STING is significantly increased in high-grade glioma with high risk of recurrence.

In this study, we aimed to comprehensively characterize the potential relationships among the frequently mutated genes, well-known homologous recombination repair (HRR) proteins, and immune proteins in glioma from a clinical perspective. A total of 126 surgical tissues from patients initially diagnosed with glioma were included. The genetic alterations were tested using the targeted next-generation sequencing technique. The expression of HRR proteins, immune proteins, and genetic alteration-related proteins were detected using immunostaining. Integrated analysis showed that ATRX is positively correlated with STING in high-grade glioma (HGG) with wild-type ATRX and IDH1. Then, a relapse predictive risk-scoring model was established using the least absolute shrinkage and selection operator regression algorithms. The scores based on the expression of ATRX and STING significantly predict the recurrence for glioma patients, which further predict the survival for specific subgroups, characterized with high expression of RAD51 and wild-type TERT. Moreover, STING is significantly higher in patients with high relapse risk. Interestingly, STING inhibitors and agonists both suppress the growth of HGG cells, regardless of their STING levels and STING pathway activity, whereas RAD51 inhibitor B02 is found to exclusively sensitize HGG cells with high expression of STING to temozolomide in vitro and in vivo. Overall, findings in the study not only reveal that ATRX is closely correlated with STING to drive the relapse of HGG, but also provide a STING-guided combined strategy to treat patients with aggressive gliomas. Translation of these findings will ultimately improve the outcomes for ATRX and IDH1 genomically stratified subgroups in HGG.

Insight into the Gas-Induced Phase Transformations in a 2D Switching Coordination Network via Coincident Gas Sorption and In Situ PXRD.

Switching coordination networks (CNs) that reversibly transform between narrow or closed pore (cp) and large pore (lp) phases, though fewer than their rigid counterparts, offer opportunities for sorption-related applications. However, their structural transformations and switching mechanisms remain underexplored at the molecular level. In this study, we conducted a systematic investigation into a 2D switching CN, [Ni(bpy)2(NCS)2]n, sql-1-Ni-NCS (1 = bpy = 4,4'-bipyridine), using coincident gas sorption and in situ powder X-ray diffraction (PXRD) under low-temperature conditions. Gas adsorption measurements revealed that C2H4 (169 K) and C2H6 (185 K) exhibited single-step type F-IVs sorption isotherms with sorption uptakes of around 180-185 cm3 g-1, equivalent to four sorbate molecules per formula unit. Furthermore, parallel in situ PXRD experiments provided insight into sorbate-dependent phase switching during the sorption process. Specifically, CO2 sorption induced single-step phase switching (path I) solely between cp and lp phases consistent with the observed single-step type F-IVs sorption isotherm. By contrast, intermediate pore (ip) phases emerged during C2H4 and C2H6 desorption as well as C3H6 adsorption, although they remained undetectable in the sorption isotherms. To our knowledge, such a cp-lp-ip-cp transformation (path II) induced by C2H4/6 and accompanied by single-step type F-IVs sorption isotherms represents a novel type of phase transition mechanism in switching CNs. By virtue of Rietveld refinements and molecular simulations, we elucidated that the phase transformations are governed by cooperative local and global structural changes involving NCS- ligand reorientation, bpy ligand twist and rotation, cavity edge (Ni-bpy-Ni) deformation, and interlayer expansion and sliding.

Ethane/Ethylene Separations in Flexible Diamondoid Coordination Networks via an Ethane-Induced Gate-Opening Mechanism.

Separating ethane (C2H6) from ethylene (C2H4) is an essential and energy-intensive process in the chemical industry. Here, we report two flexible diamondoid coordination networks, X-dia-1-Ni and X-dia-1-Ni0.89Co0.11, that exhibit gate-opening between narrow-pore (NP) and large-pore (LP) phases for C2H6, but not for C2H4. X-dia-1-Ni0.89Co0.11 thereby exhibited a type F-IV isotherm at 273 K with no C2H6 uptake and a high uptake (111 cm3 g-1, 1 atm) for the NP and LP phases, respectively. Conversely, the LP phase exhibited a low uptake of C2H4 (12.2 cm3 g-1). This C2H6/C2H4 uptake ratio of 9.1 for X-dia-1-Ni0.89Co0.11 far surpassed those of previously reported physisorbents, many of which are C2H4-selective. In situ variable-pressure X-ray diffraction and modeling studies provided insight into the abrupt C2H6-induced structural NP to LP transformation. The promise of pure gas isotherms and, more generally, flexible coordination networks for gas separations was validated by dynamic breakthrough studies, which afforded high-purity (99.9%) C2H4 in one step.

