of 3-azidopropylamine, 4-ethynylaniline and N-aminoethyl-N'-benzoylthiourea (BTU) co-modified gold nanoparticles (AuNPs). During therapy, the BTU segment would specifically chelate with copper in tumor cells after endocytosis to reduce the intracellular copper content, causing copper-deficiency to inhibit the vascularization and tumor migration. Meanwhile, the copper was also rapidly converted to be cuprous by BTU, which further catalyzed the click reaction between azido and alkynyl on the surface of AuNPs, resulting in on-demand aggregation of these AuNPs. This process not only in situ generated the photothermal agent in tumor cells to achieve accurate therapy avoiding unexpected damage, but also enhanced its retention time for sustained photothermal therapy. Both in vitro and in vivo results exhibited the strong tumor inhibition and high survival rate of tumor-bearing mice after application of our nanohybrid, indicating that this synergistic therapy could offer a promising approach for malignant tumor treatment. STATEMENT OF SIGNIFICANCE: The distinctive excessive copper in tumor cells is crucial for the growth and metastasis of tumor. Therefore, we fabricated intelligent gold nanoparticles to simultaneously response and reverse this tumorigenic physiological microenvironment for the synergistic therapy of malignant tumor. In this study, for the first time we converted and utilized the overexpressed Cu2+ in tumor cells to trigger intracellular click chemistry for tumor-specific photothermal therapy, resulting in accurate damage of primary tumor. Moreover, we effectively manipulated the content of Cu2+ in tumor cells to suppress the migration and vascularization of malignant tumor, resulting in effective metastasis inhibition.

Therapeutic implications of transcriptomics in head and neck cancer patient-derived xenografts.

There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.

Tumor-Specific Photothermal-Therapy-Assisted Immunomodulation via Multiresponsive Adjuvant Nanoparticles.

Multiresponsive adjuvant nanoparticles (RMmAGL) are fabricated to perform tumor-specific photothermal therapy while regulating the behavior of tumor-associated immune cells for primary tumor eradication and metastasis inhibition. Core-satellite-like RMmAGL have a core of mannose-functionalized mesoporous silica nanoparticles loaded with the TLR7 agonist imiquimod (R837@MSN-mannose) connected via hydrazone bonds to satellites of glutamine (Glu)- and lysine (Lys)-comodified gold nanoparticles (AuNPs-Glu/Lys). During therapy, the acidic environment in tumor tissue cleaves the hydrazone bonds to release AuNPs-Glu/Lys, which further accumulate in tumor cells. After internalization, photothermal agents (aggregated AuNPs-Glu/Lys) are generated in situ through the intratumoral enzyme-catalyzed reaction between Glu and Lys, resulting in tumor-specific photothermal therapy. The detachment of AuNPs-Glu/Lys also triggers the release of R837, which matured dendritic cells (DCs) via a vaccine-like mechanism along with the tumor-associated antigens generated by photothermal therapy. These matured DCs further activates surrounding T cells for immunotherapy. Moreover, the resulting free MSN-mannose serves as an artificial glycocalyx to continuously induce the polarization of tumor-associated macrophages from an immunosuppressive phenotype to an inflammatory phenotype, thus further enhancing immunotherapy. Both in vivo and in vitro experiments demonstrate significant inhibition of malignant tumors after therapy.

Manipulation and elimination of circulating tumor cells using multi-responsive nanosheet for malignant tumor therapy.

