Circular RNA circFIRRE drives osteosarcoma progression and metastasis through tumorigenic-angiogenic coupling.

BACKGROUND: Disappointing clinical efficacy of standard treatment has been proven in refractory metastatic osteosarcoma, and the emerging anti-angiogenic regimens are still in the infantile stage. Thus, there is an urgent need to develop novel therapeutic approach for osteosarcoma lung metastasis. METHODS: circFIRRE was selected from RNA-sequencing of 4 matched osteosarcoma and adjacent samples. The expression of circFIRRE was verified in clinical osteosarcoma samples and cell lines via quantitative real-time polymerase chain reaction (RT-qPCR). The effect of circFIRRE was investigated in cell lines in vitro models, ex vivo models and in vivo xenograft tumor models, including proliferation, invasion, migration, metastasis and angiogenesis. Signaling regulatory mechanism was evaluated by RT-qPCR, Western blot, RNA pull-down and dual-luciferase reporter assays. RESULTS: In this article, a novel circular RNA, circFIRRE (hsa_circ_0001944) was screened out and identified from RNA-sequencing, and was upregulated in both osteosarcoma cell lines and tissues. Clinically, aberrantly upregulated circFIRRE portended higher metastatic risk and worse prognosis in osteosarcoma patients. Functionally, in vitro, ex vivo and in vivo experiments demonstrated that circFIRRE could drive primary osteosarcoma progression and lung metastasis by inducing both tumor cells and blood vessels, we call as "tumorigenic-angiogenic coupling". Mechanistically, upregulated circFIRRE was induced by transcription factor YY1, and partially boosted the mRNA and protein level of LUZP1 by sponging miR-486-3p and miR-1225-5p. CONCLUSIONS: We identified circFIRRE as a master regulator in the tumorigenesis and angiogenesis of osteosarcoma, which could be purposed as a novel prognostic biomarker and therapeutic target for refractory osteosarcoma.

LncRNA NDRG1 aggravates osteosarcoma progression and regulates the PI3K/AKT pathway by sponging miR-96-5p.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumors in children and adolescents. Large numbers of studies have focused on the long non-coding RNA (lncRNA) that plays essential roles in the progression of osteosarcoma. Nevertheless, the functions and underlying mechanisms of LncRNA NDRG1 in osteosarcoma remain unknown. METHODS: Differentially expressed lncRNAs between osteosarcoma and adjacent normal tissues were identified through RNA sequencing. The role of LncRNA NDRG1 in osteosarcoma proliferation and metastasis were investigated through in vitro and in vivo functional experiments. The interaction between LncRNA NDRG1 and miR-96-5p was verified through bioinformatic analysis and luciferase reporter assay. Regulation relationship between LncRNA NDRG1 and miR-96-5p was further evaluated by the rescue experiments. Additionally, the changes in the expression of epithelial-mesenchymal transition (EMT) and the PI3K/AKT pathway were verified by Western blot. RESULTS: LncRNA NDRG1 was up-regulated in osteosarcoma cell lines and tissues and the expression of LncRNA NDRG1 was correlated with the overall survival of osteosarcoma patients. Functional experiments exhibited that LncRNA NDRG1 aggravated osteosarcoma proliferation and migration in vitro; meanwhile, animals experiments showed that LncRNA NDRG1 promoted osteosarcoma growth and metastasis in vivo. Mechanistically, LncRNA NDRG1 was found to aggravate osteosarcoma progression and regulate the PI3K/AKT pathway by sponging miR-96-5p. CONCLUSIONS: LncRNA NDRG1 aggravates osteosarcoma progression and regulates the PI3K/AKT pathway by sponging miR-96-5p. Therefore, LncRNA NDRG1 could act as a prognostic marker and a therapeutic target for osteosarcoma in the future.

Variation in cell membrane integrity and enzyme activity of the button mushroom (Agaricus bisporus) during storage and transportation.

Button mushrooms (Agaricus bisporus) were put under stimulated storage and transportation environments with different amounts of phase-change materials (PCM). Results showed that the addition of PCM effectively maintained a cooler environment and delayed a rise in temperature. And the addition of PCM, especially in a ratio 1:2 PCM:mushroom, had a significant effect on delaying the increase in cell membrane permeability, malondialdehyde and H2O2 levels, and also delayed superoxide dismutase and catalase activity. These results suggest that PCM may be candidate in postharvest mushroom during storage and transportation.

The miR-15a-5p-XIST-CUL3 regulatory axis is important for sepsis-induced acute kidney injury.

