A second-generation M1-polarized CAR macrophage with antitumor efficacy.

Chimeric antigen receptor (CAR) T cell therapies have successfully treated hematological malignancies. Macrophages have also gained attention as an immunotherapy owing to their immunomodulatory capacity and ability to infiltrate solid tumors and phagocytize tumor cells. The first-generation CD3ζ-based CAR-macrophages could phagocytose tumor cells in an antigen-dependent manner. Here we engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs resulting in a markedly enhanced antitumor effect over first-generation CAR-macrophages. Moreover, the design of a tandem CD3ζ-TIR dual signaling CAR endows iMACs with both target engulfment capacity and antigen-dependent M1 polarization and M2 resistance in a nuclear factor kappa B (NF-κB)-dependent manner, as well as the capacity to modulate the tumor microenvironment. We also outline a mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we provide a second-generation CAR-iMAC with an ability for orthogonal phagocytosis and polarization and superior antitumor functions in treating solid tumors relative to first-generation CAR-macrophages.

Structure and topography of the synaptic V-ATPase-synaptophysin complex.

Synaptic vesicles are organelles with a precisely defined protein and lipid composition1,2, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown. Here, we discovered a well-defined interface between the synaptic vesicle V-ATPase and synaptophysin by in situ cryo-electron tomography and single particle cryo-electron microscopy of functional synaptic vesicles isolated from mouse brains3. The synaptic vesicle V-ATPase is an ATP-dependent proton pump that establishes the protein gradient across the synaptic vesicle, which in turn drives the uptake of neurotransmitters4,5. Synaptophysin6 and its paralogs synaptoporin7 and synaptogyrin8 belong to a family of abundant synaptic vesicle proteins whose function is still unclear. We performed structural and functional studies of synaptophysin knockout mice, confirming the identity of synaptophysin as an interaction partner with the V-ATPase. Although there is little change in the conformation of the V-ATPase upon interaction with synaptophysin, the presence of synaptophysin in synaptic vesicles profoundly affects the copy number of V-ATPases. This effect on the topography of synaptic vesicles suggests that synaptophysin assists in their biogenesis. In support of this model, we observed that synaptophysin knockout mice exhibit severe seizure susceptibility, suggesting an imbalance of neurotransmitter release as a physiological consequence of the absence of synaptophysin.

Olfactory sensory experience regulates gliomagenesis via neuronal IGF1.

Animals constantly receive various sensory stimuli, such as odours, sounds, light and touch, from the surrounding environment. These sensory inputs are essential for animals to search for food and avoid predators, but they also affect their physiological status, and may cause diseases such as cancer. Malignant gliomas-the most lethal form of brain tumour1-are known to intimately communicate with neurons at the cellular level2,3. However, it remains unclear whether external sensory stimuli can directly affect the development of malignant glioma under normal living conditions. Here we show that olfaction can directly regulate gliomagenesis. In an autochthonous mouse model that recapitulates adult gliomagenesis4-6 originating in oligodendrocyte precursor cells (OPCs), gliomas preferentially emerge in the olfactory bulb-the first relay of brain olfactory circuitry. Manipulating the activity of olfactory receptor neurons (ORNs) affects the development of glioma. Mechanistically, olfaction excites mitral and tufted (M/T) cells, which receive sensory information from ORNs and release insulin-like growth factor 1 (IGF1) in an activity-dependent manner. Specific knockout of Igf1 in M/T cells suppresses gliomagenesis. In addition, knocking out the IGF1 receptor in pre-cancerous mutant OPCs abolishes the ORN-activity-dependent mitogenic effects. Our findings establish a link between sensory experience and gliomagenesis through their corresponding sensory neuronal circuits.

MRI-based tumor shrinkage patterns after early neoadjuvant therapy in breast cancer: correlation with molecular subtypes and pathological response after therapy.

