Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Self-Enhanced Electrochemiluminescence Imaging System Based on the Accelerated Generation of ROS under Ultrasound.

Electrochemiluminescence (ECL) imaging, as an optical technology, has been developed at full tilt in the field of life science and nanomaterials. However, the relatively low ECL intensity or the high co-reactant concentration needed in the electrochemical reaction blocks its practical application. Here, we developed an ECL imaging system based on the rGO-TiO2-x composite material, where the co-reactant, reactive oxygen species (ROS), is generated in situ under the synergetic effect of of ultrasound (US) and electric irradiation. The rGO-TiO2-x composites facilitate the separation of electron (e-) and hole (h+) pairs and inhibit recombination triggered by external US irradiation due to the high electroconductivity of rGO and oxygen-deficient structures of TiO2, thus significantly boosting ROS generation. Furthermore, the increased defects on rGO accelerate the electron transfer rate, improving the electrocatalytic performance of the composite and forming more ROS. This high ultrasonic-electric synergistic efficacy is demonstrated through the enhancement of photon emission. Compared with the luminescence intensity triggered by US irradiation and electric field, an enhancement of ∼20-fold and 10-fold of the US combined with electric field-triggered emission is observed from this composite. Under the optimized conditions, using dopamine (DA) as a model target, the sensitivity of the US combined ECL strategy for detection of DA is two orders of magnitude higher than that of the ECL method. The successful detection of DA at low concentrations makes us believe that this strategy provides the possibility of applying ECL imaging for cellular single-molecule analysis and cancer therapy.

Identification of circRNAs and circRNA-mRNA network of Epinephelus coioides during Singapore grouper iridovirus infection.

Circular RNA (circRNA), one of the important non-coding RNA molecules with a closed-loop structure, plays a key regulatory role in cell processing. In this study, circRNAs of Epinephelus coioides, an important marine cultured fish in China, were isolated and characterized, and the network of circRNAs and mRNA was explored during Singapore grouper iridovirus (SGIV) infection, one of the most important double stranded DNA virus pathogens of marine fish. 10 g of raw data was obtained by high-throughput sequencing, and 2599 circRNAs were classified. During SGIV infection, 123 and 37 circRNAs occurred differential expression in spleen and spleen cells, indicating that circRNAs would be involved in the viral infection. GO annotation and KEGG demonstrated that circRNAs could target E. coioides genes to regulate cell activity and the activation of immune factors. The results provide some insights into the circRNAs mediated immune regulatory network during bony fish virus infection.

Contactless Simultaneous Breathing and Heart Rate Detections in Physical Activity Using IR-UWB Radars.

Vital signs monitoring in physical activity (PA) is of great significance in daily healthcare. Impulse Radio Ultra-WideBand (IR-UWB) radar provides a contactless vital signs detection approach with advantages in range resolution and penetration. Several researches have verified the feasibility of IR-UWB radar monitoring when the target keeps still. However, various body movements are induced by PA, which lead to severe signal distortion and interfere vital signs extraction. To address this challenge, a novel joint chest-abdomen cardiopulmonary signal estimation approach is proposed to detect breath and heartbeat simultaneously using IR-UWB radars. The movements of target chest and abdomen are detected by two IR-UWB radars, respectively. Considering the signal overlapping of vital signs and body motion artifacts, Empirical Wavelet Transform (EWT) is applied on received radar signals to remove clutter and mitigate movement interference. Moreover, improved EWT with frequency segmentation refinement is applied on each radar to decompose vital signals of target chest and abdomen to vital sign-related sub-signals, respectively. After that, based on the thoracoabdominal movement correlation, cross-correlation functions are calculated among chest and abdomen sub-signals to estimate breath and heartbeat. The experiments are conducted under three kinds of PA situations and two general body movements, the results of which indicate the effectiveness and superiority of the proposed approach.

RhoA protects the podocytes against high glucose-induced apoptosis through YAP and plays critical role in diabetic nephropathy.