Background: Acute kidney injury (AKI) refers to a sudden loss of renal function. This study was performed to identify the key RNAs acting in the mechanism of sepsis-induced AKI. Methods: Microarray dataset GSE94717 (including six sepsis-induced AKI samples and three control samples) was downloaded from Gene Expression Omnibus database. Differentially expressed miRNAs (DE-miRNAs) were identified. The miRNA targets were predicted and enrichment analysis was performed. Protein-protein interaction (PPI) and competing endogenous RNA (ceRNA) regulatory networks were constructed. Mouse podocytes were treated with lipopolysaccharide (LPS), following by cell viability and PCR analysis. Cellular apoptosis and the ceRNA network were validated. Results: Thirty-one common DE-miRNAs (two up-regulated and 29 down-regulated) by AKI versus control and male AKI versus control were identified. We found the targets of miR-15a-5p, miR-15b-5p, and miR-16-5p were involved in mTOR signaling pathway, and those of miR-29b-3p and miR-16-5p were enriched in PI3K-Akt signaling pathway. RNAs including miR-15b-5p, miR-15a-5p, miR-107, XIST, miR-16-5p, and cullin 3 gene (CUL3) were included in the ceRNA regulatory network. The downregulation of miR-15a-5p and miR-15b-5p and the upregulation of lncRNA XIST and CUL3 gene were validated using qPCR. The miR-15a-5p-XIST-CUL3 regulatory axis was identified and was validated. We confirmed that LPS inhibited the growth of mouse podocytes and seven of the ten miRNAs, but upregulated XIST and CUL3. Transfection analysis showed XIST siRNA enhanced LPS-induced MPC5 cell apoptosis and miR-15a-5p inhibitor reserved it, so did as CUL3 overexpression for miR-15a-5p mimics. Conclusion: The miR-15a-5p-XIST-CUL3 regulatory axis was related to the pathogenesis of sepsis-induced AKI. Highlights Totally, 31 miRNAs were dysregulated between disease and control groups. MiR-15a-5p, miR-15b-5p, and miR-16-5p were involved in mTOR signaling pathway. MiR-16-5p and miR-29b-3p were implicated in PI3K-Akt signaling pathway. The miR-15a-5p-XIST-CUL3 axis was critical for sepsis-induced AKI.

Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints.

In recent years, the role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments, including surgery, chemotherapy and radiotherapy. Of note, the clinical successes of immune checkpoint blockade, such as PD-1 and CTLA-4, represent a landmark event in cancer immunotherapy development. Therefore, further exploration of how immune checkpoints are regulated in the tumor microenvironment will provide key insights into checkpoint blockade therapy. In this review, we discuss in details about the regulation of immune checkpoints mediated by immune cells, oncolytic viruses, epigenetics, and gut microbiota and mutual regulation by co-expressed checkpoints. Finally, predictions are made for future personalized cancer immunotherapy based on different checkpoint modulations.

A generalizable reactive blending strategy to construct flame-retardant, mechanically-strong and toughened poly(L-lactic acid) bioplastics.

Poly(L-lactic acid) (PLA) is an environmentally-friendly bioplastic with high mechanical strength, but suffers from inherent flammability and poor toughness. Many tougheners have been reported for PLA, but their synthesis usually involves organic solvents, and they tend to dramatically reduce the mechanical strength and cannot settle the flammability matter. Herein, we develop strong, tough, and flame-retardant PLA composites by reactive blending PLA, 6-((double (2-hydroxyethyl) amino) methyl) dibenzo [c, e] [1,2] oxyphosphate acid 6-oxide (DHDP) and diphenylmethane diisocyanate (MDI) and define it PLA/xGH, where x indicates that the molar ratio of -NCO group in MDI to -OH group in PLA and DHDP is 1.0x: 1. This fabrication requires no solvents. PLA/2GH with a -NCO/-OH molar ratio of 1.02: 1 maintains high tensile strength of 63.0 MPa and achieves a 23.4 % increase in impact strength compared to PLA due to the incorporation of rigid polyurethane chain segment. The vertical combustion (UL-94) classification and limiting oxygen index (LOI) of PLA/2GH reaches V-0 and 29.8 %, respectively, because DHDP and MDI function in gas and condensed phases. This study displays a generalizable strategy to create flame-retardant bioplastics with great mechanical performances by the in-situ formation of P/N-containing polyurethane segment within PLA.

Circular RNA CircSATB2 facilitates osteosarcoma progression through regulating the miR-661/FUS-mediated mRNA of ZNFX1.