Clinical Features and Immunogenetic Risk Factors Associated With Additional Autoantibodies in Anti-Transcriptional Intermediary Factor 1γ Juvenile-Onset Dermatomyositis.

OBJECTIVE: Novel autoantibody specificities including anti-CCAR1 were recently discovered in adult patients with anti-transcriptional intermediary factor (TIF1)-positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile-onset DM (JDM) and to determine their associated features. METHODS: Sera from 150 patients with anti-TIF1γ autoantibody-positive JDM in a cross-sectional cohort and 90 juvenile healthy controls were assayed for anti-CCAR1, anti-C1Z1, anti-IMMT, anti-TBL1XR1, and anti-Sp4 autoantibodies. Demographics, myositis autoantibodies, clinical features, medications, outcomes, and HLA-DRB1 and HLA-DQA1 alleles were compared between those with and without these autoantibodies. RESULTS: Any one of the anti-TIF1γ-associated autoantibodies was present in 44 patients (29%) overall, including 25 (17%) with anti-Sp4, 22 (15%) with anti-TBL1XR1, 14 (9%) with anti-CCAR1, 2 (1%) with anti-C1Z1, and 2 (1%) with anti-IMMT autoantibodies. These anti-TIF1γ-associated autoantibodies frequently co-occurred. Patients with any of the anti-TIF1γ-associated autoantibodies had less frequent falling (34% [15] vs. 53% [56], P = 0.032) and lower peak muscle enzymes. None of the patients had cancer. Among White patients, HLA-DRB1*03 was protective against an anti-TIF1γ-associated autoantibody (odds ratio 0.20, 95% confidence interval 0.07-0.52). CONCLUSION: Autoantibodies associated with anti-TIF1γ were found in isolation and in combination among a subset of patients with JDM. Patients with these autoantibodies had less severe muscle disease and were not enriched for HLA-DRB1*03. Additional autoantibodies among patients with positive anti-TIF1γ with JDM likely contribute to the heterogeneity of the anti-TIF1γ serologic subgroup.

MOF-GRU: A MOFid-Aided Deep Learning Model for Predicting the Gas Separation Performance of Metal-Organic Frameworks.

The remarkable versatility of metal-organic frameworks (MOFs) stems from their rich chemical information, leading to numerous successful applications. However, identifying optimal MOFs for specific tasks necessitates a thorough assessment of their chemical attributes. Conventional machine learning approaches for MOF prediction have relied on intricate chemical and structural details, hampering rapid evaluations. Drawing inspiration from recent advancements exemplified by Snurr et al., wherein a text string was used to represent a MOF (MOFid), we introduce a MOFid-aided deep learning model, named the MOF-GRU model. This model, founded on natural language processing principles and utilizing the gated recurrent unit architecture, leverages the serialized text string representation of metal-organic frameworks (MOFs) to forecast gas separation performance. Through a focused study on CH4/N2 separation, we substantiate the efficacy of this approach. Comparative assessments against traditional machine learning techniques underscore our model's superior predictive accuracy and its capacity to handle extensive data sets adeptly. The MOF-GRU model remarkably uncovers latent structure-performance relationships with only MOF sequences, obviating the necessity for intricate three-dimensional (3D) structural information. Overall, this model's judicious design empowers efficient data utilization, thereby hastening the discovery of high-performance materials tailored for gas separation applications.

Expression of IDO1 in Tumor Microenvironment Significantly Predicts the Risk of Recurrence/Distant Metastasis for Patients With Esophageal Squamous Cell Carcinoma.