BACKGROUND: Podocyte apoptosis is important mechanism that leading to proteinuria in Diabetic nephropathy (DN), but the underling mechanisms that cause podocyte apoptosis in DN are not very clear. We have recently demonstrated that RhoA, a small GTPase protein, effectively protected podocyte apoptosis induced by LPS and ADR in vitro. However, the potential role of RhoA in DN is unknown. METHODS AND RESULTS: Conditionally immortalized mouse podocyte cells, C57BL/KsJ, db/db diabetic mice, and renal biopsies from patients with DN were used for study. The treatment of podocytes with high glucose (HG) for 48h significantly induced cell apoptosis and decreased RhoA expression and its activity. The expression of RhoA was also decreased in glomerular podocytes of db/db mice and patients with DN. Knockdown of RhoA by siRNA contributed in the apoptosis of podocyte and induced proteinuria in db/db mice. Beyond the increased pro-apoptotic Bax and the decreased anti-apoptotic Bcl-2, RhoA knockdown also inhibited the expression of a nuclear protein of YAP in podocyte. Over expression active form of YAP completely abolished the apoptosis of podocyte induced by RhoA knockdown. CONCLUSION: RhoA plays a critical role in DN probably by mediating the podocyte apoptosis through YAP. RhoA may be a novel molecular target for the treatment of DN.

Specific Photothermal Ablation Therapy of Endometriosis by Targeting Delivery of Gold Nanospheres.

Endometriosis is difficult to treat since the side effects of the current therapeutic method and the high recurrence rate; thus, newer and safer therapeutic approaches are urgently needed. This work investigates the enhanced permeability and retention effect of CdTe quantum dots (QDs) and hollow gold nanospheres (HAuNS) in endometriosis to increase the delivery of HAuNS into lesion cells. The surface of HAuNS is successfully conjugated with a TNYL peptide that has specific affinity for the EphB4 receptor, which is a member of the Eph family of receptor tyrosine kinases. It is found that the EphB4 receptor is overexpressed in endometriosis lesions. The data indicate that both QDs and HAuNS can efficiently accumulate in endometriotic lesions through permeable vessels and the TNYL-conjugated HAuNS (TNYL-HAuNS) accumulate more via the interaction with EphB4. The specific photothermal ablation therapy based on TNYL-HAuNS significantly inhibits the growth of the endometriotic volume and induces the atrophy and degeneration of ectopic endometrium with no detectable toxicity to the normal organs. The level of TNF-α and estradiol also significantly decreases in the endometriotic lesions, indicating that the treatment enables a recovery from hormonal imbalance and inflammatory injury. This work can be a valuable reference for future endometriosis therapy.

Continuously tuning effective refractive index based on thermally controllable magnetic metamaterials.

By employing a thermally active magnetic material, we theoretically design a kind of electromagnetic metamaterial with intrinsic magnetic response, termed magnetic metamaterial (MM). The retrieved effective electric permittivity ε(eff) and magnetic permeability µ(eff) exhibit a nearly continuous transition from double negative to double zero, and then to double positive by controlling the temperature, indicating a flexible tunability of the effective refractive index. The beam splitting, collimation, focusing, and total reflection are achieved at different typical temperatures. Most importantly, with the MM implemented under a gradient temperature, a gradient negative-zero-positive index metamaterial (NZPIM) can possibly be realized, thus providing a new platform to study wave features in NZPIM.

Near-infrared light-sensitive liposomes for the enhanced photothermal tumor treatment by the combination with chemotherapy.

PURPOSE: To develop a near-infrared (NIR) light-sensitive liposome, which contains hollow gold nanospheres (HAuNS) and doxorubicin (DOX), and evaluate their potential utility for enhancing antitumor activity and controlling drug release. METHODS: The liposomes (DOX&HAuNS-TSL) were designed based on a thermal sensitive liposome (TSL) formulation, and hydrophobically modified HAuNS were attached onto the membrane of the liposomes. The behavior of DOX release from the liposomes was investigated by the dialysis, diffusion in agarose gel and cellular uptake of the drug. The biodistribution of DOX&HAuNS-TSL was assessed by i.v. injection in tumor-bearing nude mice. Antitumor efficacy was evaluated both histologically using excised tissue and intuitively by measuring the tumor size and weight. RESULTS: Rapid and repetitive DOX release from the liposomes (DOX&HAuNS-TSL), could be readily achieved upon NIR laser irradiation. The treatment of tumor cells with DOX&HAuNS-TSL followed by NIR laser irradiation showed significantly greater cytotoxicity than the treatment with DOX&HAuNS-TSL alone, DOX-TSL alone (chemotherapy alone) and HAuNS-TSL plus NIR laser irradiation (Photothermal ablation, PTA, alone). In vivo antitumor study indicated that the combination of simultaneous photothermal and chemotherapeutic effect mediated by DOX&HAuNS-TSL plus NIR laser presented a significantly higher antitumor efficacy than the PTA alone mediated by HAuNS-TSL plus NIR laser irradiation. CONCLUSIONS: Our study could be as the valuable reference and direction for the clinical application of PTA in tumor therapy.

Pharmacokinetics, clearance, and biosafety of polyethylene glycol-coated hollow gold nanospheres.

