Comparative effect of different mindfulness-based intervention types and deliveries on depression in patients with breast cancer: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: Breast cancer has become the most common cancer worldwide. Various types of mindfulness-based interventions (e.g., mindfulness-based cognitive therapy, mindfulness-based stress reduction) have been conducted in different delivery methods (including face to face and internet delivered) to help patients with breast cancer mitigate their depression. However, at present, there are no studies that compare the effectiveness of all these types and deliveries of mindfulness-based interventions. Therefore, this protocol aims to conduct a systematic review and network meta-analysis to assess the effectiveness of various types and deliveries of mindfulness-based interventions in mitigating depression in patients with breast cancer. METHODS: This protocol is according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The electronic databases, including PubMed, Web of Science, the Cochrane Library, Embase, Google Scholar, The China National Knowledge Infrastructure and OpenGrey, will be comprehensively retrieved for related randomised controlled trials (RCTs) from inception to December 2023. Two reviewers will independently assess the risk of bias using the Cochrane Risk of Bias Tool for Randomised Trials 2.0 (RoB 2.0). The network meta-analysis will be performed using the STATA V.16.0, and the assessment of heterogeneity, inconsistency, publication bias, evidence quality, subgroup analyses and sensitivity analyses will be conducted. ETHICS AND DISSEMINATION: This protocol does not require approval from an ethics committee as it is based on previous research findings. The results will be disseminated via peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42024495996.

Isoastragaloside I attenuates cholestatic liver diseases by ameliorating liver injury, regulating bile acid metabolism and restoring intestinal barrier.

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestatic liver diseases (CLD) are liver disorders resulting from abnormal bile formation, secretion, and excretion from various causes. Due to the lack of suitable and safe medications, liver transplantation is the ultimate treatment for CLD patients. Isoastragaloside I (IAS I) is one of the main saponin found in Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge, which has been demonstrated to obviously alleviate CLD. Nevertheless, the IAS I's specific anti-CLD mechanism remains undecipherable. AIM OF THE STUDY: This study's purpose was to elucidate the protective consequence of IAS I on 0.1% 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet-induced CLD mice, and to reveal its potential mechanism. MATERIALS AND METHODS: In this study, mice with CLD that had been fed a 0.1% DDC diet were distributed two doses of IAS I (20 mg/kg, 50 mg/kg). The effects of IAS I on CLD models were investigated by assessing blood biochemistry, liver histology, and Hyp concentrations. We investigated markers of liver fibrosis and ductular reaction using immunohistochemistry, Western blot, and qRT-PCR. Liver inflammation indicators, arachidonic acid (ARA), and ω-3 fatty acid (FA) metabolites were also analyzed. Quantitative determination of 39 bile acids (BAs) in different organs employing UHPLC-Q-Exactive Orbitrap HRMS technology. Additionally, the H&E and Western blot analysis were used to evaluate differences in intestinal barrier function in DDC-induced mice before and after administering IAS I. RESULTS: After treatment with IAS I, serum biochemical indicators and liver hydroxyproline (Hyp) increased in a dose-dependent manner in CLD mice. The IAS I group showed significant improvement in indicators of liver fibrosis and ductular response, including as α-smooth muscle actin (α-SMA) and cytokeratin 19 (CK19), and transforming growth factor-ß (TGF-ß)/Smads signaling pathway. And inflammatory factors: F4/80, tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), ARA and ω-3 FA metabolites showed significant improvement following IAS I treatment. Moreover, IAS I significantly ameliorated liver tau-BAs levels, particularly TCA, THCA, THDCA, TCDCA, and TDCA contents, which were associated with enhanced expression of hepatic farnesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (Cyp7a1), and bile-salt export pump (BSEP). Furthermore, IAS I significantly improved pathological changes and protein expression related to intestinal barrier function, including zonula occludens protein 1 (ZO-1), Muc2, and Occludin. CONCLUSIONS: IAS I alleviated cholestatic liver injury, relieved inflammation, improved the altered tau-BAs metabolism and restored intestinal barrier function to protect against DDC-induced cholestatic liver diseases.