Tumor recurrence caused by metastasis is a major cause of death for patients. Thus, a strategy to manipulate the circulating tumor cells (CTCs, initiators of tumor metastasis ) and eliminate them along with the primary tumor has significant clinical significance for malignant tumor therapy. In this study, a magnet-NIR-pH multi-responsive nanosheet (Fe3O4@SiO2-GO-PEG-FA/AMP-DOX, FGPFAD) was fabricated to capture CTCs in circulation, then magnetically transport them to the primary tumor, and finally perform NIR-dependent photothermal therapy as well as acidic-environment-triggered chemotherapy to destroy both the CTCs and the primary tumor. The FGPFAD nanosheet consists of silica-coated ferroferric oxide nanoparticles (Fe3O4@SiO2, magnetic targeting agent), graphene oxide (GO, photothermal therapy agent), polyethylene glycol (PEG, antifouling agent for sustained circulation), folic acid (FA, capturer of CTCs) and antimicrobial-peptide-conjugated doxorubicin (AMP-DOX, agent for chemotherapy), in which the AMP-DOX was bound to the FGPFAD nanosheet via a cleavable Schiff base to achieve acidic-environment-triggered drug release for tumor-specific chemotherapy. Both in vitro and in vivo results indicated that the effective capture and magnetically guided transfer of CTCs to the primary tumor, as well as the multimodal tumor extermination performed by our FGPFAD nanosheet, significantly inhibited the primary tumor and its metastasis.

COVID-19-associated monocytic encephalitis (CAME): histological and proteomic evidence from autopsy.

Severe neurological symptoms are associated with Coronavirus disease 2019 (COVID-19). However, the morphologic features, pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection. In this study, neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining, ultrastructural examination under electron microscopy, and an image threshold method, in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals. Differentially expressed proteins were identified by quantitative proteomic assays. Histopathological findings included neurophagocytosis, microglia nodules, satellite phenomena, extensive edema, focal hemorrhage, and infarction, as well as infiltrating mononuclear cells. Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes, severe damage of the blood-brain barrier (BBB) and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+ monocytes and occasionally CD4+/CD8+ T lymphocytes. Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses, autophagy and cellular metabolism in COVID-19 patient brains compared with control brains. Proteins involved in brain development, neuroprotection, and extracellular matrix proteins of the basement membrane were downregulated, potentially caused by the activation of transforming growth factor ß receptor and vascular endothelial growth factor signaling pathways. Thus, our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis (CAME) and suggest potential therapeutic targets.

A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis-Targeting Chimeras Enhanced Immunotherapy.

Although immunotherapy has revolutionized oncotherapy, only ≈15% of head and neck squamous cell carcinoma (HNSCC) patients benefit from the current therapies. An immunosuppressive tumor microenvironment (TME) and dysregulation of the polycomb ring finger oncogene BMI1 are potential reasons for the failure. Herein, to promote immunotherapeutic efficacy against HNSCC, an injectable nanocomposite hydrogel is developed with a polymer framework (PLGA-PEG-PLGA) that is loaded with both imiquimod encapsulated CaCO3 nanoparticles (RC) and cancer cell membrane (CCM)-coated mesoporous silica nanoparticles containing a peptide-based proteolysis-targeting chimeras (PROTAC) for BMI1 and paclitaxel (PepM@PacC). Upon injection, this nanocomposite hydrogel undergoes in situ gelation, after which it degrades in the TME over time, releasing RC and PepM@PacC nanoparticles to respectively perform immunotherapy and chemotherapy. Specifically, the RC particles selectively manipulate tumor-associated macrophages and dendritic cells to activate a T-cell immune response, while CCM-mediated homologous targeting and endocytosis delivers the PepM@PacC particles into cancer cells, where endogenous glutathione promotes disulfide bond cleavage to release the PROTAC peptide for BMI1 degradation and frees the paclitaxel from the particle pores to elicit apoptosis meanwhile enhance immunotherapy. Thus, the nanocomposite hydrogel, which is designed to exploit multiple known vulnerabilities of HNSCC, succeeds in suppressing both growth and metastasis of HNSCC.

Glutamine-dependent effects of nitric oxide on cancer cells subjected to hypoxia-reoxygenation.

