High Peritumoral and Intratumoral T2 Signal Intensity in HER2-Positive Breast Cancers on Preneoadjuvant Breast MRI: Assessment of Associations With Histopathologic Characteristics.

BACKGROUND. Intratumoral necrosis and peritumoral edema are features of aggressive breast cancer that may present as high T2 signal intensity (T2 SI). Implications of high T2 SI in HER2-positive cancers are unclear. OBJECTIVE. The purpose of this study was to assess associations with histopathologic characteristics of high peritumoral T2 SI and intratumoral T2 SI of HER2-positive breast cancer on MRI performed before initiation of neoadjuvant therapy. METHODS. This retrospective study included 210 patients (age, 24-82 years) with 211 HER2 breast cancers who, from January 1, 2015, to July 30, 2022, underwent breast MRI before receiving neoadjuvant therapy. Two radiologists independently assessed cancers for high peritumoral T2 SI and high intratumoral T2 SI on fat-suppressed T2-weighted imaging and classified patterns of high peritumoral T2 SI (adjacent to tumor vs prepectoral extension). A third radiologist resolved discrepancies. Multivariable logistic regression analyses were performed to identify associations of high peritumoral and intratumoral T2 SI with histopathologic characteristics (associated ductal carcinoma in situ, hormone receptor status, histologic grade, lymphovascular invasion, and axillary lymph node metastasis). RESULTS. Of 211 HER2-positive cancers, 81 (38.4%) had high peritumoral T2 SI, and 95 (45.0%) had high intratumoral T2 SI. A histologic grade of 3 was independently associated with high peritumoral T2 SI (OR = 1.90; p = .04). Otherwise, none of the five assessed histopathologic characteristics were independently associated with high intratumoral T2 SI or high peritumoral T2 SI (p > .05). Cancers with high T2 SI adjacent to the tumor (n = 29) and cancers with high T2 SI with prepectoral extension (n = 52) showed no significant difference in frequency for any of the histopathologic characteristics (p > .05). Sensitivities and specificities for predicting the histopathologic characteristics ranged from 35.6% to 43.7% and from 59.7% to 70.7%, respectively, for high peritumoral T2 SI, and from 37.3% to 49.6% and from 49.3% to 62.7%, respectively, for high intratumoral T2 SI. Interreader agreement was almost perfect for high peritumoral T2 SI (Gwet agreement coefficient [AC] = 0.93), high intratumoral T2 SI (Gwet AC = 0.89), and a pattern of high peritumoral T2 SI (Gwet AC = 0.95). CONCLUSION. The only independent association between histopathologic characteristics and high T2 SI of HER2-positive breast cancer was observed between a histologic grade of 3 and high peritumoral T2 SI. CLINICAL IMPACT. In contrast with previously reported findings in broader breast cancer subtypes, peritumoral and intratumoral T2 SI had overall limited utility as prognostic markers of HER2-positive breast cancer.

Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer.

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Transcatheter arterial tendinopathy embolization as a treatment for painful and refractory tendinopathy: a systematic review and meta-analysis.

OBJECTIVE: Transcatheter arterial embolization (TAE) is a novel minimally invasive therapy for painful tendinopathy in patients with pain refractory to conservative management. The purpose of this study was to evaluate evidence on the efficacy of TAE for tendinopathy related pain. MATERIALS AND METHODS: Using Embase, PubMed, and Web of Science, a systematic review and meta-analysis was performed to identify studies evaluating TAE for painful tendinopathy. The primary outcome measure was change in pain scale score at 6 months. A Ratio of Means (ROM) was used to compare the effect size post treatment as compared to baseline. The Visual Analog Scale (VAS) was used as the metric for comparison. RESULTS: After screening titles, abstracts, and the full text, 5 studies met inclusion criteria. A total of 97 tendinopathy embolization procedures performed in 74 patients were included. Patients who underwent TAE demonstrated declines in VAS ROM at 1 day 0.53 [95% CI 0.31,0.88], 1 week (0.51 [95% CI 0.32,0.79]), 1 month (0.45 [95% CI 0.29, 0.71]), 3-4 months (0.33 [95% CI 0.22,0.48]), and 6 months following embolization (0.18[95% CI 0.13,0.26]), respectively. DISCUSSION: TAE provides substantial short-term reductions in pain scores for patients suffering with refractory tendinopathy related pain of the rotator cuff, elbow extensor and flexor, Achilles, and patellar tendons.

