Drug-resistant exosome miR-99b-3p induces macrophage polarization and confers chemoresistance on sensitive cells by targeting PPP2CA.

The most frequent cancer in women to be diagnosed is breast cancer, and chemotherapy's ability to be effective is still significantly hampered by drug resistance. Tumor-derived exosomes play a significant role in drug resistance, immunological modulation, metastasis, and tumor proliferation. In this work, the differential miRNAs in the exosomes of drug-resistant and susceptible breast cancer cell lines were screened using miRNA-seq. It was demonstrated that drug-resistant human breast cancer cells and their exosomes expressed more miR-99b-3p than did susceptible cells and their exosomes. While drug-resistant cells' migration and paclitaxel resistance can be inhibited by driving down the expression of miR-99b-3p in those cells, exosomes containing miR-99b-3p from those cells can help susceptible cells migrate and become resistant. miR-99b-3p affects cell migration and paclitaxel resistance by targeting PPP2CA to promote AKT/mTOR phosphorylation. The drug-resistant cell exosome miR-99b-3p can be taken up by macrophages and affect the drug resistance and migration ability of sensitive cells by promoting the M2 polarization of macrophages. Downregulating miR-99b-3p has been shown in vivo to reverse macrophage M2 polarization, suppress tumor development, and prevent treatment resistance. The present study shows that drug-resistant cell exosomes miR-99b-3p can directly influence the migration, proliferation, and paclitaxel sensitivity of sensitive cells via PPP2CA. Additionally, the exosomes from drug-resistant cells can influence the polarization of macrophage M2 in the tumor microenvironment, which can also have an impact on the proliferation, migration, and paclitaxel sensitivity of sensitive cells.

Telemedicine-medical "snack community"-PHS ecosystem: Insights into the double-edged sword role of telemedicine in clinical practice and medical education during the COVID-19 pandemic and beyond.

Telemedicine has gained tremendous development during the COVID-19 pandemic. With deblocking and opening, telemedicine accelerates the evolvution of the medical "snack community" and undermines the perception of medical students and staff, which promotes the incidence of psychosocial-related disorders. Moreover, the inconsistent telemedicine adaptability between medical workers and patients aggravates the doctor-patient conflict due to the aging population and COVID-19 squeal. Telemedicine is colliding with the national healthcare system, whose synchronization with conventional medical service is crucial to coordinate the relationship among medical payment, patient privacy and qualifications of clinicians. This study puts more emphasis on the double-edged sword role of telemedicine in clinical practice and medical education during the COVID-19 pandemic and beyond. Overall, while telemedicine has demonstrated its utility in health care throughout the COVID pandemic, it is pretty critical to continue evaluating the efficacy and limitations of telemedicine in order to maintain equal access to medical service and high-quality medical education. A new concept as telemedicine-medical "snack community"-PHS ecosystem, where the psychological health education system and partners healthcare system with enough bandwidth, especially 5G technology, could optimize the effect of telemedicine on medical practice and education, is proposed.

Integrative Pan-Cancer Analysis Reveals the Oncogenic Role of MND1 and Validation of MND1's Role in Breast Cancer.

Purpose: Meiotic nuclear division 1 (MND1) is a meiosis-specific protein that promotes lung adenocarcinoma progression. However, its expression and biological function across cancers remain largely unexplored. Patients and Methods: The expression, prognostic significance, mutation status, and methylation profile of MND1 in various cancers were comprehensively analyzed using the TIMER, GTEX, Kaplan-Meier plotter, cBioPortal, and GSCA databases. Additionally, we constructed a PPI network, enrichment analysis and single-cell transcriptomic sequencing to elucidate the underlying mechanism of MND1. Furthermore, we investigated the association between MND1 expression and drug sensitivity using CellMiner. Moreover, we also explored the correlation between MND1 expression and immune infiltration. Finally, we validated the functional role of MND1 in breast cancer through IHC staining, CCK8, EdU, colony formation, and flow cytometry assays. Results: MND1 has been reported to be highly expressed in Pan-cancer, High MND1 expression was significantly associated with poor prognosis in cancers. Additionally, MND1 mutation frequency is high in most cancers, and its expression correlates with methylation. Furthermore, MND1 expression significantly correlates with immune checkpoint blockade (ICB) markers, including PD-L1, PD-1, and CTLA-4. The PPI network reveals interactions between MND1 and PSMC3IP, BRCA1, and BRCA2. Enrichment analysis and single-cell sequencing indicate that MND1 positively correlates with cell cycle. ROC curve reveals favorable diagnostic efficacy of MND1 in breast cancer. In vitro, MND1 overexpression promotes breast cancer cell proliferation and increases the expression of key cell cycle regulators (CDK4, CDK6, and cyclin D3), accelerating the G1/S phase transition and leading to abnormal breast cancer cell proliferation. The immunohistochemical analysis revealed a robust expression of MND1 in breast cancer tissues, exhibiting a significant positive correlation with PD-L1 and FOXP3. Conclusion: MND1 is an oncogene and may serve as a biomarker for cancer prognosis and immunotherapy. Targeting MND1 may be a potential tumor treatment strategy.