Comprehensive characterization of tumor therapeutic response with simultaneous mapping cell size, density, and transcytolemmal water exchange.

Early assessment of tumor therapeutic response is an important topic in precision medicine to optimize personalized treatment regimens and reduce unnecessary toxicity, cost, and delay. Although diffusion MRI (dMRI) has shown potential to address this need, its predictive accuracy is limited, likely due to its unspecific sensitivity to overall pathological changes. In this work, we propose a new quantitative dMRI-based method dubbed EXCHANGE (MRI of water Exchange, Confined and Hindered diffusion under Arbitrary Gradient waveform Encodings) for simultaneous mapping of cell size, cell density, and transcytolemmal water exchange. Such rich microstructural information comprehensively evaluates tumor pathologies at the cellular level. Validations using numerical simulations and in vitro cell experiments confirmed that the EXCHANGE method can accurately estimate mean cell size, density, and water exchange rate constants. The results from in vivo animal experiments show the potential of EXCHANGE for monitoring tumor treatment response. Finally, the EXCHANGE method was implemented in breast cancer patients with neoadjuvant chemotherapy, demonstrating its feasibility in assessing tumor therapeutic response in clinics. In summary, a new, quantitative dMRI-based EXCHANGE method was proposed to comprehensively characterize tumor microstructural properties at the cellular level, suggesting a unique means to monitor tumor treatment response in clinical practice.

Iron photocatalysis via Brønsted acid-unlocked ligand-to-metal charge transfer.

Reforming sustainable 3d-metal-based visible light catalytic platforms for inert bulk chemical activation is highly desirable. Herein, we demonstrate the use of a Brønsted acid to unlock robust and practical iron ligand-to-metal charge transfer (LMCT) photocatalysis for the activation of multifarious inert haloalkylcarboxylates (CnXmCOO-, X = F or Cl) to produce CnXm radicals. This process enables the fluoro-polyhaloalkylation of non-activated alkenes by combining easily available Selectfluor as a fluorine source. Valuable alkyl fluorides including potential drug molecules can be easily obtained through this protocol. Mechanistic studies indicate that the real light-harvesting species may derive from the in situ-assembly of Fe3+, CnXmCOO-, H+, and acetonitrile solvent, in which the Brønsted acid indeed increases the efficiency of LMCT between the iron center and CnXmCOO- via hydrogen-bond interactions. We anticipate that this Brønsted acid-unlocked iron LMCT platform would be an intriguing sustainable option to execute the activation of inert compounds.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy.

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

Fully Bio-Based 2,5-Furandicarboxylic Acid Polyester toward Plastics with Mechanically Robust, Excellent Gas Barrier and Fast Degradation.

Aliphatic-aromatic copolyesters offer a promising solution to mitigate plastic pollution, but high content of aliphatic units (>40 %) often suffer from diminished comprehensive performances. Poly(butylene oxalate-co-furandicarboxylate) (PBOF) copolyesters were synthesized by precisely controlling the oxalic acid content from 10 % to 60 %. Compared with commercial PBAT, the barrier properties of PBOF for H2O and O2 increased by more than 6 and 26 times, respectively. The introduction of the oxalic acid units allowed the water contact angle to be reduced from 82.5° to 62.9°. Superior hydrophilicity gave PBOF an excellent degradation performance within a 35-day hydrolysis. Interestingly, PBO20F and PBO30F also displayed obvious decrease of molecular weight during hydrolysis, with elastic modulus >1 GPa and tensile strength between 35-54 MPa. PBOF achieved the highest hydrolysis rates among the reported PBF-based copolyesters. The hydrolytic mechanism was further explored based on Fukui function analysis and density functional theory (DFT) calculation. Noncovalent analysis indicated that the water molecules formed hydrogen bonding interaction with adjacent ester groups and thus improved the reactivity of carbonyl carbon. PBOF not only meet the requirements of the high-performance packaging market but can quickly degrade after the end of their usage cycles, providing a new choice for green and environmental protection.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Association between polyunsaturated fatty acids and progression among patients with diabetic kidney disease.