STAT3 promotes differentiation of monocytes to MDSCs via CD39/CD73-adenosine signal pathway in oral squamous cell carcinoma.

Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.

Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.

BACKGROUND: Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens. METHODS: We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m2) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life. DISCUSSION: Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).

Tumor and Ablation Margin Visibility during Cryoablation of Musculoskeletal Tumors: Comparing Intraprocedural PET/CT Images with CT-Only Images.

PURPOSE: To compare tumor and ice-ball margin visibility on intraprocedural positron emission tomography (PET)/computed tomography (CT) and CT-only images and report technical success, local tumor progression, and adverse event rates for PET/CT-guided cryoablation procedures for musculoskeletal tumors. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant and institutional review board-approved retrospective study evaluated 20 PET/CT-guided cryoablation procedures performed with palliative and/or curative intent to treat 15 musculoskeletal tumors in 15 patients from 2012 to 2021. Cryoablation was performed using general anesthesia and PET/CT guidance. Procedural images were reviewed to determine the following: (a) whether the tumor borders could be fully assessed on PET/CT or CT-only images; and (b) whether tumor ice-ball margins could be fully assessed on PET/CT or CT-only images. The ability to visualize tumor borders and ice-ball margins on PET/CT images was compared with that on CT-only images. RESULTS: Tumor borders were fully assessable for 100% (20 of 20; 95% CI, 0.83-1) of procedures on PET/CT versus 20% (4 of 20; 95 CI, 0.057-0.44) of procedures on CT only (P < .001). The tumor ice-ball margin was fully assessable in 80% (16 of 20; 95% CI, 0.56-0.94) of procedures using PET/CT versus 5% (1 of 20; 95% CI, 0.0013-0.25) of procedures using CT only (P < .001). Primary technical success was achieved in 75% (15 of 20; 95% CI, 0.51-0.91) of procedures. There was local tumor progression in 23% (3/13; 95% CI, 0.050-0.54) of the treated tumors with at least 6 months of follow-up. There were 3 adverse events (1 Grade 3, 1 Grade 2, and 1 Grade 1). CONCLUSIONS: PET/CT-guided cryoablation of musculoskeletal tumors can provide superior intraprocedural visualization of the tumor and ice-ball margins compared with that provided by CT alone. Further studies are warranted to confirm the long-term efficacy and safety of this approach.

Ferroptosis promotes anti-tumor immune response by inducing immunogenic exposure in HNSCC.

Accumulated evidence indicates that immune cell populations play pivotal roles in the process of tumor initiation, progression, recurrence, metastasis, and immune escape. Ferroptosis is a form of regulating cell death in the nexus between metabolism, redox biology, and human health. Ferroptosis is considered as a vital important event in HNSCC, but the underling mechanism of regulating immune cell populations remains poorly understood. Our tissue microarray study showed that patients with high expression of GPX4 were related to poor survival. Moreover, the expression of GPX4 has been negatively associated with immunogenic cell death-related protein calreticulin in HNSCC tissue cohort. Further, RSL3 was used to induce ferroptosis in HNSCC xenograft of C3H/He mouse. We found that the occurrence of ferroptosis had significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (M2 TAMs) in tumor microenvironment. Meanwhile, the tumor-infiltrating CD4+ and CD8+ T cells were increased. And the calreticulin and HMGB1 may be potential candidate proteins improving the immunosuppressive tumor microenvironment. Taken together, our project suggests that ferroptosis can promote anti-tumor immune response by reversing immunosuppressive microenvironment, indicating that ferroptosis inducer is a promising therapeutic strategy in HNSCC.

Pectolinarigenin shows lipid-lowering effects by inhibiting fatty acid biosynthesis in vitro and in vivo.