In this study, we aimed to explore immune markers predicting locoregional recurrence/distant metastasis (R/M) for patients with esophageal squamous cell carcinoma (ESCC) post-surgical intervention by using a novel high-throughput spatial tool to quantify multiple immune proteins expressed in ESCC and lymphocytes in tumor microenvironment (TME-L). First, formalin-fixed paraffin-embedded tissues from surgical patients with ESCC (n = 94) were constructed on a microarray, which was then divided into discovery (n = 36) and validation cohorts (n = 58). Using a newly developed GeoMx digital spatial profiling tool, 31 immune proteins in paired ESCC and TME-L, morphologically segmented by PANCK and CD45, respectively, from the discovery cohort were quantified, releasing 2,232 variables. Next, the correlation matrix was analyzed using the Corrplot package in R Studio, resulting in 6 closely correlated clusters. The Least Absolute Shrinkage and Selection Operator regression scoring model predictive of R/M risk with superior specificity was successfully established based on the 3 following hierarchically clustered immune proteins: ARG1 in ESCC/PANCK+, STING, and IDO1 in TME-L/CD45+. Moreover, the expression of IDO1 in TME-L, rather than in ESCC, significantly predicted the R/M risk score with an area under curve of 0.9598. In addition, its correlation with R/M status was further validated by dual immunohistochemistry staining of IDO1 and CD45 in discovery and validation cohorts. Above all, our findings not only provide a more accurate scoring approach based on quantitative immune proteins for the prediction of R/M risk, but also propose that IDO1 in TME-L potentially plays a driving role in mediating R/M in ESCC.

Non-heme Iron Single-Atom Nanozymes as Peroxidase Mimics for Tumor Catalytic Therapy.

Single-atom nanozymes (SAzymes) open new possibilities for the development of artificial enzymes that have catalytic activity comparable to that of natural peroxidase (POD). So far, most efforts have focused on the structural modulation of the Fe-N4 moiety to mimic the metalloprotein heme center. However, non-heme-iron POD with much higher activity, for example, HppE, has not been mimicked successfully due to its structural complexity. Herein, carbon dots (CDs)-supported SAzymes with twisted, nonplanar Fe-O3N2 active sites, highly similar to the non-heme iron center of HppE, was synthesized by exploiting disordered and subnanoscale domains in CDs. The Fe-CDs exhibit an excellent POD activity of 750 units/mg, surpassing the values of conventional SAzymes with planar Fe-N4. We further fabricated an activatable Fe-CDs-based therapeutic agent with near-infrared enhanced POD activity, a photothermal effect, and tumor-targeting ability. Our results represent a big step in the design of high-performance SAzymes and provide guidance for future applications for synergistic tumor therapy.

Novel applications of histopathological markers to distinguish prognostic subgroups in colorectal adenocarcinoma.

OBJECTIVE: To explore the novel applications of histological factors by stratifying the prognostic markers of the overall CRC patients in subgroups. MATERIALS AND METHODS: A total of 17 histopathological and molecular factors were retrospectively collected and systematically analyzed for the prediction of CRC prognosis in the overall and stratified subgroups by using the Kaplan-Meier curve analysis as well as the Cox regression test. The χ2 test was used to analyze the correlation of the prognostic markers with other factors. RESULTS: The histopathological markers including the lymph node metastasis (LNM), perineural/venous invasion (PVI), TNM stage, the local recurrence or distant metastasis after surgery (R/M) and the molecular markers Ki-67 expression as well as KRAS mutation were identified to be the independent prognostic biomarkers in the overall CRC. The differential prognosis of LNM was found to be significant in age, tumor site, histological classification (histo_classification), cell differentiation, and KRAS/NRAS/BRAF (KNB) mutation stratified subgroups. The PVI was discovered to differently predict survival for patients in age, histo_classification, differentiation, and R/M stratified subgroups. Same as LNM and PVI, TNM was also found to demonstrate differential prognosis in age, tumor site, histo_classification, differentiation, R/M status and KRAS/KNB mutation stratified subgroups. More importantly, R/M was firstly identified not to be terrible for patients in age, histo_classification, LNM, TNM, Ki-67, and KRAS/KNB stratified subgroups. Besides, KRAS mutation was innovatively found to show differential prognosis in age, differentiation, and LNM stratified subgroups. CONCLUSIONS: The stratification analyses of prognostic markers in CRC patients indicate novel applications of the above histopathological and molecular markers in clinic and the findings provide new insights into future investigations of precision pathology.