Circular RNAs (circRNAs) are a class of non-coding RNAs which take part in the regulation of the initiation and development of different types of cancer. Numerous studies have demonstrated that circRNAs are involved in the progression of osteosarcoma (OS) as well. Thus, we put our emphasis on the exploration of crucial circRNAs in the process of OS initiation and progression. Using RNA sequencing, we found that circSATB2 was highly expressed in OS tissues compared with adjacent normal tissues. Then, we confirmed the high expression of circSATB2 in OS cell lines and OS tissues and its high expression was related to poor prognosis of OS patients. Functional experiments exhibited that circSATB2 promoted OS proliferation and migration in vitro, primary OS model and OS lung metastasis model showed that circSATB2 aggravated OS progression in vivo. Mechanistically, circSATB2 was found to promote OS progression through sponging miR-661 and FUS regulating the mRNA of ZNFX1. Therefore, circSATB2 could act as a prognostic marker and a therapeutic target for osteosarcoma in the future.

Utilization and Mechanisms of Tannic Acid as a Depressant for Chalcopyrite and Pyrite Separation.

Current flotation practices using lime or cyanide as depressants in chalcopyrite and pyrite separation have significant disadvantages, such as substantial reagent consumption, high slurry pH, and environmental hazards. This work aimed to explore the utilization and mechanisms of tannic acid (TA) as an eco-friendly alternative to lime or cyanide in chalcopyrite-pyrite separation. Flotation results showed that TA selectively depressed pyrite yet allowed chalcopyrite to float at neutral or alkaline pH. Adsorption density and zeta potential results indicated that TA adsorbed intensely on pyrite but minorly on chalcopyrite. Besides, potassium ethyl xanthate was still largely adsorbed on chalcopyrite but not on pyrite after TA adsorption. Surface analysis by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy further showed that the oxidation species of FeOOH and Fe2 (SO4)3, particularly FeOOH were the main active sites for TA chemical adsorption. Owing to the greater and faster oxidation of pyrite, more FeOOH and Fe2 (SO4)3 were generated on the pyrite surface, and the chemical adsorption of TA was more pronounced on the pyrite surface than on the chalcopyrite surface.

Flame-retardant poly(L-lactic acid) with enhanced UV protection and well-preserved mechanical properties by a furan-containing polyphosphoramide.

Despite good biodegradability and mechanical strength, the intrinsic flammability of poly(L-lactic acid) (PLA) impede its practical application. Introducing phosphoramide is an effective method to enhance the flame retardancy of PLA. However, most of the reported phosphoramides derive from petroleum resources, and their addition tends to deteriorate the mechanical properties, especially toughness, of PLA. Herein, a bio-based, furan-containing polyphosphoramide (DFDP) with high flame-retardant efficiency was synthesized for PLA. Our study found that 2 wt% DFDP enabled PLA to pass a UL-94 V-0 rating, and 4 wt% DFDP increased the limiting oxygen index (LOI) to 30.8 %. DFDP effectively maintained the mechanical strength and toughness of PLA. The tensile strength of PLA with 2 wt% DFDP reached 59.9 MPa, and its elongation at break and impact strength were increased by 15.8 % and 34.3 %, respectively, relative to those of virgin PLA. The UV protection of PLA was significantly enhanced by introducing DFDP. Hence, this work provides a sustainable and comprehensive strategy for the creation of flame-retardant biomaterials with improved UV protection and well-preserved mechanical properties, which possess a broad prospect in industrial application.

T cell immunotherapy for cervical cancer: challenges and opportunities.

Cancer cellular immunotherapy has made inspiring therapeutic effects in clinical practices, which brings new hope for the cure of cervical cancer. CD8+T cells are the effective cytotoxic effector cells against cancer in antitumor immunity, and T cells-based immunotherapy plays a crucial role in cellular immunotherapy. Tumor infiltrated Lymphocytes (TIL), the natural T cells, is approved for cervical cancer immunotherapy, and Engineered T cells therapy also has impressive progress. T cells with natural or engineered tumor antigen binding sites (CAR-T, TCR-T) are expanded in vitro, and re-infused back into the patients to eradicate tumor cells. This review summarizes the preclinical research and clinical applications of T cell-based immunotherapy for cervical cancer, and the challenges for cervical cancer immunotherapy.

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma.