Pectolinarigenin is the main flavonoid compound and presents in Linaria vulgaris and Cirsium chanroenicum. In this study, RNA sequencing (RNA-seq) was applied to dissect the effect of pectolinarigenin on the transcriptome changes in the high lipid Huh-7 cells induced by oleic acid. RNA-seq results revealed that 15 pathways enriched by downregulated genes are associated with cell metabolism including cholesterol metabolism, glycerophospholipid metabolism, steroid biosynthesis, steroid hormone biosynthesis, fatty acid biosynthesis, etc. Moreover, 13 key genes related to lipid metabolism were selected. Among them, PPARG coactivator 1 beta (PPARGC1B) and carnitine palmitoyltransferase 1A (CPT1A) were found to be upregulated, solute carrier family 27 member 1(SLC27A1), acetyl-CoA carboxylase alpha (ACACA), fatty-acid synthase (FASN), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), etc. were found to be downregulated. Glycolysis/gluconeogenesis, steroid hormone biosynthesis, and fatty acid biosynthesis were all significantly downregulated, according to gene set variation analysis and gene set enrichment analysis. Besides, protein levels of FASN, ACACA, and SLC27A1 were all decreased, whereas PPARγ and CPT1A were increased. Docking models showed that PPARγ may be a target for pectolinarigenin. Furthermore, pectolinarigenin reduced serum TG and hepatic TG, and improved insulin sensitivity in vivo. Our findings suggest that pectolinarigenin may target PPARγ and prevent fatty acid biosynthesis.

Advanced materials and technologies for oral diseases.

Oral disease, as a class of diseases with very high morbidity, brings great physical and mental damage to people worldwide. The increasing burden and strain on individuals and society make oral diseases an urgent global health problem. Since the treatment of almost all oral diseases relies on materials, the rapid development of advanced materials and technologies has also promoted innovations in the treatment methods and strategies of oral diseases. In this review, we systematically summarized the application strategies in advanced materials and technologies for oral diseases according to the etiology of the diseases and the comparison of new and old materials. Finally, the challenges and directions of future development for advanced materials and technologies in the treatment of oral diseases were refined. This review will guide the fundamental research and clinical translation of oral diseases for practitioners of oral medicine.

Geostatistical modeling of positive-definite matrices: An application to diffusion tensor imaging.

Geostatistical modeling for continuous point-referenced data has extensively been applied to neuroimaging because it produces efficient and valid statistical inference. However, diffusion tensor imaging (DTI), a neuroimaging technique characterizing the brain's anatomical structure, produces a positive-definite (p.d.) matrix for each voxel. Currently, only a few geostatistical models for p.d. matrices have been proposed because introducing spatial dependence among p.d. matrices properly is challenging. In this paper, we use the spatial Wishart process, a spatial stochastic process (random field), where each p.d. matrix-variate random variable marginally follows a Wishart distribution, and spatial dependence between random matrices is induced by latent Gaussian processes. This process is valid on an uncountable collection of spatial locations and is almost-surely continuous, leading to a reasonable way of modeling spatial dependence. Motivated by a DTI data set of cocaine users, we propose a spatial matrix-variate regression model based on the spatial Wishart process. A problematic issue is that the spatial Wishart process has no closed-form density function. Hence, we propose an approximation method to obtain a feasible Cholesky decomposition model, which we show to be asymptotically equivalent to the spatial Wishart process model. A local likelihood approximation method is also applied to achieve fast computation. The simulation studies and real data application demonstrate that the Cholesky decomposition process model produces reliable inference and improved performance, compared to other methods.

Pectolinarigenin reduces the expression of sterol regulatory element-binding proteins and cellular lipid levels.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that have important roles in the genes involved in lipid biosynthesis. In this study, it was found that the flavonoid pectolinarigenin, reduced the activity of SRE-containing fatty acid synthase (FAS) promoter and the mRNA expressions of SREBP target genes in human hepatoma (Huh-7) cells. Moreover, compared with other flavonoids, pectolinarigenin reduced the mature forms of SREBPs in a dose-dependent manner. The insulin-induced gene (INSIG) and proteasome were not involved in the pectolinarigenin-mediated reduction of mature forms of SREBPs. Pectolinarigenin also reduced the lipid contents in vitro. These results suggest that pectolinarigenin may inhibit lipogenesis through suppressing SREBP activity, at least partially, via the formation of SREBPs mature forms, thereby reducing the expression of their downstream genes related to lipogenesis. To the best of our knowledge, this is the first work that shows how pectolinarigenin affects cellular lipid levels by affecting SREBPs.

CD24 blockade promotes anti-tumor immunity in oral squamous cell carcinoma.