OBJECTIVE: Gold nanoparticles have attracted enormous interest as potential theranostic agents. However, little is known about the long-term elimination and systemic toxicity of gold nanoparticles in the literature. Hollow gold nanospheres (HAuNS) is a class of photothermal conducting agent that have shown promises in photoacoustic imaging, photothermal ablation therapy, and drug delivery. It's very necessary to make clear the biosafety of HAuNS for its further application. METHODS: We investigated the cytotoxicity, complement activation, and platelet aggregation of polyethylene glycol (PEG)-coated HAuNS (PEG-HAuNS, average diameter of 63 nm) in vitro and their pharmacokinetics, biodistribution, organ elimination, hematology, clinical chemistry, acute toxicity, and chronic toxicity in mice. RESULTS: PEG-HAuNS did not induce detectable activation of the complement system and did not induce detectable platelet aggregation. The blood half-life of PEG-HAuNS in mice was 8.19 ± 1.4 hr. The single effective dose of PEG-HAuNS in photothermal ablation therapy was determined to be 12.5 mg/kg. PEG-HAuNS caused no adverse effects after 10 daily intravenous injections over a 2-week period at a dose of 12.5 mg/kg per injection (accumulated dose: 125 mg/kg). Quantitative analysis of the muscle, liver, spleen, and kidney revealed that the levels of Au decreased 45.2%, 28.6%, 41.7%, and 40.8%, respectively, from day 14 to day 90 after the first intravenous injection, indicating that PEG-HAuNS was slowly cleared from these organs in mice. CONCLUSION: Our data support the use of PEG-HAuNS as a promising photothermal conducting agent.

Diagnostic performance of ultrasound-based artificial intelligence for predicting key molecular markers in breast cancer: A systematic review and meta-analysis.

BACKGROUND: Breast cancer (BC) diagnosis and treatment rely heavily on molecular markers such as HER2, Ki67, PR, and ER. Currently, these markers are identified by invasive methods. OBJECTIVE: This meta-analysis investigates the diagnostic accuracy of ultrasound-based radiomics as a novel approach to predicting these markers. METHODS: A comprehensive search of PubMed, EMBASE, and Web of Science databases was conducted to identify studies evaluating ultrasound-based radiomics in BC. Inclusion criteria encompassed research on HER2, Ki67, PR, and ER as key molecular markers. Quality assessment using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and Radiomics Quality Score (RQS) was performed. The data extraction step was performed systematically. RESULTS: Our meta-analysis quantifies the diagnostic accuracy of ultrasound-based radiomics with a sensitivity and specificity of 0.76 and 0.78 for predicting HER2, 0.80, and 0.76 for Ki67 biomarkers. Studies did not provide sufficient data for quantitative PR and ER prediction analysis. The overall quality of studies based on the RQS tool was moderate. The QUADAS-2 evaluation showed that the studies had an unclear risk of bias regarding the flow and timing domain. CONCLUSION: Our analysis indicated that AI models have a promising accuracy for predicting key molecular biomarkers' status in BC patients. We performed the quantitative analysis for HER2 and Ki67 biomarkers which yielded a moderate to high accuracy. However, studies did not provide adequate data for meta-analysis of ER and PR prediction accuracy of developed models. The overall quality of the studies was acceptable. In future research, studies need to report the results thoroughly. Also, we suggest more prospective studies from different centers.

Probabilistic Scatter Plots for visualizing carbohydrate and lipid metabolism states in Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by dysregulated carbohydrate and lipid metabolism, which are its primary features. However, traditional biochemical markers pose challenges for accurate quantification and visualization of metabolic states. This study introduces a novel states-based approach for accurate NAFLD assessment. METHODS: Joint probabilistic distributions of triglycerides and glycemia were constructed using dual-indicator Probabilistic Scatter Plots based on clinical data (healthy controls: n = 1978; NAFLD patients: n = 471). Patterns of metabolic dysregulation were revealed through comparison against healthy profiles. Self-organizing feature mapping (SOFM) clustered the distributions into four dominant states. RESULTS: Healthy scatter plots demonstrated a distinct progression of sub-states ranging from very healthy to sub-healthy. In contrast, NAFLD plots exhibited shifted probability centers and outward divergence. SOFM clustering classified the states into: mild; moderate and severe lipid metabolism disorders; and carbohydrate metabolism disorders. CONCLUSIONS: Probabilistic Scatter Plots, when combined with SOFM clustering, facilitate a states-based quantification of NAFLD metabolic dysregulation. This method integrates multi-dimensional biochemical indicators and their distributions into a cohesive framework, enabling precise and intuitive visualization for personalized diagnosis and monitoring of prognostic developments.