BACKGROUND: MRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze the relationship between TSP after early NAT and pathological response after therapy in different molecular subtypes. METHODS: We prospectively enrolled participants with invasive ductal breast cancers who received NAT and performed pretreatment DCE-MRI from September 2020 to August 2022. Early-stage MRIs were performed after the first (1st-MRI) and/or second (2nd-MRI) cycle of NAT. Tumor shrinkage patterns were categorized into four groups: concentric shrinkage, diffuse decrease (DD), decrease of intensity only (DIO), and stable disease (SD). Logistic regression analysis was performed to identify independent variables associated with pathologic complete response (pCR), and stratified analysis according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. RESULTS: 344 participants (mean age: 50 years, 113/345 [33%] pCR) with 345 tumors (1 bilateral) had evaluable 1st-MRI or 2nd-MRI to comprise the primary analysis cohort, of which 244 participants with 245 tumors had evaluable 1st-MRI (82/245 [33%] pCR) and 206 participants with 207 tumors had evaluable 2nd-MRI (69/207 [33%] pCR) to comprise the 1st- and 2nd-timepoint subgroup analysis cohorts, respectively. In the primary analysis, multivariate analysis showed that early DD pattern (OR = 12.08; 95% CI 3.34-43.75; p < 0.001) predicted pCR independently of the change in tumor size (OR = 1.37; 95% CI 0.94-2.01; p = 0.106) in HR+/HER2- subtype, and the change in tumor size was a strong pCR predictor in HER2+ (OR = 1.61; 95% CI 1.22-2.13; p = 0.001) and triple-negative breast cancer (TNBC, OR = 1.61; 95% CI 1.22-2.11; p = 0.001). Compared with the change in tumor size, the SD pattern achieved a higher negative predictive value in HER2+ and TNBC. The statistical significance of complete 1st-timepoint subgroup analysis was consistent with the primary analysis. CONCLUSION: The diffuse decrease pattern in HR+/HER2- subtype and stable disease in HER2+ and TNBC after early NAT could serve as additional straightforward and comprehensible indicators of treatment response. TRIAL REGISTRATION: Trial registration at https://www.chictr.org.cn/ . REGISTRATION NUMBER: ChiCTR2000038578, registered September 24, 2020.

A transformation clustering algorithm and its application in polyribosomes structural profiling.

Improvements in cryo-electron tomography sample preparation, electron-microscopy instrumentations, and image processing algorithms have advanced the structural analysis of macromolecules in situ. Beyond such analyses of individual macromolecules, the study of their interactions with functionally related neighbors in crowded cellular habitats, i.e. 'molecular sociology', is of fundamental importance in biology. Here we present a NEighboring Molecule TOpology Clustering (NEMO-TOC) algorithm. We optimized this algorithm for the detection and profiling of polyribosomes, which play both constitutive and regulatory roles in gene expression. Our results suggest a model where polysomes are formed by connecting multiple nonstochastic blocks, in which translation is likely synchronized.

Improvements in cryo-electron tomography sample preparation, electron-microscopy instrumentations, and image processing algorithms have advanced the structural analysis of macromolecules in situ. Beyond such analyses of individual macromolecules, the study of their interactions with functionally related neighbors in crowded cellular habitats, i.e. "molecular sociology", is of fundamental importance in biology. Here we present a NEighboring Molecule TOpology Clustering (NEMO-TOC) algorithm. We optimized this algorithm for the detection and profiling of polyribosomes, which play both constitutive and regulatory roles in gene expression. Our results suggest a model where polysomes are formed by connecting multiple nonstochastic blocks, in which translation is likely synchronized.

The miR-29b/Matrix Metalloproteinase 2 Axis Regulates Transdifferentiation and Calcification of Vascular Smooth Muscle Cells in a Calcified Environment.

BACKGROUND: Vascular calcification (VC) is a common pathological lesion that promotes progress and mortality in cardiovascular disease. Vascular smooth muscle cells (VSMCs) acquiring an osteogenic phenotype facilitate VC occurrence and development. We recently reported that miR-29b-3p directly regulates the expression of matrix metalloproteinase 2 (MMP2). Herein, we test whether miR-29b-3p functions in the phenotypic transition and calcification in a calcified environment. METHODS AND RESULTS: VSMC calcification in vitro was induced with calcification medium containing ß-glycerophosphoric acid or high calcium. MiR-29b-3p expression in VSMCs tended to decrease during culturing in calcification medium. MiR-29b-3p overexpression ameliorated VSMC calcification, whereas miR-29b-3p knockdown exacerbated VSMC calcification. Furthermore, ectopic expression of miR-29b-3p inhibited the expression of osteogenic markers and MMP2 (a known target gene of miR-29b-3p). By contrast, miR-29b-3p deficiency facilitated VSMC osteogenesis differentiation and upregulated MMP2 expression. CONCLUSION: Our research suggests that miR-29b-3p regulates VSMC calcification and osteogenesis differentiation, at least in part, by targeting MMP2. Regulation of miR-29b-3p expression is therefore a potential therapeutic target for VSMC calcification.