OBJECTIVES: Our study elucidates the prognostic role of cluster of differentiation (CD) 24 expression in oral squamous cell carcinoma (OSCC) and determines whether targeting CD24 enhances the anti-tumor immune response by inhibiting tumor-associated macrophages (TAMs). MATERIALS AND METHODS: The expression of CD24 and CD68 was analyzed immunohistochemically via tissue microarrays constructed using 56 cohorts of patients with OSCC and 20 control specimens. Further, CD24 was inhibited in an allograft squamous cell carcinoma (SCC) related mouse model with CD24mAb to determine the tumor volume and weight. Changes in immune cells such as TAMs and T cells in the tumor microenvironment (TME) were analyzed by Flow cytometry. The expression of CD4, CD8, and Ki67 was analyzed via immunohistochemistry. The inhibition of CD24 was confirmed by Western blot and immunohistochemistry. RESULTS: CD24 was overexpressed in OSCC. High expression of CD24 indicated poor survival in patients with OSCC (p = 0.0334). CD24 expression was significantly correlated with CD68 (p = 0.0424). The inhibition of CD24 delayed tumor growth in vivo. A decrease in TAMs number and an increase in T cell number were confirmed, while the ability of tumor proliferation was impaired. CONCLUSION: Targeting CD24 could enhance anti-tumor immune response by inhibiting TAMs.

Asthma susceptibility in prenatal nicotine-exposed mice attributed to ß-catenin increase during CD4+ T cell development.

Cigarette smoke is a common global environmental pollutant. Asthma, the most frequent allergic airway disease, is related to maternal exposure to cigarette smoke. Our previous studies demonstrated that prenatal exposure to nicotine (PNE), the major active product of smoking, impairs fetal thymopoiesis and CD4+ T cell development after birth. This study aimed to investigate whether PNE contributes to asthma susceptibility through CD4+ T cell development alterations. First, A PNE model was established by administering 3 mg/kg/day nicotine to maternal mice, and then an ovalbumin-induced asthma model was established in the offspring. Further, ß-catenin and downstream pathways were inhibited in vitro to confirm the molecular mechanisms underlying the phenotype observed during the in vivo phase. The results showed that PNE induced Th2 and Th17 biases at developmental checkpoints and aggravated asthma symptoms in the offspring. In fetuses, PNE up-regulated α7 nAChR, activated PI3K-AKT, promoted ß-catenin level increase, and established potential Th2- and Th17-biased gene expression patterns during thymopoiesis, which persisted after birth. Similar results were also observed in 1 µM nicotine-treated thymocytes in vitro. Moreover, inhibiting PI3K-AKT by LY294002 abrogated nicotine-mediated ß-catenin level increase and thymopoiesis abnormalities, and an α7 nAChR antagonist (α-btx) also reversed nicotine-induced PI3K-AKT activation. Our findings provide strong evidence that PNE is a risk factor for T cell deviation and postnatal asthma, and revealed that nicotine-induced ß-catenin level increase induces thymopoiesis abnormalities.

Mechanosensitive TRPV4 is required for crystal-induced inflammation.

Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and Trpv4eGFP mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca2+ imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1ß which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.

Augmented autophagy suppresses thymocytes development via Bcl10/p-p65 pathway in prenatal nicotine exposed fetal mice.

Tobacco smoke is a common global environmental pollutant. Maternal tobacco smoke/nicotine exposure has long-term toxic effects on immune organs. We previously found that prenatal nicotine exposure (PNE)-induced programmed immune diseases caused by fetal thymic hypoplasia, but the mechanism still unknown. Autophagy has important functions in maintaining thymopoiesis, whether autophagy was involved in PNE-inhibited fetal thymocytes development is also obscure. Therefore, this study aimed to investigate how nicotine changed the development of fetal thymocytes from the perspective of autophagy in vivo and in vitro. PNE model was established by 3 mg/kg nicotine administration in Balb/c mice from gestational day 9 to 18. The results showed that PNE reduced the percentage and absolute number of CD69-CD4+SP cells, suggesting a block of fetal thymocytes mature. PNE promoted autophagosome formation, autophagy related proteins (Beclin1, LC3I/II) expression, and upregulated α7 nAChR as well as AMPK phosphorylation in fetal thymus. Moreover, PNE promoted Bcl10 degradation via autophagy-mediated proteolysis and inhibited p65 activation, blocking the transition of thymocytes between the DP to SP stage. Further, primary thymocytes were treated with nicotine in vitro and showed induced autophagy in a dose- and time-dependent manner. In addition, nicotine-inhibited CD69-CD4+SP cells and the Bcl10/p-p65 pathway have been reversed by an autophagy inhibitor. The α7 nAChR specific antagonist abrogated nicotine-induced AMPK phosphorylation and autophagy initiation. In conclusion, our findings showed that PNE repressed the Bcl10/p-p65 development pathway of CD4+SP cells by triggering autophagy, and illuminated the developmental origin mechanism of programmed immune diseases in PNE offspring.