AIMS: Diabetic kidney disease (DKD) is the major complication of diabetes mellitus (DM) and one of the leading causes of end-stage renal disease. Early detection and treatment are contributing to delay the progression of DKD. Dietary management has potential benefits for DKD, especially the intake of polyunsaturated fatty acids (PUFAs). However, there is a lack of sufficient evidence, so we aimed to explore the association between PUFAs intake and DKD progression. METHODS: In the National Heath and Nutrition Examination Survey (NHANES) between 2011-2018, a cross-sectional study was conducted among adults with T2DM. DKD was diagnosed with urine albumin to creatinine ratio (ACR) ≥ 30 mg/g or estimated glomerular filtration rate (eGFR) ＜60 ml/min/1.73 m2. Using Survey package of R to arrange the collected PUFAs intake data in order from small to large and divide them into four equal parts, which were expressed as Q1, Q2, Q3 and Q4 respectively. To investigate the association between PUFAs intake and DKD, a weighted univariate logistic regression analysis was performed and the odds ratio (OR) and 95% confidence interval (CI) were calculated for the association with DKD and PUFAs quartiles. RESULTS: The study involved 3287 participants with T2DM, including 2043 non-DKD and 1244 DKD patients. The results showed that the intake of PUFAs was a protective factor for DKD (p = 0.022), and with the increase of the PUFAs, renal function improved in DKD patients, the adjusted mean of eGFR and Scr changing from 57 (41, 86) in Q1 to 71 (55, 101) ml/min in Q4 (p 0.001), 103 (73, 131) in Q1 to 90 (68, 117) in Q4 (p = 0.031), respectively. CONCLUSION: Our study indicated that intake of more PUFAs may contribute to delay DKD progression, while different n-6/n-3 ratios need to be explored to protect the kidney.

Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner.

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

Detection of Treatment Response in Triple-Negative Breast Tumors to Paclitaxel Using MRI Cell Size Imaging.

BACKGROUND: Breast cancer treatment response evaluation using the response evaluation criteria in solid tumors (RECIST) guidelines, based on tumor volume changes, has limitations, prompting interest in novel imaging markers for accurate therapeutic effect determination. PURPOSE: To use MRI-measured cell size as a new imaging biomarker for assessing chemotherapy response in breast cancer. STUDY TYPE: Longitudinal; animal model. STUDY POPULATION: Triple-negative human breast cancer cell (MDA-MB-231) pellets (4 groups, n = 7) treated with dimethyl sulfoxide (DMSO) or 10 nM of paclitaxel for 24, 48, and 96 hours, and 29 mice with MDA-MB-231 tumors in right hind limbs treated with paclitaxel (n = 16) or DMSO (n = 13) twice weekly for 3 weeks. FIELD STRENGTH/SEQUENCE: Oscillating gradient spin echo and pulsed gradient spin echo sequences at 4.7 T. ASSESSMENT: MDA-MB-231 cells were analyzed using flowcytometry and light microscopy to assess cell cycle phases and cell size distribution. MDA-MB-231 cell pellets were MR imaged. Mice were imaged weekly, with 9, 6, and 14 being sacrificed for histology after MRI at weeks 1, 2, and 3, respectively. Microstructural parameters of tumors/cell pellets were derived by fitting diffusion MRI data to a biophysical model. STATISTICAL TESTS: One-way ANOVA compared cell sizes and MR-derived parameters between treated and control samples. Repeated measures 2-way ANOVA with Bonferroni post-tests compared temporal changes in MR-derived parameters. A P-value <0.05 was considered statistically significant. RESULTS: In vitro experiments showed that the mean MR-derived cell sizes of paclitaxel-treated cells increased significantly with a 24-hours treatment and decreased (P = 0.06) with a 96-hour treatment. For in vivo xenograft experiments, the paclitaxel-treated tumors showed significant decreases in cell size at later weeks. MRI observations were supported by flowcytometry, light microscopy, and histology. DATA CONCLUSIONS: MR-derived cell size may characterize the cell shrinkage during treatment-induced apoptosis, and may potentially provide new insights into the assessment of therapeutic response. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 4.

