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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Two-Week Central Macular Thickness Reduction Rate >37% Predicts the Long-Term Efficacy of Anti-vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Retinal Vein Occlusion.

Objective: To determine if the early response assessments can predict the long-term efficacy of anti-vascular endothelial growth factor (VEGF) treatment for macular edema secondary to retinal vein occlusion (RVO-ME). Methods: A retrospective study of patients with diagnosis of RVO-ME and intravitreal anti-VEGF treatment was conducted. Clinical characteristics including age, gender, disease subtype and disease duration were recorded at baseline. The best corrected visual acuity (BCVA and logMAR), intraocular pressure (IOP), and central macular thickness (CMT) were recorded at baseline, 2 weeks, and every month (months 1-6) after injection. Further, we compared the early response assessments between the cured group (6-month CMT ≤ 250 µm) and the uncured group (6-month CMT > 250 µm). Results: A total of 164 eyes in 164 patients (77 male and 87 female) were included. At each post-injection time point, both BCVA and CMT are significantly decreased from baseline (all P < 0.001). Spearman's test showed that 2-week CMT reduction rate after the first injection was negatively correlated with BCVA at 6 months (r = -0.359, P < 0.001). Compared with the uncured group (47 cases), the cured group (117 cases) was younger (59.53 ± 11.68 vs. 65.19 ± 13.10 years old, P < 0.01), had more BRVO patients (76.1% vs. 44.7%, P < 0.01), a shorter disease duration (1.92 ± 2.43 vs. 5.05 ± 4.32 months, P < 0.01), lower baseline CMT (527.09 ± 154.95 vs. 768.96 ± 287.75 µm, P < 0.01), and lower baseline BCVA (0.86 ± 0.44 vs. 1.31 ± 0.51, P < 0.01). At each post-injection time point, the cured group had lower CMT and BCVA values when compared to the uncured group (all P < 0.01), and the 2-week CMT reduction rate was identified as the earliest response time to predict the long-term treatment efficacy. Moreover, ROC curve analysis indicated that a 2-week CMT reduction rate >37% yielded the best cut-off point for predicting the long-term cure of anti-VEGF treatment at 6 months (P < 0.001). Multivariable logistic regression confirmed that the 2-week CMT reduction rate >37% was independently associated with the 6-month cured rate (OR = 9.639, 95% Cl = 1.030-90.227, P = 0.047). Conclusion: Age, disease duration, baseline CMT, and baseline BCVA are associated with visual outcomes at 6-month of anti-VEGF treatment for RVO-ME. The "2-week CMT reduction rate >37%" after the first injection is an independent factor to predict better long-term outcomes.

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.

Crossed Pathways for Radiation-Induced and Immunotherapy-Related Lung Injury.

Radiation-induced lung injury (RILI) is a form of radiation damage to normal lung tissue caused by radiotherapy (RT) for thoracic cancers, which is most commonly comprised of radiation pneumonitis (RP) and radiation pulmonary fibrosis (RPF). Moreover, with the widespread utilization of immunotherapies such as immune checkpoint inhibitors as first- and second-line treatments for various cancers, the incidence of immunotherapy-related lung injury (IRLI), a severe immune-related adverse event (irAE), has rapidly increased. To date, we know relatively little about the underlying mechanisms and signaling pathways of these complications. A better understanding of the signaling pathways may facilitate the prevention of lung injury and exploration of potential therapeutic targets. Therefore, this review provides an overview of the signaling pathways of RILI and IRLI and focuses on their crosstalk in diverse signaling pathways as well as on possible mechanisms of adverse events resulting from combined radiotherapy and immunotherapy. Furthermore, this review proposes potential therapeutic targets and avenues of further research based on signaling pathways. Many new studies on pyroptosis have renewed appreciation for the value and importance of pyroptosis in lung injury. Therefore, the authors posit that pyroptosis may be the common downstream pathway of RILI and IRLI; discussion is also conducted regarding further perspectives on pyroptosis as a crucial signaling pathway in lung injury treatment.

Signal Pathways and Markers Involved in Acute Lung Injury Induced by Acute Pancreatitis.

Acute pancreatitis (AP) is a common acute abdominal disease with a mortality rate of about 30%. Acute lung injury (ALI) is a common systemic complication of acute pancreatitis, with progressive hypoxemia and respiratory distress as the main manifestations, which can develop into acute respiratory distress syndrome or even multiple organ dysfunction syndrome (MODS) in severe cases, endangering human health. In the model of AP, pathophysiological process of the lung can be summarized as oxidative stress injury, inflammatory factor infiltration, and alveolar cell apoptosis. However, the intrinsic mechanisms underlying AP and how it leads to ALI are not fully understood. In this paper, we summarize recent articles related to AP leading to ALI, including the signal transduction pathways and biomarkers of AP-ALI. There are factors or pathway aggravating ALI, the JAK2-STAT3 signaling pathway, NLRP3/NF-κB pathway, mitogen-activated protein kinase, PKC pathway, neutrophil protease (NP)-LAMC2-neutrophil pathway, and the P2X7 pathway, and there are important transcription factors in the NRF2 signal transduction pathway which could give researchers better understanding of the underlying mechanisms controlling AP and ALI and lay the foundation for finally curing ALI induced by AP.

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.

The chaperone-binding activity of the mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress.

Most mitochondrial proteins are synthesized as precursors in the cytosol and post-translationally transported into mitochondria. The mitochondrial surface protein Tom70 acts at the interface of the cytosol and mitochondria. In vitro import experiments identified Tom70 as targeting receptor, particularly for hydrophobic carriers. Using in vivo methods and high-content screens, we revisit the question of Tom70 function and considerably expand the set of Tom70-dependent mitochondrial proteins. We demonstrate that the crucial activity of Tom70 is its ability to recruit cytosolic chaperones to the outer membrane. Indeed, tethering an unrelated chaperone-binding domain onto the mitochondrial surface complements most of the defects caused by Tom70 deletion. Tom70-mediated chaperone recruitment reduces the proteotoxicity of mitochondrial precursor proteins, particularly of hydrophobic inner membrane proteins. Thus, our work suggests that the predominant function of Tom70 is to tether cytosolic chaperones to the outer mitochondrial membrane, rather than to serve as a mitochondrion-specifying targeting receptor.