The miR-182/SORT1 axis regulates vascular smooth muscle cell calcification in vitro and in vivo.

Arterial calcification is a common feature of cardiovascular disease. Sortilin is involved in the development of atherosclerosis, but the specific mechanism is unclear. In this study, we established calcification models in vivo and in vitro by using vitamin D3 and ß-glycerophosphate, respectively. In vivo, the expression of SORT1 was up-regulated and the expression of miR-182 was down-regulated in calcified arterial tissues. Meanwhile there was a negative correlation between SORT1 expression and miR-182 levels. In vitro, downregulating SORT1 expression using shRNA inhibited ß-glycerophosphoric induced vascular smooth muscle cells (VSMCs) calcification. Moreover, reduced sortilin levels followed transfection of miR-182 mimics, whereas there was a significant increase in sortilin levels after transfection of miR-182 inhibitors. A luciferase reporter assay confirmed that SORT1 is the direct target of miR-182. Our study suggests that SORT1 plays a vital role in the development of arterial calcification and is regulated by miR-182.

Metformin Inhibit Lung Cancer Cell Growth and Invasion in Vitro as Well as Tumor Formation in Vivo Partially by Activating PP2A.

BACKGROUND The aim of this study was to investigate whether PP2A activation is involved in the anti-cancer activity of metformin. MATERIAL AND METHODS A549 and H1651 human lung cancer cells were constructed with stable a4 overexpression (O/E α4) or knockdown of PP2A catalytic subunit A/B(sh-PP2Ac). Influences of okadaic acid (OA) treatment, O/E α4 or sh-PP2Ac on metformin treated cells were investigated by cell viability, proliferation, apoptosis, and Transwell invasion assay in vitro. Protein expression levels of Bax, Bcl-2, Myc, and Akt as well as serine phosphorylation level of Bax, Myc, and Akt were examined by western blot. For in vivo assays, wild type (WT) or modified A549 cells were subcutaneously injected in nude mice, and metformin treatment on these xenografted tumors were assayed by tumor formation assay and western blot detecting cell proliferation marker PCNA (proliferating cell nuclear antigen) as well as protein expression level and serine phosphorylation level of Akt and Myc. RESULTS Metformin treatment significantly reduced A549 or H1651 cell growth and invasive capacity in vitro as well as Ser184 phosphorylation of Bax, Ser62 phosphorylation of Myc, and Ser473 phosphorylation of Akt, all of which could be partially attenuated by OA treatment, O/E α4 or sh-PP2Ac. Metformin treatment also significantly reduced tumor formation in vivo as well as protein expression of PCNA, Akt, Myc, and serine phosphorylation of the latter 2, which can be partially blocked by O/E α4 or sh-PP2Ac. CONCLUSIONS Metformin reduced lung cancer cell growth and invasion in vitro as well as tumor formation in vivo partially by activating PP2A.

Liquid Crystals under Confinement in Submicrometer Capsules.

Liquid crystal (LC) ordering and phase transition behavior under confined conditions have attracted extensive attention and enabled many applications. However, the ordering and phase transition behavior of LCs in submicrometer capsules have seldom been studied, primarily due to the lack of proper capsulizing and visualization approaches to such small LC microcapsules. Herein, we achieve submicrometer LC capsules with the sizes down to 100 nm by using emulsion-based interfacial sol-gel reaction. The behavior of LCs under the submicrometer confinement conditions is investigated while the sizes and chemical composition of the microcapsule shell surface are tuned in a controllable way. The phase transition temperatures of LCs in the submicrometer capsules shift from those of bulk LCs due to the surface-induced ordering of LCs under the strong confinement conditions, which causes formation of topological defects and alters the order parameter. Using nonlinear optical imaging technology, we explore the structures of director field of LCs that arise as a result of the competition between the surface boundary conditions and LC elasticity. The results show that the nanoscale encapsulation can significantly influence the structural configurations of the director and phase transitions of LCs under various confinement conditions.