Numerical Simulation Investigation on Natural Gas Leakage under Different Kitchen Layouts in China.

The safety of an open kitchen is a controversial topic in China. In this study, natural gas leakage and ventilation processes under an open kitchen layout and closed kitchen layout are simulated by CFD. The evolution of a hazardous gas cloud and the triggering behaviors of alarms are analyzed and discussed. For closing all windows in the leakage process, the state of the partition door is a major factor. A closed kitchen layout with a closing partition door performs best in confining a hazardous gas cloud. At this point, it is difficult for a hazardous gas cloud to appear in the living area. With the partition door open, the gas cloud develops rapidly. For opening windows in the leakage process, a large scale hazardous gas cloud is not able to form under all layouts. For alarm-triggering behaviors, a closed kitchen layout when closing the partition door also performs best. When opening the partition door, alarms cannot trigger stably under all layouts. For the ventilation process, hazardous gas cloud dissipation under an open kitchen layout is slightly faster than the closed kitchen layout. Under a weak convection effect, there is a transition stage which delays the time point for exhausting leaked gas. Based on the analysis, some recommendations for accident prevention are proposed. Residents should try to use closed kitchens and close partition doors when not cooking. If open kitchens are used, multiple alarms with lower trigger values should be installed. It is better to choose a ceiling type for gas alarms. The windows of the house are recommended to select two layers type. Higher layers can open during the ventilation process to accelerate the exhaust of leaked gas. These recommendations provide a reference for preventing fires and explosions.

Prostaglandin F2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F2α-dependent and F2α-independent mechanism.

BACKGROUND: Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F2α synthase (PGF2α) (PGFS), an enzyme that catalyzes the production of PGF2α, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear. AIM: To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC. METHODS: The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products. RESULTS: Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment in vitro and in vivo. The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF2α reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF2α-independent manner. PGF2α exerts its protective effect against DNA damage by reducing ROS levels. CONCLUSION: PGFS promotes resistance to Oxa in CRC via both PGF2α-dependent and PGF2α-independent mechanisms.

Correction: The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways.

[This corrects the article DOI: 10.1158/2767-9764.CRC-21-0022.][This corrects the article DOI: 10.1158/2767-9764.CRC-21-0022.].

Molecular subtypes of lung adenocarcinoma patients for prognosis and therapeutic response prediction with machine learning on 13 programmed cell death patterns.