Mechanism and role of nuclear laminin B1 in cell senescence and malignant tumors.

Nuclear lamin B1 (LMNB1) is a member of the nuclear lamin protein family. LMNB1 can maintain and ensure the stability of nuclear structure and influence the process of cell senescence by regulating chromatin distribution, DNA replication and transcription, gene expression, cell cycle, etc. In recent years, several studies have shown that the abnormal expression of LMNB1, a classical biomarker of cell senescence, is highly correlated with the progression of various malignant tumors; LMNB1 is therefore considered a new potential tumor marker and therapeutic target. However, the mechanism of action of LMNB1 is influenced by many factors, which are difficult to clarify at present. This article focuses on the recent progress in understanding the role of LMNB1 in cell senescence and malignant tumors and offers insights that could contribute to elucidating the mechanism of action of LMNB1 to provide a new direction for further research.

Overcoming Endosomal Escape Barriers in Gene Drug Delivery Using De Novo Designed pH-Responsive Peptides.

A major challenge in using nanocarriers for intracellular drug delivery is their restricted capacity to escape from endosomes into the cytosol. Here, we significantly enhance the drug delivery efficiency by accurately predicting and regulating the transition pH (pH0) of peptides to modulate their endosomal escape capability. Moreover, by inverting the chirality of the peptide carriers, we could further enhance their ability to deliver nucleic acid drugs as well as antitumor drugs. The resulting peptide carriers exhibit versatility in transfecting various cell types with a high efficiency of up to 90% by using siRNA, pDNA, and mRNA. In vivo antitumor experiments demonstrate a tumor growth inhibition of 83.4% using the peptide. This research offers a potent method for the rapid development of peptide vectors with exceptional transfection efficiencies for diverse pathophysiological indications.

PIWI-interacting RNAs: Critical roles and therapeutic targets in cancer.

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a novel class of small regulatory RNAs (approximately 24-31 nucleotides in length) that often bind to members of the PIWI protein family. piRNAs regulate transposons in animal germ cells; piRNAs are also specifically expressed in many human tissues and regulate pivotal signaling pathways. Additionally, the abnormal expression of piRNAs and PIWI proteins has been associated with various malignant tumours, and multiple mechanisms of piRNA-mediated target gene dysregulation are involved in tumourigenesis and progression, suggesting that they have the potential to serve as new biomarkers and therapeutic targets for tumours. However, the functions and potential mechanisms of action of piRNAs in cancer have not yet been elucidated. This review summarises the current findings on the biogenesis, function, and mechanisms of piRNAs and PIWI proteins in cancer. We also discuss the clinical significance of piRNAs as diagnostic or prognostic biomarkers and therapeutic tools for cancer. Finally, we present some critical questions regarding piRNA research that need to be addressed to provide insight into the future development of the field.

Pathogenetic and Therapeutic Role of Gut Microbiome in Immunoglobin A Nephropathy.

Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephritis, which is mainly characterized by excessive IgA deposition in the glomerular mesangial area. Although exploring the pathogenesis of IgAN and improving the treatment strategies continuously, the exact pathogenesis of IgAN remains unclear and the disease still leads to high mortality. Recently, emerging evidence has demonstrated that dysregulated intestinal mucosal immunity and gut microbiome imbalance may play a combined role in the development and progression of IgAN. It has been suggested that reconstructing the intestinal microenvironment and maintaining the stability and metabolic balance of gut microbiome are expected to become new treatment strategies. Meanwhile, inhibiting mucosa-associated lymphoid tissue (MALT) controlled by the gut microbiome may become an alternative treatment, especially used to reduce the excessive production of IgA in IgAN. In this review, we summarized the correlation between gut microbiome and the pathogenesis of IgAN, as well as the therapeutic potential of gut microbiome in this disease.

An ultra pH-responsive peptide nanocarrier for cancer gene therapy.

The tumor microenvironment is a very complex and dynamic ecosystem. Although a variety of pH-responsive peptides have been reported to deliver nucleic acid drugs for cancer treatment, these responses typically only target the acidic microenvironment of the tumor or the lysosome, and the carrier suffers from issues such as low transfection efficiency and poor lysosomal escape within the cell. To address this problem, we have developed an ultra pH-responsive peptide nanocarrier that can efficiently deliver siRNA, pDNA, and mRNA into cancer cells by performing progressive dynamic assembly in response to pH changes in the acidic tumor microenvironment (pH 6.5-6.8) and the acidic intracellular lysosomal environment (pH 5.0-6.0). The maximum transfection efficiency was 87.1% for pDNA and 74.9% for mRNA, which is higher than that of peptide-based nanocarrier reported to date. In addition, the targeting sequence on the surface allows the peptide@siRNA complex to efficiently enter cancer cells, causing 96% of cancer cell mortality. The carrier has high biocompatibility and low cytotoxicity, making it highly promising for application in immunotherapy and gene therapy of tumors.

