Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer Therapy Resistance: from Biology to Clinical Opportunity.

Mesenchymal stem cells (MSCs) are a type of stromal cells characterized by their properties of self-renewal and multi-lineage differentiation, which make them prominent in regenerative medicine. MSCs have shown significant potential for the treatment of various diseases, primarily through the paracrine effects mediated by soluble factors, specifically extracellular vesicles (EVs). MSC-EVs play a crucial role in intercellular communication by transferring various bioactive substances, including proteins, RNA, DNA, and lipids, highlighting the contribution of MSC-EVs in regulating cancer development and progression. Remarkably, increasing evidence indicates the association between MSC-EVs and resistance to various types of cancer treatments, including radiotherapy, chemotherapy, targeted therapy, immunotherapy, and endocrinotherapy. In this review, we provide an overview of the recent advancements in the biogenesis, isolation, and characterization of MSC-EVs, with an emphasis on their functions in cancer therapy resistance. The clinical applications and future prospects of MSC-EVs for mitigating cancer therapy resistance and enhancing drug delivery are also discussed. Elucidating the role and mechanism of MSC-EVs in the development of treatment resistance in cancer, as well as evaluating the clinical significance of MSC-EVs, is crucial for advancing our understanding of tumor biology. Meanwhile, inform the development of effective treatment strategies for cancer patients in the future.

Electrically Doped PNPN Tunnel Field-Effect Transistor Using Dual-Material Polarity Gate with Improved DC and Analog/RF Performance.

A new structure for PNPN tunnel field-effect transistors (TFETs) has been designed and simulated in this work. The proposed structure incorporates the polarity bias concept and the gate work function engineering to improve the DC and analog/RF figures of merit. The proposed device consists of a control gate (CG) and a polarity gate (PG), where the PG uses a dual-material gate (DMG) structure and is biased at -0.7 V to induce a P+ region in the source. The PNPN structure introduces a local minimum on the conduction band edge curve at the tunneling junction, which dramatically reduces the tunneling width. Furthermore, we show that incorporating the DMG architecture further enhances the drive current and improves the subthreshold slope (SS) characteristics by introducing an additional electric field peak. The numerical simulation reveals that the electrically doped PNPN TFET using DMG improves the DC and analog/RF performances in comparison to a conventional single-material gate (SMG) device.

Noncoding RNAs in cancer ferroptosis: From biology to clinical opportunity.

Ferroptosis is a recently discovered pattern of programmed cell death that is nonapoptotic and irondependent. It is involved in lipid peroxidation dependent on reactive oxygen species. Ferroptosis has been verified to play a crucial regulatory role in a variety of pathological courses of disease, in particularly cancer. Emerging research has highlighted the potential of ferroptosis in tumorigenesis, cancer development and resistance to chemotherapy. However, the regulatory mechanism of ferroptosis remains unclear, which limits the application of ferroptosis in cancer treatment. Noncoding RNAs (ncRNAs) are noncoding transcripts that regulate gene expression in various ways to affect the malignant phenotypes of cancer cells. At present, the biological function and underlying regulatory mechanism of ncRNAs in cancer ferroptosis have been partially elucidated. Herein, we summarize the current knowledge of the central regulatory network of ferroptosis, with a focus on the regulatory functions of ncRNAs in cancer ferroptosis. The clinical application and prospects of ferroptosis-related ncRNAs in cancer diagnosis, prognosis and anticancer therapies are also discussed. Elucidating the function and mechanism of ncRNAs in ferroptosis, along with assessing the clinical significance of ferroptosis-related ncRNAs, provides new perspectives for understanding cancer biology and treatment approaches, which may benefit numerous cancer patients in the future.

Autophagy-induced intracellular signaling fractional nano-drug system for synergistic anti-tumor therapy.