The pathological markers LNM, PVI, TNM stage, R/M, the histological marker Ki-67 expression and the molecular marker KRAS mutation are all the early biomarkers capable of independently predicting the 2-year survival rate for CRC.Differential prognosis of the histopathological and molecular markers is commonly found in age, tumor site, differentiation, histological type, LNM, TNM, and R/M stratified CRC subgroups.

Efficient Capture of Th(IV) and U(VI) by Radiation-Resistant Oxygen-Rich Ion Traps Based on a Metal-Organic Framework.

Herein, based on a well-stabilized Ti-MOF (IEF-11), an oxygen-rich ion trap with synergy interaction of active atoms was proposed for the removal of Th(IV) and U(VI) from aqueous solutions. Due to the high coordination number of Ti and compact framework structure, IEF-11 has excellent resistance toward ß-ray irradiation, even under 1000 kGy irradiation dosage. Meanwhile, owing to the special chelating effect of the oxygen-rich ion traps, the maximum adsorption amounts of IEF-11 for Th(IV) (pH = 3.0) and U(VI) (pH = 5.0) ions can reach 305.9 and 240.7 mg g-1, and the separation coefficients exceed 200 for Th(IV)/Nd(III), Th(IV)/Sm(III), and Th(IV)/Eu(III) and 100 for U(VI)/Eu(III), U(VI)/La(III), and U(VI)/Sr(II). Moreover, IEF-11 shows fast adsorption kinetics with an equilibrium time of ∼100 min. The adsorption amount almost remains even after four adsorption-desorption cycles. Finally, experimental and theoretical calculations indicate that Th(IV) and U(VI) ions are anchored in the ion trap in the form of chemical bonds. Meanwhile, the circular pore trap (class I trap) than the long pore trap (class II trap) is considered to be the better adsorption site. We expect that our work will provide a new insight for constructing effective adsorbents for radioactive nuclides.

Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.

Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm2 elliptical field with a dose rate of ~120 Gy/s was provided by a 228 MeV proton pencil beam. Partial abdominal irradiation was delivered to C57BL/6j and immunodeficient Rag1-/-/C57 mice. Proliferating crypt cells were counted at 2 days post exposure, and the thickness of the muscularis externa was measured at 280 days following irradiation. FLASH irradiation did not reduce the morbidity or mortality of conventional irradiation in either strain of mice; in fact, a tendency for worse survival in FLASH-irradiated mice was observed. There were no significant differences in lymphocyte numbers between FLASH and conventional-dose-rate mice. A similar number of proliferating crypt cells and a similar thickness of the muscularis externa following FLASH and conventional dose rate irradiation were observed. Partial abdominal FLASH proton irradiation at 120 Gy/s did not spare normal intestinal tissue, and no difference in lymphocyte depletion was observed. This study suggests that the effect of FLASH irradiation may depend on multiple factors, and in some cases dose rates of over 100 Gy/s do not induce a FLASH effect and can even result in worse outcomes.

Exercise Mitigates Endothelial Pyroptosis and Atherosclerosis by Downregulating NEAT1 Through N6-Methyladenosine Modifications.