Background: Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Methods: Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. Results: The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. Conclusions: We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine storms, and lymphopenia. Due to immunosuppression, cancer patients may be more susceptible to SARS-CoV-2 and have more serious complications. According to recent research, cyclic GMP-AMP synthase (cGAS) could be a potential SARS-CoV-2 sensor. However, at present, no studies have been conducted on cGAS gene alterations in pan-cancer. This study aimed to discover therapeutic implications for COVID-19-infected tumor patients by performing a comprehensive analysis of cGAS in malignant tumors. Methods: cGAS expression matrices were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases, which were used to evaluate cGAS expression in various tumors, its prognostic value, and its relationship to the immune microenvironment, microsatellite instability (MSI), immune neoantigens, gene mutations, immune checkpoints, MSI, tumor mutational burden (TMB), mismatch repair (MMR) genes, and DNA methyltransferases (DNMT). We also used the cBioPortal, Human Protein Atlas (HPA), and GeneMANIA databases to explore the types of changes, gene networks and immunofluorescence localization, and protein expression of these genes. Results: Compared to normal tissues, cGAS was highly expressed in 13 types of cancer (e.g., lung cancer) and lowly expressed in other cancers (e.g., pancreatic cancer). cGAS expression was associated with prognosis in nine cancers, such as renal clear cell carcinoma (P<0.05). Furthermore, deep deletion was the most common type of cGAS genomic mutation. DNMT, immune infiltration levels, TMB, MSI, MMR genes, neoantigens, and immune checkpoints were all correlated with cGAS expression. Moreover, we used the GSE30589 dataset to investigate the post-SARS-CoV infection changes in cGAS expression in vitro. Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of cGAS expression. According to the evidence presented above, cGAS may become an important target for cancer therapy. Conclusions: This study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of cGAS, making patients with tumors expressing high cGAS more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, cGAS may be a novel biomarker for diagnosing and treating COVID-19-infected tumor patients.

In vivo self-assembly and delivery of VEGFR2 siRNA-encapsulated small extracellular vesicles for lung metastatic osteosarcoma therapy.

The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS, but there is a lack of safe and efficient delivery systems to encapsulate siRNAs for in vivo administration. This study presented a synthetic biological strategy that remolds the host liver with synthesized genetic circuits for efficient in vivo VEGFR2 siRNA delivery. After being taken-up by hepatocytes, the genetic circuit (in the form of a DNA plasmid) reprogrammed the liver to drive the autonomous intrahepatic assembly and encapsulation of VEGFR2 siRNAs into secretory small extracellular vesicles (sEVs), thus allowing for the transport of self-assembled VEGFR2 siRNAs towards the lung. The results showed that our strategy was superior to the positive medicine (Apatinib) for OS lung metastasis in terms of therapeutic efficacy and toxic adverse effects and may provide a feasible and viable therapeutic solution for lung metastatic OS.

Effect of Angiogenesis in Bone Tissue Engineering.

The reconstruction of large skeletal defects is still a tricky challenge in orthopedics. The newly formed bone tissue migrates sluggishly from the periphery to the center of the scaffold due to the restrictions of exchange of oxygen and nutrition impotent cells osteogenic differentiation. Angiogenesis plays an important role in bone reconstruction and more and more studies on angiogenesis in bone tissue engineering had been published. Promising advances of angiogenesis in bone tissue engineering by scaffold designs, angiogenic factor delivery, in vivo prevascularization and in vitro prevascularization are discussed in detail. Among all the angiogenesis mode, angiogenic factor delivery is the common methods of angiogenesis in bone tissue engineering and possible research directions in the future.

PLOD2 high expression associates with immune infiltration and facilitates cancer progression in osteosarcoma.

Background: Osteosarcoma (OS) is the most common primary malignant bone tumors in children and adolescents. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is a key gene in mediating the formation of the stabilized collagen cross-link, playing an important role in the progression of cancer. However, the interaction between OS and PLOD2 has not been clarified so far. Methods: The target gene PLOD2 was screened through our own RNA-seq results and other two RNA-seq results from GEO database. The expression of PLOD2 in OS was detected by RT-qPCR, Western blot and immunohistochemistry. Functional experiments were performed to investigate the role of PLOD2 in OS cell invasion, migration and angiogenesis in vitro. An OS lung metastasis model was established to investigate the function of PLOD2 in OS metastasis and angiogenesis in vivo. The role of PLOD2 in immune infiltration in OS was explored by KEGG/GO analysis and immune infiltration analysis with TARGET, TCGA and TIMER. Results: PLOD2 was high-expressed in OS, which was related to poor prognosis of OS patients. PLOD2 promoted OS cell migration, invasion and angiogenesis in vitro and aggravated OS metastasis and angiogenesis in vivo. Bioinformatic analysis showed that PLOD2 played an important role in immune cell infiltration in OS, including CD8 positive T cells, macrophages M0 cells, DC cells, endothelial cells, iDC cells, ly endothelial cells, MEP cells, mv endothelial cells, native B cells, smooth muscle cells and Th1 cells. Immunohistochemical results showed that the expression of CD4 and CD8A was negatively correlated with the expression of PLOD2 in OS. Conclusion: PLOD2 was high-expressed in OS and promoted OS migration, invasion and angiogenesis in vitro and facilitated OS metastasis and angiogenesis in vivo. PLOD2 was associated with immune cell infiltration in OS, which could be a promising target to treat OS patients with metastasis and utilized to guide clinical immunotherapy in the future.