Doxycycline affects gene expression profiles in aortic tissues in a rat model of vascular calcification.

Vitamin D3-induced vascular calcification (VC) in rats shares many phenotypical similarities with calcification occurring in human atherosclerosis, diabetes mellitus and chronic kidney disease, thereby it is a reliable model for identifying chemopreventive agents. Doxycycline has been shown to effectively attenuated VC. This study aimed to explore the effects of doxycycline on gene expression profiles in VC rats. The model of VC in rats was established by subcutaneous injection of vitamin D3 for 3days. Doxycycline at 120mgkg-1day-1 was given via subcutaneous injection for 14days. Rat pathological changes, calcium deposition and calcium content in aortic tissues were measured by Hematoxylin-eosin, von Kossa staining and colorimetry, respectively. The gene change profile of aortic tissues after doxycycline treatment was assessed by Gene Microarray analysis using the Agilent Whole Rat Genome Oligo Microarray. The results showed that doxycycline significantly decreased the deposition of calcium, reduced the relative calcification area and alleviated pathological injury in aortic tissues. In addition, doxycycline treatment altered 88 gene expressions compared with untreated VD group. Of these, 61 genes were down-regulated and 27 genes were up-regulated. The functions of differentially expressed (DE) genes were involved in neutrophil chemotaxis, chronic inflammatory response, negative regulation of apoptotic process, cellular response to mechanical stimulus and immune response, etc. In conclusions, this study might provide the potential novel insights into the molecular mechanisms of doxycycline on VC.

Frozen tissue preparation for high-resolution multiplex histological analyses of human brain specimens.

The availability of a comprehensive tissue library is essential for elucidating the function and pathology of human brains. Considering the irreplaceable status of the formalin-fixation-paraffin-embedding (FFPE) preparation in routine pathology and the advantage of ultra-low temperature to preserve nucleic acids and proteins for multi-omics studies, these methods have become major modalities for the construction of brain tissue libraries. Nevertheless, the use of FFPE and snap-frozen samples is limited in high-resolution histological analyses because the preparation destroys tissue integrity and/or many important cellular markers. To overcome these limitations, we detailed a protocol to prepare and analyze frozen human brain samples that is particularly suitable for high-resolution multiplex immunohistological studies. As an alternative, we offered an optimized procedure to rescue snap-frozen tissues for the same purpose. Importantly, we provided a guideline to construct libraries of frozen tissue with minimal effort, cost and space. Taking advantage of this new tissue preparation modality to nicely preserve the cellular information that was otherwise damaged using conventional methods and to effectively remove tissue autofluorescence, we described the high-resolution landscape of the cellular composition in both lower-grade gliomas and glioblastoma multiforme samples. Our work showcases the great value of fixed frozen tissue in understanding the cellular mechanisms of CNS functions and abnormalities.

The effect of process parameters and microstructural changes on a new convenience food - quick-frozen paste-coated mushrooms (Agaricus bisporus).

The technology of quick-freezing paste-coated mushrooms (Agaricus bisporus) was studied and optimized. The best microwave pretreatment condition for 1 cm slices, regarding color protection, was 5.4 W/g, for 55, 55-60 and 60 s for mushrooms with 3, 4 and 5 cm diameter caps respectively. For a batch of paste (668.2-1034.6 g), the process parameters considered were oil content (46.6-63.4 g), water content (381-562.6 g) and flour content (166-334 g) with a constant additional content of 30 g starch, 9 g baking powder, 2.6 g carrageenan, 30 g salt and 3 g pepper. These parameters were investigated using response surface methodology (RSM) with a central composite design. The optimal levels of the major paste components were 300 g flour, 432.5 g water and 50 g oil. The freezing time and sensory acceptability for paste-coated Agaricus bisporus(PCAB) under the optimized conditions were 7.49 min and 6.2 respectively. The freezing curves of PCAB were established at different temperatures and the freezing rates were calculated to find the freezing characteristics. In addition, the cell structure of PCAB, frozen at -75 °C, the lowest freezing temperature, and studied using transmission electron microscopy, was similar in quality to that of fresh Agaricus bisporus. The results suggested that Agaricus bisporus can be quick-frozen with a paste coating to produce an acceptable and nutritious convenience food.