BACKGROUND: The benefits of exercise on the cardiovascular system are widely recognized; however, the underlying mechanisms are unknown. Here, we report the effect of the long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1), which is regulated by exercise, on atherosclerosis development after N6-methyladenosine (m6A) modifications. METHODS: Using clinical cohorts and NEAT1-/- mice, we determined the exercise-mediated expression and role of NEAT1 in atherosclerosis. To investigate the mechanism of epigenetic modification of NEAT1 regulated by exercise, we identified METTL14 (methyltransferase-like 14)-a key m6A modification enzyme under exercise-and found that METTL14 alters the expression and role of NEAT1 through m6A modification and elucidated the specific mechanism of METTL14 in vitro and in vivo. Finally, the NEAT1 downstream regulatory network was investigated. RESULTS: We found that NEAT1 expression was downregulated with exercise and that downregulation of NEAT1 was an important factor in the improvement of atherosclerosis with exercise. Exercise-mediated loss of function of NEAT1 can delay atherosclerosis. Mechanistically, we showed that exercise induced a significant downregulation of m6A modification and METTL14, which binds to the m6A sites of NEAT1 and promotes NEAT1 expression through subsequent YTHDC1 (YTH domain-containing 1) recognition to promote endothelial pyroptosis. Furthermore, NEAT1 induces endothelial pyroptosis by binding KLF4 (Kruppel-like factor 4) to promote the transcriptional activation of the key pyroptotic protein NLRP3 (NOD-like receptor thermal protein domain-associated protein 3), whereas exercise can attenuate NEAT1-mediated endothelial pyroptosis to improve atherosclerosis. CONCLUSIONS: Our study of NEAT1 provides new insights into the improvement of atherosclerosis by exercise. This finding demonstrates the role of exercise-mediated NEAT1 downregulation in atherosclerosis while expanding our understanding of the mechanisms by which exercise regulates long noncoding RNA function through epigenetic modifications.

Proton FLASH effects on mouse skin at different oxygen tensions.

Objective. Irradiation at FLASH dose rates (>40 Gy s-1) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration.Approach. Our double scattering proton system provided a 1.2 × 1.6 cm2elliptical field at a dose rate of ∼130 Gy s-1. The conventional dose rate was ∼0.4 Gy s-1. The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time.Main results. FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response.Significance. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.

The Risk Factors and Outcomes for Radiological Abnormalities in Early Convalescence of COVID-19 Patients Caused by the SARS-CoV-2 Omicron Variant: A Retrospective, Multicenter Follow-up Study.

BACKGROUND: The emergence of the severe acute respiratory syndrome coronavirus 2 omicron variant has been triggering the new wave of coronavirus disease 2019 (COVID-19) globally. However, the risk factors and outcomes for radiological abnormalities in the early convalescent stage (1 month after diagnosis) of omicron infected patients are still unknown. METHODS: Patients were retrospectively enrolled if they were admitted to the hospital due to COVID-19. The chest computed tomography (CT) images and clinical data obtained at baseline (at the time of the first CT image that showed abnormalities after diagnosis) and 1 month after diagnosis were longitudinally analyzed. Uni-/multi-variable logistic regression tests were performed to explore independent risk factors for radiological abnormalities at baseline and residual pulmonary abnormalities after 1 month. RESULTS: We assessed 316 COVID-19 patients, including 47% with radiological abnormalities at baseline and 23% with residual pulmonary abnormalities at 1-month follow-up. In a multivariate regression analysis, age ≥ 50 years, body mass index ≥ 23.87, days after vaccination ≥ 81 days, lymphocyte count ≤ 1.21 × 10-9/L, interleukin-6 (IL-6) ≥ 10.05 pg/mL and IgG ≤ 14.140 S/CO were independent risk factors for CT abnormalities at baseline. The age ≥ 47 years, presence of interlobular septal thickening and IL-6 ≥ 5.85 pg/mL were the independent risk factors for residual pulmonary abnormalities at 1-month follow-up. For residual abnormalities group, the patients with less consolidations and more parenchymal bands at baseline could progress on CT score after 1 month. There were no significant changes in the number of involved lung lobes and total CT score during the early convalescent stage. CONCLUSION: The higher IL-6 level was a common independent risk factor for CT abnormalities at baseline and residual pulmonary abnormalities at 1-month follow-up. There were no obvious radiographic changes during the early convalescent stage in patients with residual pulmonary abnormalities.

Pore-Structure Control in Metal-Organic Frameworks (MOFs) for Capture of the Greenhouse Gas SF6 with Record Separation.