BACKGROUND: Lung adenocarcinoma (LUAD) seriously threatens people's health worldwide. Programmed cell death (PCD) plays a critical role in regulating LUAD growth and metastasis as well as in therapeutic response. However, currently, there is a lack of integrative analysis of PCD-related signatures of LUAD for accurate prediction of prognosis and therapeutic response. METHODS: The bulk transcriptome and clinical information of LUAD were obtained from TCGA and GEO databases. A total of 1382 genes involved in regulating 13 various PCD patterns (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, netotic cell death, entotic cell death, lysosome-dependent cell death, parthanatos, autophagy-dependent cell death, oxeiptosis, alkaliptosis and disulfidptosis) were included in the study. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were performed to identify PCD-associated differential expression genes (DEGs). An unsupervised consensus clustering algorithm was used to explore the potential subtypes of LUAD based on the expression profiles of PCD-associated DEGs. Univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression, Random Forest (RF) analysis and stepwise multivariate Cox analysis were performed to construct a prognostic gene signature. The "oncoPredict" algorithm was utilized for drug-sensitive analysis. GSVA and GSEA were utilized to perform function enrichment analysis. MCPcounter, quanTIseq, Xcell and ssGSEA algorithms were used for tumor immune microenvironment analysis. A nomogram incorporating PCDI and clinicopathological characteristics was established to predict the prognosis of LUAD patients. RESULTS: Forty PCD-associated DEGs related to LUAD were obtained by WGCNA analysis and differential expression analysis, followed by unsupervised clustering to identify two LUAD molecular subtypes. A programmed cell death index (PCDI) with a five-gene signature was established by machine learning algorithms. LUAD patients were then divided into a high PCDI group and a low PCDI group using the median PCDI as a cutoff. Survival and therapeutic analysis revealed that the high PCDI group had a poor prognosis and was more sensitive to targeted drugs but less sensitive to immunotherapy compared to the low PCDI group. Further enrichment analysis showed that B cell-related pathways were significantly downregulated in the high PCDI group. Accordingly, the decreased tumor immune cell infiltration and the lower tumor tertiary lymphoid structure (TLS) scores were also found in the high PCDI group. Finally, a nomogram with reliable predictive performance PCDI was constructed by incorporating PCDI and clinicopathological characteristics, and a user-friendly online website was established for clinical reference ( https://nomogramiv.shinyapps.io/NomogramPCDI/ ). CONCLUSION: We performed the first comprehensive analysis of the clinical relevance of genes regulating 13 PCD patterns in LUAD and identified two LUAD molecular subtypes with distinct PCD-related gene signature which indicated differential prognosis and treatment sensitivity. Our study provided a new index to predict the efficacy of therapeutic interventions and the prognosis of LUAD patients for guiding personalized treatments.

USP35 promotes cell proliferation and chemotherapeutic resistance through stabilizing FUCA1 in colorectal cancer.

Ubiquitin-specific-processing proteases 35 (USP35) is an under-characterized deubiquitinase and its role in colorectal cancer (CRC) remains unclear. Here, we focus on delineating the impact of USP35 on CRC cell proliferation and chemo-resistance, as well as the possible regulatory mechanism. By examining the genomic database and clinical samples, we found that USP35 was overexpressed in CRC. Further functional studies showed that enhanced USP35 expression promoted CRC cell proliferation and resistance to oxaliplatin (OXA) and 5-fluorouracil (5-FU), whereas USP35 depletion impeded cell proliferation and sensitized cells to OXA and 5-FU treatments. Then, to explore the possible mechanism underlying USP35-triggered cellular responses, we performed co-immunoprecipitation (co-IP) followed by mass spectrometry (MS) analysis and identified α-L-fucosidase 1 (FUCA1) as a direct deubiquitiation target of USP35. Importantly, we demonstrated that FUCA1 was an essential mediator for USP35-induced cell proliferation and chemo-resistance in vitro and in vivo. Finally, we observed that nucleotide excision repair (NER) components (e.g., XPC, XPA, ERCC1) were up-regulated by USP35-FUCA1 axis, indicating a potential mechanism for USP35-FUCA1-mediated platinum resistance in CRC. Together, our results for the first time explored the role and important mechanism of USP35 in CRC cell proliferation and chemotherapeutic response, providing a rationale for USP35-FUCA1-targeted therapy in CRC.

Diffusion time dependency of extracellular diffusion.