Value Evaluation of Quantitative Aspergillus fumigatus-Specific IgG Antibody Test in the Diagnosis of Non-neutropenic Invasive Pulmonary Aspergillosis.

Background: The role of Aspergillus-specific IgG antibody test in the diagnosis of non-neutropenic invasive pulmonary aspergillosis (IPA) is still uncertain, and related studies are also limited. Purpose: This study aims to evaluate the quantitative test value of Aspergillus fumigatus-specific IgG antibody in non-neutropenic IPA, which could provide additional evidence for related clinical diagnosis. Methods: This prospective study collected clinical data of suspected IPA patients from January, 2020 to December, 2022, and patients were divided into two groups, IPA and non-IPA. The study analyzed clinical characteristics and diagnostic value of Aspergillus-specific IgG antibody test, using the receiver operating characteristic (ROC) curve to evaluate diagnostic efficacy. Results: The study enrolled 59 IPA cases and 68 non-IPA cases, the average admission age of IPA group was 63.2±9.6 (33-79), and the gender ratio (male:female) of IPA group was 42:17. The proportion of patients with history of smoking and COPD were higher in IPA group (59.3% vs 39.7%, P=0.027; 33.9% vs 14.7%, P =0.011, respectively). The level of Aspergillus fumigatus-specific IgG antibody in IPA group was significantly higher than non-IPA group (202.1±167.0 vs 62.6±58.0, P<0.001). The area under the ROC curve was 0.799 (95%CI: 0.718, 0.865 P<0.001), and the cut-off with best diagnostic efficacy was 91 AU/mL. Conclusion: Immunological test plays an important role in the diagnosis of pulmonary aspergillosis, and Aspergillus-specific IgG antibody test has the good diagnostic value in non-neutropenic IPA.

Endovenous radiofrequency ablation vs laser ablation in patients with lower extremity varicose veins: A meta-analysis.

BACKGROUND: Endovenous radiofrequency ablation (RFA) and laser ablation (LA) have been commonly used for treating lower extremity varicose veins (LEVVs). Their therapeutic effects have been widely recognized compared with conventional surgery. However, there have been some controversies regarding the choice between RFA and LA. The objective of our study was to conduct a systematic review and meta-analysis comparing the early and long-term outcomes of RFA and LA. METHODS: A comprehensive search was performed in the PubMed, Embase, and Cochrane databases to identify relevant literature on endovenous thermal ablation for primary LEVV up until June 2023. Randomized controlled trials, cohort studies, and case-control studies involving RFA and LA for LEVV treatment were included. The primary endpoints were the occlusion rate of the great saphenous vein (GSV) and occurrence of venous thrombotic events. Secondary outcomes included nerve injury, hyperpigmentation, burns, recurrence of VVs, postoperative pain, and phlebitis. Data were analyzed using Review Manager 5.3 software. RESULTS: A total of 29 studies met the inclusion criteria, consisting of 16 randomized controlled trials and 13 cohort studies. At 1 month, the occlusion rates of GSV were 98.35% for RFA and 98.04% for LA, whereas at 1 year, the rates were 93.13% for RFA and 94.18% for LA. Subgroup analyses revealed that RFA had higher GSV occlusion rates at 1 year since 2016 (93.27% vs 91.24%; odds ratio [OR], 1.35; 95% confidence interval [CI], 1.0-1.83; P = .05). The incidence of postoperative venous thrombotic events was 0.78% for RFA and 0.87% for LA at 1 month (OR, 1.46; 95% CI, 0.77-2.74; P = .24). RFA showed a reduced risk of burns and ecchymosis (OR, 0.65; 95% CI, 0.48-0.87; P = .005), postprocedural pain (mean difference, -0.85; 95% CI, -1.06 to -0.64; P < .001), recurrence of VVs (OR, 0.58; 95% CI, 0.36-0.92; P = .02), and paresthesia since 2016 (OR, 0.42; 95% CI, 0.19-0.91; P = .03), but an increased risk of skin pigmentation (OR, 1.75; 95% CI, 1.06-2.9; P = .03) compared with LA therapy. The rate of phlebitis was similar between RFA and LA (OR, 0.87; 95% CI, 0.33-2.27; P = .78). CONCLUSIONS: RFA and LA demonstrated similar efficacy in terms of early and long-term occlusion rates of GSV and the incidence of thrombotic and phlebitis complications. However, since 2016, RFA has shown higher GSV occlusion rates compared with LA. Furthermore, RFA was associated with fewer complications such as paresthesia, burns and ecchymosis, and recurrence of VVs when compared with LA.