In the electronics industry, the efficient recovery and capture of sulfur hexafluoride (SF6 ) from SF6 /N2 mixtures is of great importance. Herein, three metal-organic frameworks with fine-tuning pore structures, Cu(peba)2 , Ni(pba)2 , and Ni(ina)2 , were designed for SF6 capture. Among them, Ni(ina)2 has perfect pore sizes (6 Å) that are comparable to the kinetic diameter of sulfur hexafluoride (5.2 Å), affording the benchmark binding affinity for SF6 gas. Ni(ina)2 exhibits the highest SF6 /N2 selectivity (375.1 at 298 K and 1 bar) and ultra-high SF6 uptake capacity (53.5 cm3 g-1 at 298 K and 0.1 bar) at ambient conditions. The remarkable separation performance of Ni(ina)2 was verified by dynamic breakthrough experiments. Theoretical calculations and the SF6 -loaded single-crystal structure provided critical insight into the adsorption/separation mechanism. This porous coordination network has the potential to be used in industrial applications.

Nickel-Based Metal-Organic Frameworks for Coal-Bed Methane Purification with Record CH4 /N2 Selectivity.

The enrichment and purification of coal-bed methane provides a source of energy and helps offset global warming. In this work, we demonstrate a strategy involving the regulation of the pore size and pore chemistry to promote the separation of CH4 /N2 mixtures in four nickel-based coordination networks, named Ni(ina)2 , Ni(3-ain)2 , Ni(2-ain)2 , and Ni(pba)2 , (where ina=isonicotinic acid, 3-ain=3-aminoisonicotinic acid, 2-ain=2-aminoisonicotinic acid, and pba=4-(4-pyridyl)benzoic acid). Among them, Ni(ina)2 and Ni(3-ain)2 can effectively separate CH4 from N2 with top-performing performance because of the suitable pore size (≈0.6 and 0.5 nm) and pore environment. Explicitly, Ni(ina)2 exhibits the highest ever reported CH4 /N2 selectivity of 15.8 and excellent CH4 uptake (40.8 cm3 g-1 ) at ambient conditions, thus setting new benchmarks for all reported MOFs and traditional adsorbents. The exceptional CH4 /N2 separation performance of Ni(ina)2 is confirmed by dynamic breakthrough experiments. Under different CH4 /N2 ratios, Ni(ina)2 selectively extracts methane from the gaseous blend and produces a high purity of CH4 (99 %). Theoretical calculations and CH4 -loading single-crystal structure analysis provide critical insight into the adsorption/separation mechanism. Ni(ina)2 and Ni(3-ain)2 can form rich intermolecular interactions with methane, indicating a strong adsorption affinity between pore walls and CH4 molecules. Importantly, Ni(ina)2 has good thermal and moisture stability and can easily be scaled up at a low cost ($25 per kilogram), which will be valuable for potential industrial applications. Overall, this work provides a powerful approach for the selective adsorption of CH4 from coal-bed methane.

Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) turn out to be a promising source of cell-free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose-derived MSC-EVs (haMSC-EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC-EVs in healthy volunteers. DiR-labelled haMSC-EVs were used to explore the distribution of nebulized haMSC-EVs in the murine model. Pseudomonas aeruginosa-induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL-6, TNF-α and IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC-EVs through the nebulized route. Twenty-four healthy volunteers were involved and received the haMSC-EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC-EVs improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC-EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC-EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC-EVs in lung injury diseases.

Nanoplatform based on GSH-responsive mesoporous silica nanoparticles for cancer therapy and mitochondrial targeted imaging.