PURPOSE: To quantify the variations of the power-law dependences on diffusion time t or gradient frequency f $$ f $$ of extracellular water diffusion measured by diffusion MRI (dMRI). METHODS: Model cellular systems containing only extracellular water were used to investigate the t / f $$ t/f $$ dependence of D ex $$ {D}_{ex} $$ , the extracellular diffusion coefficient. Computer simulations used a randomly packed tissue model with realistic intracellular volume fractions and cell sizes. DMRI measurements were performed on samples consisting of liposomes containing heavy water(D2 O, deuterium oxide) dispersed in regular water (H2 O). D ex $$ {D}_{ex} $$ was obtained over a broad t $$ t $$ range (∼1-1000 ms) and then fit power-law equations D ex ( t ) = D const + const · t - ϑ t $$ {D}_{ex}(t)={D}_{\mathrm{const}}+\mathrm{const}\cdotp {t}^{-{\vartheta}_t} $$ and D ex ( f ) = D const + const · f ϑ f $$ {D}_{ex}(f)={D}_{\mathrm{const}}+\mathrm{const}\cdotp {f}^{\vartheta_f} $$ . RESULTS: Both simulated and experimental results suggest that no single power-law adequately describes the behavior of D ex $$ {D}_{ex} $$ over the range of diffusion times of most interest in practical dMRI. Previous theoretical predictions are accurate over only limited t $$ t $$ ranges; for example, θ t = θ f = - 1 2 $$ {\theta}_t={\theta}_f=-\frac{1}{2} $$ is valid only for short times, whereas θ t = 1 $$ {\theta}_t=1 $$ or θ f = 3 2 $$ {\theta}_f=\frac{3}{2} $$ is valid only for long times but cannot describe other ranges simultaneously. For the specific t $$ t $$ range of 5-70 ms used in typical human dMRI measurements, θ t = θ f = 1 $$ {\theta}_t={\theta}_f=1 $$ matches the data well empirically. CONCLUSION: The optimal power-law fit of extracellular diffusion varies with diffusion time. The dependency obtained at short or long t $$ t $$ limits cannot be applied to typical dMRI measurements in human cancer or liver. It is essential to determine the appropriate diffusion time range when modeling extracellular diffusion in dMRI-based quantitative microstructural imaging.

A Cell-Penetrating Peptide Modified Cu2-xSe/Au Nanohybrid with Enhanced Efficacy for Combined Radio-Photothermal Therapy.

Radiotherapy (RT) is one of the main clinical therapeutic strategies against cancer. Currently, multiple radiosensitizers aimed at enhancing X-ray absorption in cancer tissues have been developed, while limitations still exist for their further applications, such as poor cellular uptake, hypoxia-induced radioresistance, and unavoidable damage to adjacent normal body tissues. In order to address these problems, a cell-penetrating TAT peptide (YGRKKRRQRRRC)-modified nanohybrid was constructed by doping high-Z element Au in hollow semiconductor Cu2-xSe nanoparticles for combined RT and photothermal therapy (PTT) against breast cancer. The obtained Cu2-xSe nanoparticles possessed excellent radiosensitizing properties based on their particular band structures, and high photothermal conversion efficiency beneficial for tumor ablation and promoting RT efficacy. Further doping high-Z element Au deposited more high-energy radiation for better radiosensitizing performance. Conjugation of TAT peptides outside the constructed Cu2-xSe/Au nanoparticles facilitated their cellular uptake, thus reducing overdosage-induced side effects. This prepared multifunctional nanohybrid showed powerful suppression effects towards breast cancer, both in vitro and in vivo via integrating enhanced cell penetration and uptake, and combined RT/PTT strategies.

Versatile Red Blood Cells for Triple-Negative Breast Cancer Treatment via Stepwise Photoactivations.