Chinese chestnut shell polyphenol extract regulates the JAK2/STAT3 pathway to alleviate high-fat diet-induced, leptin-resistant obesity in mice.

Chinese chestnut shell is a by-product of chestnut food processing and is rich in polyphenols. This study sought to investigate the effect of chestnut shell polyphenol extract (CSP) on weight loss and lipid reduction in a 12-week high-fat diet (HFD)-induced murine obesity model. CSP (300 mg per kg body weight) was administered intragastrically daily. AG490, a JAK2 protein tyrosine kinase inhibitor, was also intraperitoneally injected. The results showed that an HFD induced leptin resistance (LR). Compared to corresponding values in the HFD group, CSP treatment improved blood lipid levels, weight, and leptin levels in obese mice (p < 0.01). Additionally, CSP treatment enhanced enzyme activity by improving total antioxidant capacity, attenuating oxidative stress, and reducing fat droplet accumulation and inflammation in the liver, epididymal, and retroperitoneal adipose tissue. CSP also activated the LEPR-JAK2/STAT3-PTP1B-SOCS-3 signal transduction pathway in hypothalamus tissue and improved LR while regulating the expression of proteins related to lipid metabolism (PPARγ, FAS, and LPL) in white adipose tissue in the retroperitoneal cavity. However, the amelioration of lipid metabolism by CSP was dependent on JAK2. Molecular docking simulation further demonstrated the strong binding affinity of procyanidin C1 (-10.3983297 kcal mol-1) and procyanidin B1 (-9.12686729 kcal mol-1) to the crystal structure of JAK2. These results suggest that CSP may be used to reduce HFD-induced obesity with potential application as a functional food additive.

Correlation between synthetic MRI relaxometry and apparent diffusion coefficient in breast cancer subtypes with different neoadjuvant therapy response.

BACKGROUND: To evaluate the correlation between synthetic MRI (syMRI) relaxometry and apparent diffusion coefficient (ADC) maps in different breast cancer subtypes and treatment response subgroups. METHODS: Two hundred sixty-three neoadjuvant therapy (NAT)-treated breast cancer patients with baseline MRI were enrolled. Tumor annotations were obtained by drawing regions of interest (ROIs) along the lesion on T1/T2/PD and ADC maps respectively. Histogram features from T1/T2/PD and ADC maps were respectively calculated, and the correlation between each pair of identical features was analyzed. Meanwhile, features between different NAT treatment response groups were compared, and their discriminatory power was evaluated. RESULTS: Among all patients, 20 out of 27 pairs of features weakly correlated (r = - 0.13-0.30). For triple-negative breast cancer (TNBC), features from PD map in the pathological complete response (pCR) group (r = 0.60-0.86) showed higher correlation with ADC than that of the non-pCR group (r = 0.30-0.43), and the mean from the ADC and PD maps in the pCR group strongly correlated (r = 0.86). For HER2-positive, few correlations were found both in the pCR and non-pCR groups. For luminal HER2-negative, T2 map correlated more with ADC than T1 and PD maps. Significant differences were seen in T2 low percentiles and median in the luminal-HER2 negative subtype, yielding moderate AUCs (0.68/0.72/0.71). CONCLUSIONS: The relationship between ADC and PD maps in TNBC may indicate different NAT responses. The no-to-weak correlation between the ADC and syMRI suggests their complementary roles in tumor microenvironment evaluation. CRITICAL RELEVANCE STATEMENT: The relationship between ADC and PD maps in TNBC may indicate different NAT responses, and the no-to-weak correlation between the ADC and syMRI suggests their complementary roles in tumor microenvironment evaluation. KEY POINTS: • The relationship between ADC and PD in TNBC indicates different NAT responses. • The no-to-weak correlations between ADC and syMRI complementarily evaluate tumor microenvironment. • T2 low percentiles and median predict NAT response in luminal-HER2-negative subtype.