Mitochondria, as the energy factory of most cells, are not only responsible for the generation of adenosine triphosphoric acid (ATP) but also essential targets for therapy and diagnosis of various diseases, especially cancer. The safe and potential nanoplatform which can deliver various therapeutic agents to cancer cells and mitochondrial targeted imaging is urgently required. Herein, Au nanoparticles (AuNPs), mesoporous silica nanoparticles (MSN), cationic ligand (triphenylphosphine (TPP)), doxorubicin (DOX), and carbon nanodots (CDs) were utilized to fabricate mitochondrial targeting drug delivery system (denoted as CDs(DOX)@MSN-TPP@AuNPs). Since AuNPs, as the gatekeepers, can be etched by intracellular glutathione (GSH) via ligand exchange induced etching process, DOX can be released into cells in a GSH-dependent manner which results in the superior GSH-modulated tumor inhibition activity. Moreover, after etching by GSH, the CDs(DOX)@MSN-TPP@AuNPs can serve as promising fluorescent probe (λex = 633 nm, λem = 650 nm) for targeted imaging of mitochondria in living cells with near-infrared fluorescence. The induction of apoptosis derived from the membrane depolarization of mitochondria is the primary anti-tumor route of CDs(DOX)@MSN-TPP@AuNPs. As a kind of GSH-responsive mitochondrial targeting nanoplatform, it holds great promising for effective cancer therapy and mitochondrial targeted imaging. The mitochondrial targeting drug delivery system was fabricated by AuNPs, MSN, TPP, and CDs. The nanoplatform can realize redox-responsive drug delivery and targeted imaging of mitochondria in living cells to improve the therapeutic efficiency and security.

Hollow mesoporous MnO2-carbon nanodot-based nanoplatform for GSH depletion enhanced chemodynamic therapy, chemotherapy, and normal/cancer cell differentiation.

A redox-responsive chemodynamic therapy (CDT)-based theranostic system composed of hollow mesoporous MnO2 (H-MnO2), doxorubicin (DOX), and fluorescent (FL) carbon nanodots (CDs) is reported for the diagnosis and therapy of cancer. In general, since H-MnO2 can be degraded by intracellular glutathione (GSH) to form Mn2+ with excellent Fenton-like activity to generate highly reactive ·OH, the normal antioxidant defense system can be injured via consumption of GSH. This in turn can potentiate the cytotoxicity of CDT and release DOX. The cancer cells can be eliminated effectively by the nanoplatform via the synergistic effect of chemotherapy and CDT. The FL of CDs can be restored after H-MnO2 is degraded which blocked the fluorescence resonance energy transfer process between CDs as an energy donor and H-MnO2 as an FL acceptor. The GSH can be determined by recovery of the FL and limit of detection is 1.30 µM with a linear range of 0.075-0.825 mM. This feature can be utilized to efficiently distinguish cancerous cells from normal ones based on different GSH concentrations in the two types of cells. As a kind of CDT-based theranostic system responsive to GSH, simultaneously diagnostic (normal/cancer cell differentiation) and therapeutic function (chemotherapy and CDT) in a single nanoplatform can be achieved. The redox-responsive chemodynamic therapy (CDT)-based theranostic system is fabricated by H-MnO2, DOX, and fluorescent CDs. The nanoplatform can realize simultaneously diagnostic (normal/cancer cell differentiation) and therapeutic function (chemotherapy and CDT) to improve the therapeutic efficiency and security.

Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex.

OBJECTIVE: The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer. METHODS: A case-control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of 35 S-methionine-labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups. RESULTS: Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody-negative patients; P = 0.009). CONCLUSION: SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer.

FLASH Investigations Using Protons: Design of Delivery System, Preclinical Setup and Confirmation of FLASH Effect with Protons in Animal Systems.

Extremely high-dose-rate irradiation, referred to as FLASH, has been shown to be less damaging to normal tissues than the same dose administrated at conventional dose rates. These results, typically seen at dose rates exceeding 40 Gy/s (or 2,400 Gy/min), have been widely reported in studies utilizing photon or electron radiation as well as in some proton radiation studies. Here, we report the development of a proton irradiation platform in a clinical proton facility and the dosimetry methods developed. The target is placed in the entry plateau region of a proton beam with a specifically designed double-scattering system. The energy after the double-scattering system is 227.5 MeV for protons that pass through only the first scatterer, and 225.5 MeV for those that also pass through the second scatterer. The double-scattering system was optimized to deliver a homogeneous dose distribution to a field size as large as possible while keeping the dose rate >100 Gy/s and not exceeding a cyclotron current of 300 nA. We were able to obtain a collimated pencil beam (1.6 × 1.2 cm2 ellipse) at a dose rate of ∼120 Gy/s. This beam was used for dose-response studies of partial abdominal irradiation of mice. First results indicate a potential tissue-sparing effect of FLASH.