Covalent immobilization of VEGF on allogeneic bone through polydopamine coating to improve bone regeneration.

Objective: Promoting bone regeneration and repairing in bone defects is of great significance in clinical work. Using a simple and effective surface treatment method to enhance the osteogenic ability of existing bone scaffold is a promising method. In this article, we study the application of catecholic amino acid 3,4-dihydroxyphenylalanine (DOPA) surface coating chelated with vascular endothelial growth factor (VEGF) on allogeneic bone. Method: Allogeneic bone is immersed in DOPA solution and DOPA form polydopamine (PDA) with good adhesion. Electron microscopy is used to characterize the surface characteristics of allogeneic bone. MC3T3-E1 cells were tested for biocompatibility and osteogenic signal expression. Finally, a 12-week rabbit bone defect model was established to evaluate bone regeneration capability. Results: We found that the surface microenvironment of DOPA bonded allogeneic bone was similar to the natural allogeneic bone. VEGF loaded allografts exhibited satisfying biocompatibility and promoted the expression of osteogenic related signals in vitro. The VEGF loaded allografts healed the bone defect after 12 weeks of implantation that continuous and intact bone cortex was observed. Conclusion: The PDA coating is a simple surface modification method and has mild properties and high adhesion. Meanwhile, the PDA coating can act on the surface modification of different materials. This study provides an efficient surface modification method for enhancing bone regeneration by PDA coating, which has a high potential for translational clinical applications.

Real-time bulk-motion-correction free Doppler variance optical coherence tomography for choroidal capillary vasculature imaging.

In this paper, we analyze the retinal and choroidal blood vasculature in the posterior segment of the human eye with optimized color Doppler and Doppler variance optical coherence tomography. Depth-resolved structure, color Doppler and Doppler variance images are compared. Blood vessels down to the capillary level were detected and visualized with the optimized optical coherence color Doppler and Doppler variance method. For in-vivo imaging of human eyes, bulk-motion induced bulk phase must be identified and removed before using the color Doppler method. It was found that the Doppler variance method is not sensitive to bulk-motion and the method can be used without correcting the bulk-motion when the sample-movement-induced velocity changes gradually. Real-time processing and displaying of the structure and blood vessel images are very interesting and is demonstrated using a dual quad-core Central Processing Unit (CPU) workstation. High resolution images of choroidal capillary of the vasculature network with phased-resolved color Doppler and Doppler variance are shown.

Engineered T Cell Therapy for Gynecologic Malignancies: Challenges and Opportunities.

Gynecologic malignancies, mainly including ovarian cancer, cervical cancer and endometrial cancer, are leading causes of death among women worldwide with high incidence and mortality rate. Recently, adoptive T cell therapy (ACT) using engineered T cells redirected by genes which encode for tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) has demonstrated a delightful potency in B cell lymphoma treatment. Researches impelling ACT to be applied in treating solid tumors like gynecologic tumors are ongoing. This review summarizes the preclinical research and clinical application of engineered T cells therapy for gynecologic cancer in order to arouse new thoughts for remedies of this disease.

Three-dimensional speckle suppression in Optical Coherence Tomography based on the curvelet transform.

Optical coherence tomography is an emerging non-invasive technology that provides high resolution, cross-sectional tomographic images of internal structures of specimens. OCT images, however, are usually degraded by significant speckle noise. Here we introduce to our knowledge the first 3D approach to attenuating speckle noise in OCT images. Unlike 2D approaches which only consider information in individual images, 3D processing, by analyzing all images in a volume simultaneously, has the advantage of also taking the information between images into account. This, coupled with the curvelet transform's nearly optimal sparse representation of curved edges that are common in OCT images, provides a simple yet powerful platform for speckle attenuation. We show the approach suppresses a significant amount of speckle noise, while in the mean time preserves and thus reveals many subtle features that could get attenuated in other approaches.