Prognostic model and treatment choices for patients with primary intracranial central nervous system lymphoma: A population-based study.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma that occurs in the CNS. With the advancement of medical care, its prognosis and treatment have also undergone tremendous changes. This study aimed to construct a prognostic model and compare the effects of different treatments for intracranial PCNSL. METHODS: Cases diagnosed as PCNSL between 2004 and 2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Data were analyzed using Kaplan-Meier method and Cox regression analysis. Nomogram was built and validated using the R program. RESULTS: A total of 2861 PCNSL patients were included in the analysis. Age, year of diagnosis, surgery and chemotherapy were independent predictors for both overall survival (OS) and cancer-specific survival (CSS). A nomogram was established to predict 3-, 5- and 10-year OS and CSS for patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) showed the nomogram had good predictive performance and clinical application value. We also revealed that gross total resection had significantly better OS and CSS than biopsy alone (P < 0.001). Patients who received only chemotherapy had the best prognosis and did not benefit from additional radiotherapy. CONCLUSION: We developed a nomogram to predict patient survival rates based on independent predictors. It is an effective tool to help clinicians make survival predictions. Our results showed that patients can benefit from gross total resection of tumor, if it is feasible, and chemotherapy. The role of radiotherapy remained to be further assessed.

Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas.

The water-selective channel protein aquaporin-4 (AQP4) contributes to the migration and proliferation of gliomas, and to their resistance to therapy. Here we show, in glioma cell cultures, in subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression and can be measured via conventional dynamic-contrast-enhanced magnetic resonance imaging. Water-efflux rates correlated with stages of glioma proliferation as well as with changes in the heterogeneity of intra-tumoural and inter-tumoural AQP4 in rodent and human gliomas following treatment with temozolomide and with the AQP4 inhibitor TGN020. Regions with low water-efflux rates contained higher fractions of stem-like slow-cycling cells and therapy-resistant cells, suggesting that maps of water-efflux rates could be used to identify gliomas that are resistant to therapies.

Curcumin attenuates vascular calcification via the exosomal miR-92b-3p/KLF4 axis.

Vascular calcification (VC) is the most widespread pathological change in diseases of the vascular system. However, we do not have a good understanding of the molecular mechanisms and effective therapeutic approaches for VC. Curcumin (CUR) is a natural polyphenolic compound that has hypolipidemic, anti-inflammatory, and antioxidant effects on the cardiovascular system. Exosomes are known to have extensive miRNAs for intercellular regulation. This study investigated whether CUR attenuates VC by affecting the secretion of exosomal miRNAs. Calcification models were established in vivo and in vitro using vitamin D3 and ß-glycerophosphate, respectively. Appropriate therapeutic concentrations of CUR were detected on vascular smooth muscle cells (VSMCs) using a cell counting kit 8. Exosomes were extracted by super speed centrifugation from the supernatant of cultured VSMCs and identified by transmission electron microscopy and particle size analysis. Functional and phenotypic experiments were performed in vitro to verify the effects of CUR and exosomes secreted by VSMCs treated with CUR on calcified VSMCs. Compared with the calcified control group, both CUR and exosomes secreted by VSMCs after CUR intervention attenuated calcification in VSMCs. Real-Time quantitative PCR (RT-qPCR) experiments showed that miR-92b-3p, which is important for alleviating VC, was expressed highly in both VSMCs and exosomes after CUR intervention. The mimic miR-92b-3p significantly decreased the expression of transcription factor KLF4 and osteogenic factor RUNX2 in VSMCs, while the inhibitor miR-92b-3p had the opposite effect. Based on bioinformatics databases and dual luciferase experiments, the prospective target of miR-92b-3p was determined to be KLF4. Both mRNA and protein of RUNX2 were decreased and increased in VSMCs by inhibiting and overexpressing of KLF4, respectively. In addition, in the rat calcification models, CUR attenuated vitamin D3-induced VC by increasing miR-92b-3p expression and decreasing KLF4 expression in the aorta. In conclusion, our study suggests that CUR attenuates vascular calcification via the exosomal miR-92b-3p/KLF4 axis.