Icariin Ameliorates Amyloid Pathologies by Maintaining Homeostasis of Autophagic Systems in Aß1-42-Injected Rats.

Macroautophagy, a sole pathway for dysfunctional organelles or aggregated proteins turnover, has been implicated in the early development of Alzheimer's disease (AD). Previous studies have found that reversal of autophagy dysfunction in APP transgenic mice ameliorates amyloid pathologies. Icariin (ICA), the main component from traditional Chinese herb Epimedium brevicornu Maxim., can reduce accumulations of amyloid-ß (Aß) peptide in vivo and in vitro, but the mechanism remains unclear. Here, we explored the effects of ICA on autophagy-lysosomal pathway in intracerebroventricular (icv) injection of human Aß1-42 peptide rats. We demonstrated that feeding the rats with ICA (30 mg/kg, 60 mg/kg and 90 mg/kg rat, per os) for 4 weeks rescued the Aß1-42-induced spatial memory impairments, reduced endogenous rat Aß42 tested by ELISA and decreased Aß accumulation using 6E10 antibody. Furthermore, Aß1-42 induced strong autophagy response, however ICA decreased the levels of microtubule-associated protein 1 light chain 3 (LC3) II/LC3I, Beclin1, Cathepsin D (Cat D) and brain lysosomal Cathepsin D activity. We also observed that ICA enhanced the phosphorylation of protein kinase B (PKB/AKT) and p70 ribosomal protein S6 kinase (p70S6K). In addition, ICA arrested Aß1-42-induced cells loss, mitochondrias damage, nuclear membranes unclear and abundant nucleas chromatin agglutinates in hippocampus, lessened the expression of Cleaved-caspase-3, brain oxidative stress, astroglial activation. These findings suggest that ICA can ameliorate amyloid pathologies with improving autophagy-lysosome function and Chinese materia medica may be potential for AD treatment.

Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity.

Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFß pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 µM) as compared with those in controls. Zoledronate treatments in cells (50 µM) and mice (3 mg/kg) increased TGFß/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid ß-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.

OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.

Bayesian network feature finder (BANFF): an R package for gene network feature selection.

MOTIVATION: Network marker selection on genome-scale networks plays an important role in the understanding of biological mechanisms and disease pathologies. Recently, a Bayesian nonparametric mixture model has been developed and successfully applied for selecting genes and gene sub-networks. Hence, extending this method to a unified approach for network-based feature selection on general large-scale networks and creating an easy-to-use software package is on demand. RESULTS: We extended the method and developed an R package, the Bayesian network feature finder (BANFF), providing a package of posterior inference, model comparison and graphical illustration of model fitting. The model was extended to a more general form, and a parallel computing algorithm for the Markov chain Monte Carlo -based posterior inference and an expectation maximization-based algorithm for posterior approximation were added. Based on simulation studies, we demonstrate the use of BANFF on analyzing gene expression on a protein-protein interaction network. AVAILABILITY: https://cran.r-project.org/web/packages/BANFF/index.html CONTACT: jiankang@umich.edu, tianwei.yu@emory.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors.

Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a-o and 10a-o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit µM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 9o showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines and EGFR kinase, with the IC50 values of 1.32±0.38µM, 0.07±0.01µM, 0.91±0.29µM and 4.89±0.69µM, which were equal to more active than afatinib (1.40±0.83µM, 1.33±1.28µM, 2.63±1.06µM and 3.96±0.59µM), respectively. Activity of the most promising compound 9o (IC50 56nM) against EGFR kinase was slightly lower to the positive compound afatinib (IC50 1.6nM) but more active than reference staurosporine (IC50 238nM). The result of flow cytometry, with the dose of compound 9o increasing, which indicated the compound 9o could induce remarkable apoptosis of A549 and cells in a dose dependent manner. Structure-activity relationships (SARs) and docking studies indicated that replacement of the cinnamamide group by aryl semicarbazone scaffolds slightly decreased the anti-tumor activity. The results suggested that hydroxy substitution at C-4 had a significant impact on the activity and replacement of the tetrahydrofuran group by methyl moiety was not beneficial for the activity.