Limited O2 availability can decrease essential processes in energy metabolism. However, cancers have developed distinct metabolic adaptations to these conditions. For example, glutaminolysis can maintain energy metabolism and hypoxia signaling. Additionally, it has been observed that nitric oxide (NO) possesses concentration-dependent, biphasic effects in cancer. NO has potent anti-tumor effects through modulating events such as angiogenesis and metastasis at low physiological concentrations and inducing cell death at higher concentrations. In this study, Ewing Sarcoma cells (A-673), MIA PaCa, and SKBR3 cells were treated with DetaNONOate (DetaNO) in a model of hypoxia (1% O2) and reoxygenation (21% O2). All 3 cell types showed NO-dependent inhibition of cellular O2 consumption which was enhanced as O2-tension decreased. L-Gln depletion suppressed the mitochondrial response to decreasing O2 tension in all 3 cell types and resulted in inhibition of Complex I activity. In A-673 cells the O2 tension dependent change in mitochondrial O2 consumption and increase in glycolysis was dependent on the presence of L-Gln. The response to hypoxia and Complex I activity were restored by α-ketoglutarate. NO exposure resulted in the A-673 cells showing greater sensitivity to decreasing O2 tension. Under conditions of L-Gln depletion, NO restored HIF-1α levels and the mitochondrial response to O2 tension possibly through the increase of 2-hydroxyglutarate. NO also resulted in suppression of cellular bioenergetics and further inhibition of Complex I which was not rescued by α-ketoglutarate. Taken together these data suggest that NO modulates the mitochondrial response to O2 differentially in the absence and presence of L-Gln. These data suggest a combination of metabolic strategies targeting glutaminolysis and Complex I in cancer cells.

Morphological Effect of Side Chain Length in Sulfonated Poly(arylene ether sulfone)s Polymer Electrolyte Membranes via Molecular Dynamics Simulation.

With the recognition of the multiple advantages of sulfonated hydrocarbon-based polymers that possess high chemical and mechanical stability with significant low cost, we employed molecular dynamics simulation to explore the morphological effects of side chain length in sulfonated polystyrene grafted poly(arylene ether sulfone)s (SPAES) proton exchange membranes. The calculated diffusion coefficients of hydronium ions (H3O+) are in range of 0.61-1.15 × 10-7 cm2/s, smaller than that of water molecules, due to the electrical attraction between the oppositely charged sulfonate group and H3O+. The investigation into the radial distribution functions suggests that phase segregation in the SPAES membrane is more probable with longer side chains. As the hydration level of the membranes in this study is relatively low (λ = 3), longer side chains correspond to more water molecules in the amorphous cell, which provides better solvent effects for the distribution of sulfonated side chains. The coordination number of water molecules and hydronium ions around the sulfonate group increases from 1.67 to 2.40 and from 2.45 to 5.66, respectively, with the increase in the side chain length. A significant proportion of the hydronium ions appear to be in bridging configurations coordinated by multiple sulfonate groups. The microscopic conformation of the SPAES membrane is basically unaffected by temperature during the evaluated temperature range. Thus, it can be revealed that the side chain length plays a key role in the configuration of the polymer chain and would contribute to the formation of the microphase separation morphology, which profits proton transport in the hydrophilic domains.

Direct adsorption sampling and ambient mass spectrometry analysis of tobacco smoke with porous paper strips.

Chemical analysis of atmospheric aerosols by conventional analytical methods is usually required to perform complicated and time-consuming sample preparation processes. In recent decades, ambient ionization mass spectrometry (AI-MS) methods have been proven to be simple, rapid, and effective analytical tools for direct analysis of various complex samples. In this work, we applied porous paper filters for direct adsorptive sampling of tobacco smoke, and then the sampled paper filters were performed the emitters of the paper spray ionization (PSI) device. An auto-sampling device was made to control the generation and collection of tobacco smoke. Nicotine, the typical compound of tobacco smoke, was used to optimize the key conditions of auto-sampling. Moreover, different types of tobacco smoke were also compared with multivariate variable analysis, and the makers of tobacco smoke from different sources of tobacco smoke were investigated. By using this method, direct sampling and analysis of a single tobacco sample can be completed within minutes. Overall, our results show that PSI-MS is a powerful tool that integrates collection, extraction, ionization, and identification analytes in smoke.