Related Markers for the Precision Diagnosis of Complex Appendicitis in Children.

Acute appendicitis is the most common surgical emergency in children. Despite the high incidence rate of appendicitis, it is sometimes misdiagnosed or missed. Complex appendicitis (CA) in children is characterized by a critical condition, several complications, and high mortality. Precision distinguishing between simple appendicitis and CA correctly is key to choosing appropriate treatment. A safe, cheap, rapid, extensive and accurate diagnostic marker of appendicitis will be of great significance for emergency general surgeons to treat suspected CA. Many studies have investigated possible diagnostic markers for the diagnosis of CA in children. In this study, studies related to CA in children in recent years are summarized, and the related markers and scoring system for the diagnosis of CA in children are summarized.

The multi-factor modulated biogenesis of the mitochondrial multi-span protein Om14.

The mitochondrial outer membrane (MOM) harbors proteins that traverse the membrane via several helical segments and are called multi-span proteins. To obtain new insights into the biogenesis of these proteins, we utilized yeast mitochondria and the multi-span protein Om14. Testing different truncation variants, we show that while only the full-length protein contains all the information that assures perfect targeting specificity, shorter variants are targeted to mitochondria with compromised fidelity. Employing a specific insertion assay and various deletion strains, we show that proteins exposed to the cytosol do not contribute significantly to the biogenesis process. We further demonstrate that Mim1 and Porin support optimal membrane integration of Om14 but none of them are absolutely required. Unfolding of newly synthesized Om14, its optimal hydrophobicity, and higher fluidity of the membrane enhanced the import capacity of Om14. Collectively, these findings suggest that MOM multi-span proteins follow different biogenesis pathways in which proteinaceous elements and membrane behavior contribute to a variable extent to the combined efficiency.

Case report: An intraretinal macrocyst with crystalline content and retinal detachment.

Introduction: An intraretinal macrocyst is a cavity located in the outer plexiform layer of the retina. It is commonly filled with liquid or blood. To date, few case reports of intraretinal macrocysts with crystalline content and retinal detachment have been published. Case presentation: A 44-year-old woman with no history of other diseases complained of decreased vision in her right eye that had persisted for 20 days. The best corrected visual acuity of the right eye was hand motion. Comprehensive ophthalmic examinations were performed, including a vision test, slit lamp fundus examination, ocular B-scan ultrasound, and orbital magnetic resonance imaging. We performed vitrectomy and retinotomy to sufficiently remove the macrocyst and relieve retinal traction. We then reattached the retina and filled it with silicone oil. During the surgery, we found that the cyst had crystalline content, which has not been previously reported, to the best of our knowledge. Finally, the pathological results confirmed a final diagnosis of intraretinal macrocyst. Six months later, we performed a second operation to remove the silicone oil and implant an intraocular lens. After both surgeries, the best corrected visual acuity of the patient's right eye was restored to 20/200, and the retina had repositioned. Conclusion: Intraretinal macrocysts are very rare. Both orbital magnetic resonance imaging and ocular B-scan ultrasound are essential for their diagnosis. Our results indicated that vitrectomy was the best way to remove the cyst and reattach the retina.

Recent progress of metal nanoclusters in electrochemiluminescence.

Metal nanoclusters (MeNCs), composed of a few to hundreds of metal atoms and appropriate surface ligands, have attracted extensive interest in the electrochemiluminescence (ECL) realm owing to their molecule-like optical, electronic, and physicochemical attributes and are strongly anticipated for discrete energy levels, fascinating electrocatalytic activity, and good biocompatibility. Over the past decade, huge efforts have been devoted to the synthesis, properties, and application research of ECL-related MeNCs, and this field is still a subject of heightened concern. Therefore, this perspective aims to provide a comprehensive overview of the recent advances of MeNCs in the ECL domain, mainly covering the emerged ECL available MeNCs, unique chemical and optical properties, and the general ECL mechanisms. Synthesis strategies for desirable ECL performance are further highlighted, and the resulting ECL sensing applications utilizing MeNCs as luminophores, quenchers, and substrates are discussed systematically. Finally, we anticipate the future prospects and challenges in the development of this area.