Unraveling links between aging, circadian rhythm and cancer: Insights from evidence-based analysis.

Aging and circadian rhythms have been connected for decades, but their molecular interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using the bibliometric analysis. Publications in the PubMed and Web of Science databases were retrieved. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, melatonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer. These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.

Modulus alteration of thin polystyrene films by their neighboring PDMS: Soft and hard confinement.

It is highly demanded to understand the confinement effect on nanoconfined polymers. Recent studies reported a strong perturbation of local dynamics and substantial alteration of glass transition temperature Tg at nanoscale. However, how confinement affects the mechanical properties of polymers is not fully understood. Here, we show that the modulus of thin polymer films could be remarkedly altered through a polymer-polymer interface. The modulus of a thin polystyrene (PS) film next to a polydimethylsiloxane (PDMS) was determined from the PS-PDMS bilayer bulging test. A series of experiments show that the modulus of PS can be increased up to 37%, when the modulus of the neighboring PDMS varies from 1.04 to 4.88 MPa. The results demonstrate a strong sensitivity of mechanical properties of thin polymers to the hard/soft environment, which we attribute to the change of high-mobility layer by the polymer-polymer interface.

SKA3 targeted therapies in cancer precision surgery: bridging bench discoveries to clinical applications - review article.

Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore, which plays a vital role in proper chromosomal segregation and cell division. Recently, SKA3 have been demonstrated its oncogenic role of tumorigenesis and development in cancers. In this review, the authors comprehensively deciphered SKA3 in human cancer from various aspects, including bibliometrics, pan-cancer analysis, and narrative summary. The authors also provided the top 10 predicted drugs targeting SKA3. The authors proposed that SKA3 was a potential target and brought new therapeutic opportunities for cancer patients.

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation.

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

Roles of PPAR activation in cancer therapeutic resistance: Implications for combination therapy and drug development.

Therapeutic resistance is a major obstacle to successful treatment or effective containment of cancer. Peroxisome proliferator-activated receptors (PPARs) play an essential role in regulating energy homeostasis and determining cell fate. Despite of the pleiotropic roles of PPARs in cancer, numerous studies have suggested their intricate relationship with therapeutic resistance in cancer. In this review, we provided an overview of the roles of excessively activated PPARs in promoting resistance to modern anti-cancer treatments, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The mechanisms through which activated PPARs contribute to therapeutic resistance in most cases include metabolic reprogramming, anti-oxidant defense, anti-apoptosis signaling, proliferation-promoting pathways, and induction of an immunosuppressive tumor microenvironment. In addition, we discussed the mechanisms through which activated PPARs lead to multidrug resistance in cancer, including drug efflux, epithelial-to-mesenchymal transition, and acquisition and maintenance of the cancer stem cell phenotype. Preliminary studies investigating the effect of combination therapies with PPAR antagonists have suggested the potential of these antagonists in reversing resistance and facilitating sustained cancer management. These findings will provide a valuable reference for further research on and clinical translation of PPAR-targeting treatment strategies.

Direct measurement and modeling of viscoelastic-viscoplastic properties of freely standing thin polystyrene films.