Comparing outcomes of single-port insufflation endoscopic breast-conserving surgery and conventional open approach for breast cancer.

BACKGROUND: In the surgical treatment of breast cancer, the goal of surgeons is to continually create and improve minimally invasive surgical techniques to increase patients' quality of life. Currently, routine breast-conserving surgery is often performed using two obvious incisions. Here, we compare the clinical efficacy and aesthetic outcomes of a novel technique using one incision, called 'single-port insufflation endoscopic breast-conserving surgery' (SIE-BCS), vs. conventional breast-conserving surgery (C-BCS) in patients with early-stage breast cancer. METHODS: A total of 180 patients with stage I or stage II breast cancer participated in this study, of whom 63 underwent SIE-BCS and 117 underwent C-BCS. Logistic regression analysis was conducted to assess the risk of local recurrence and metastasis. Aesthetic outcomes were evaluated using the BREAST-Q scale. RESULTS: The mean operation time was significantly longer for SIE-BCS (194.9 ± 71.5 min) than for C-BCS (140.3 ± 56.9 min), but the mean incision length was significantly shorter for SIE-BCS than for C-BCS (3.4 ± 1.2 cm vs. 8.6 ± 2.3 cm). While both surgeries yielded similar BREAST-Q ratings for satisfaction with breasts and sexual well-being, SIE-BCS was associated with significantly better ratings for physical well-being (chest area) and psychological well-being. Additionally, SIE-BCS was associated with decreased rates of adverse effects of radiation. The preliminary analysis showed that SIE-BCS did not increase the risk of local recurrence or metastasis. CONCLUSION: The novel single-port insufflation endoscopic assisted BCS technique is feasible, safe, and improves patients' postoperative comfort and psychological well-being, as compared to the conventional technique.

Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling.

Rationale: Angiogenesis is a fundamental process of tumorigenesis, growth, invasion and metastatic spread. Extracellular vesicles, especially exosomes, released by primary tumors promote angiogenesis and cancer progression. However, the mechanism underlying the pro-angiogenic potency of cancer cell-derived exosomes remains poorly understood. Methods: Exosomes were isolated from breast cancer cells with high metastatic potential (HM) and low metastatic potential (LM). The pro-angiogenic effects of these exosomes were evaluated by in vitro tube formation assays, wound healing assays, rat arterial ring budding assays and in vivo Matrigel plug assays. Subsequently, RNA sequencing, shRNA-mediated gene knockdown, overexpression of different EPHA2 mutants, and small-molecule inhibitors were used to analyze the angiogenesis-promoting effect of exosomal EPHA2 and its potential downstream mechanism. Finally, xenograft tumor models were established using tumor cells expressing different levels of EPHA2 to mimic the secretion of exosomes by tumor cells in vivo, and the metastasis of cancer cells were monitored using the IVIS Spectrum imaging system and Computed Tomography. Results: Herein, we demonstrated that exosomes produced by HM breast cancer cells can promote angiogenesis and metastasis. EPHA2 was rich in HM-derived exosomes and conferred the pro-angiogenic effect. Exosomal EPHA2 can be transferred from HM breast cancer cells to endothelial cells. Moreover, it can stimulate the migration and tube-forming abilities of endothelial cells in vitro and promote angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal EPHA2 activates the AMPK signaling via the ligand Ephrin A1-dependent canonical forward signaling pathway. Moreover, inhibition of the AMPK signaling impairs exosomal EPHA2-mediated pro-angiogenic effects. Conclusion: Our findings identify a novel mechanism of exosomal EPHA2-mediated intercellular communication from breast cancer cells to endothelial cells in the tumor microenvironment to provoke angiogenesis and metastasis. Targeting the exosomal EPHA2-AMPK signaling may serve as a potential strategy for breast cancer therapy.

A map of the spatial distribution and tumour-associated macrophage states in glioblastoma and grade 4 IDH-mutant astrocytoma.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.