Phototherapies have many advantages for triple-negative breast cancer (TNBC) treatment. However, their effects are often limited by short blood circulation time, poor tumor selectivity and weak penetration of phototherapeutic agents, and tumor hypoxia. For overcoming these limitations, a versatile biomimetic system is developed based on red blood cells (RBCs). Photothermal agent new indocyanine green (IR820) is conjugated with the cell/tissue-penetrating TAT peptide and further efficiently encapsulated into the intact RBCs by crossing cell membranes to realize the long blood circulation. Meanwhile, cyclic RGD peptide (cRGD) is linked to the surfaces of RBCs through phospholipid insertion to obtain tumor vessel-targeting ability. Photosensitizer temoporfin (mTHPC) is next loaded into the membranes of RBCs by spontaneous transferring. The acquired biomimetic system (cRGD-RBC@mTHPC/TAT-IR820) exhibits potent photodynamic performance upon 652 nm laser irradiation with the facilitation of oxyhemoglobin, which could not only trigger TAT-IR820 release but also destroy tumor vessels. TAT-IR820 penetrates deeply into tumor tissue via the mediation of TAT peptide, exerting greatly promoted photothermal ablation against TNBC upon 808 nm laser irradiation. In situ generated tumor antigens further induce robust immune responses to suppress TNBC recurrence and metastasis. In summary, this study provides a versatile biomimetic system for comprehensive TNBC treatment via stepwise photodynamic and photothermal activations.

Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway.

When pathological hypertrophy progresses to heart failure (HF), the prognosis is often very poor. Therefore, it is crucial to find new and effective intervention targets. Here, myocardium-specific Trim44 knockout rats were generated using CRISPR-Cas9 technology. Cardiac phenotypic observations revealed that Trim44 knockout affected cardiac morphology at baseline. Rats with Trim44 deficiency exhibited resistance to cardiac pathological changes in response to stimulation via isoproterenol (ISO) treatment, including improvement of cardiac remodeling and dysfunction by morphological and functional observations, reduced myocardial fibrosis and reduced expression of molecular markers of cardiac stress. Furthermore, signal transduction validation associated with growth and hypertrophy development in vivo and in vitro demonstrated that Trim44 deficiency inhibited the activation of signaling pathways involved in myocardial hypertrophy, especially response to pathological stress. In conclusion, the present study indicates that Trim44 knockout attenuates ISO-induced pathological cardiac remodeling through blocking the AKT/mTOR/GSK3ß/P70S6K signaling pathway. This is the first study to demonstrate the function and importance of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy and HF.

Cellular Prion Protein Attenuates OGD/R-Induced Damage by Skewing Microglia toward an Anti-inflammatory State via Enhanced and Prolonged Activation of Autophagy.

Modulation of microglial pro/anti-inflammatory states and autophagy are promising new therapies for ischemic stroke, but the underlying mechanisms remain largely unexplored. The objective of the study is to determine the intrinsic role of PrPC (cellular prion protein) in the regulation of microglial inflammatory states and autophagy in ischemic stroke. PrPC was expressed in murine microglia, and an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established in microglia of different PRNP genotypes. During reperfusion following OGD, wild-type (WT) microglia had significantly increased pro/anti-inflammatory microglial percentages and related cytokine [interleukin [IL]-6, IL-10, IL-4, tumor necrosis factor, and interferon-gamma] release at reperfusion after 48 or 72 h. WT microglia also showed greater accumulation of the autophagy markers LC3B-II/I (microtubule-associated protein B-light chain 3), but not of p62 or LAMP1 (lysosome-associated membrane protein) at reperfusion after 24 h and 48 h. Inhibition of autophagy using 3-methyladenine or bafilomycin A1 aggravated the OGD/R-induced pro-inflammatory state, and the effect of 3-methyladenine was significantly stronger than that of bafilomycin A1. Concomitantly, PRNP knockout shortened the accumulation of LC3B-II/I, suppressed microglial anti-inflammatory states, and further aggravated the pro-inflammatory states. Conversely, PRNP overexpression had the opposite effects. Bafilomycin A1 reversed the effect of PrPC on microglial inflammatory state transformation. Moreover, microglia with PRNP overexpression exhibited higher levels of LAMP1 expression in the control and OGD/R groups and delayed the OGD/R-induced decrease of LAMP1 to reperfusion after 48 h. PrPC attenuates OGD/R-induced damage by skewing microglia toward an anti-inflammatory state via enhanced and prolonged activation of autophagy.