The demand for applications, such as coatings, separation filters, and electronic packaging, has greatly driven the research of polymer films. At nanometer scale, mechanical properties of thin polymer films can significantly deviate from bulk. Despite outstanding progresses, there still lack deep discussions on nonlinear viscoelastic-viscoplastic response and their interactions under nanoconfinement. In this work, by conducting measurements via the bubble inflation method and modelling using Schapery and Perzyna equations, we demonstrate nonlinear viscoelastic-viscoplastic properties of freely standing thin polystyrene (PS) films. The results show the unchanged glassy compliance and the rubbery stiffening phenomenon for thin PS films, where the lower rubbery plateau in rubbery stiffening may originate from the induced molecular orientation by plastic deformation. With decreasing film thickness, viscosity and yield stress in viscoplasticity increase in an exponential and a linear trend, respectively, indicating the significant role of nanoconfinement effect on viscoplastic properties. These findings may reveal that there are many properties from linear viscoelasticity to nonlinear viscoelasticity-viscoplasticity that need to be explored and unveiled for sufficient understanding of the nanoconfinement effect on altering mechanical behavior of polymers.

Focal ablation therapy presents promising results for selectively localized prostate cancer patients.

Due to its lower risk of consequences when compared to a radical approach, focal treatment is a viable and minimally invasive option for treating specific localized prostate cancer. Although several recent good non-randomized trials have suggested that focused therapy may be an alternative choice for some patients, additional high-quality evidence is needed before it can be made widely available as a conventional treatment. As a result, we have summarized the most recent findings from the 38th Annual European Association of Urology Congress, one of the most renowned annual conferences in the area of urology, regarding focal ablation therapy for patients with localized prostate cancer. Additionally, we also provided clinical trials in progress for researchers to better understand the current research status of this field.

Surface plasmonic coupling of Au nanoparticle arrays with ultrathin hexagonal boron nitride nanosheets for Raman enhancement.

Integration of hexagonal boron nitride (h-BN) with plasmonic nanostructures that possess nanoscale field confinement will enable unusual properties; hence, the manipulation and understanding of the light interactions are highly desirable. Here, we demonstrate the surface plasmonic coupling of Au nanoparticles (ANPs) with ultrathin h-BN nanosheets (BNNS) in nonspecific nanocomposites leading to a great enhancement of the Raman signal of E2g in both experimental and theoretical manner. The nanocomposites were fabricated from liquid-exfoliated atomically thin BNNS and diblock copolymer-based ANPs with excellent dispersion through a self-assembly approach. By precisely varying the size of ANPs from 3 to 9 nm, the Raman signal of BNNS was improved from 1.7 to 71. In addition, the underlying mechanism has been explored from the aspects of electromagnetic field coupling strength between the localized surface plasmons excited from ANPs and the surrounding dielectric h-BN layers, as well as the charge transfer at the BNNS/ANPs interfaces. Moreover, we also demonstrate its capability to detect dye molecules as a surface enhanced Raman scattering (SERS) substrate. This work provides a basis for the self-assembly of BNNS hierarchical nanocomposites allowing for plasmon-mediated modulation of their optoelectronic properties, thereby showing the great potential not only in the field of SERS but also in large-scale h-BN-based plasmonic devices.

Non-convulsive Status Epilepticus in SEMA6B-Related Progressive Myoclonic Epilepsy: A Case Report With Literature Review.

Progressive myoclonic epilepsy (PME) is a group of rare diseases characterized by progressive myoclonus, cognitive impairment, ataxia, and other neurologic deficits. PME has high genetic heterogeneity, and more than 40 genes are reportedly associated with this disorder. SEMA6B encodes a member of the semaphorin family and was first reported to cause PME in 2020. Herein, we present a rare case of PME due to a novel SEMA6B gene mutation in a 6-year-old boy born to healthy non-consanguineous Chinese parents. His developmental milestones were delayed, and he developed recurrent atonic seizures and myoclonic seizures without fever at 3 years and 11 months of age. He experienced recurrent myoclonic seizures, non-convulsive status epilepticus (NCSE), atonic seizures, and atypical absence seizures during the last 2 years. At different time points since onset, valproic acid, levetiracetam, piracetam, and clobazam were used to control the intractable seizures. Notably, NCSE was controlled by a combination of piracetam with clobazam and valproic acid instead of intravenous infusion of midazolam and phenobarbital. Due to the limited number of cases reported to date, the clinical description of our case provides a better understanding of the genotype-phenotype correlations associated with PME and indicate that piracetam may be effective against NCSE in patients with SEMA6B-related PME.