Autophagy inducers increase the sensitivity of tumor cells to chemotherapeutic drugs and enhance anti-tumor efficacy. An autophagy-induced intracellular signaling fractional nano-drug system was constructed for the co-delivery of the autophagy inducer rapamycin (RAPA) and the anti-tumor drug 9-nitro-20(S)-camptothecin (9-NC). Link peptides, including cathepsin B-sensitive peptides (Ala-Leu-Ala-Leu, ALAL), nucleus-targeting peptides (TAT, sequence: YGRKKRRQRRR), and chrysin (CHR)-modified hydrophobic biodegradable polymers (poly(-caprolactone)) (PCL), were grafted onto hyaluronic acid (HA) to yield two amphiphiles, HA-ALAL-PCL-CHR (CPAH) and HA-ALAL-TAT-PCL-CHR (CPTAH). Spherical RAPA- and 9-NC-loaded micelles were obtained by the self-assembly of amphiphiles comprising CPAH and RAPA and CPTAH and 9-NC. In this fractional nano-drug system, RAPA was released earlier than 9-NC, as CPAH as a RAPA carrier lacked a nucleus-targeting TAT (unlike CPTAH as an 9-NC carrier). RAPA induced autophagy in tumor cells and improved their sensitivity, whereas the secondary nucleus-targeting micelles directly delivered 9-NC to the nucleus, considerably improving anti-tumor efficacy. Immunofluorescence staining, acridine orange (AO) staining, and western blotting results demonstrated that the system induced a high level of autophagy in combination chemotherapy. The proposed system possesses a high level of cytotoxicity in vitro and in vivo and provides a potential method for enhancing anti-tumor efficacy in clinical settings.

Structural insights into RNase J that plays an essential role in Mycobacterium tuberculosis RNA metabolism.

Ribonucleases (RNases) are responsible for RNA metabolism. RNase J, the core enzyme of the RNA degradosome, plays an essential role in global mRNA decay. Emerging evidence showed that the RNase J of Mycobacterium tuberculosis (Mtb-RNase J) could be an excellent target for treating Mtb infection. Here, crystal structures of Mtb-RNase J in apo-state and complex with the single-strand RNA reveal the conformational change upon RNA binding and hydrolysis. Mtb-RNase J forms an active homodimer through the interactions between the ß-CASP and the ß-lactamase domain. Knockout of RNase J slows the growth rate and changes the colony morphologies and cell length in Mycobacterium smegmatis, which is restored by RNase J complementation. Finally, RNA-seq analysis shows that the knockout strain significantly changes the expression levels of 49 genes in metabolic pathways. Thus, our current study explores the structural basis of Mtb-RNase J and might provide a promising candidate in pharmacological treatment for tuberculosis.

Controlling Drain Side Tunneling Barrier Width in Electrically Doped PNPN Tunnel FET.

In this paper, we propose and investigate an electrically doped (ED) PNPN tunnel field effect transistor (FET), in which the drain side tunneling barrier width is effectively controlled to obtain a suppressed ambipolar current. We present that the proposed PNPN tunnel FETs can be realized without chemically doped junctions by applying the polarity bias concept to a doped N+/P- starting structure. Using numerical device simulations, we demonstrate how the tunneling barrier width on the drain side can be influenced by several design parameters, such as the gap length between the channel and the drain (Lgap), the working function of the polarity gate, and the dielectric material of the spacer. The simulation results show that an ED PNPN tunneling FET with an ED drain, which has been explored for the first time, exhibits a low ambipolar current of 5.87 × 10-16 A/µm at a gap length of 20 nm. The ambipolar current is reduced by six orders of magnitude compared to that which occurs with a conventional ED PNPN tunnel FET with a uniformly doped drain, while the average subthreshold slope and the ON state and OFF state currents remained nearly identical.

Bone Health Status of Children with Spinal Muscular Atrophy

Background@#Spinal muscular atrophy (SMA) is a group of rare, inherited neuromuscular disorders. Bone health is often a neglected issue in children with SMA. This study aimed to evaluate the bone health status of children with SMA in Hong Kong. @*Methods@#This retrospective study included children with SMA who were managed in the Neuromuscular Disorder Clinics of 2 quaternary centers in Hong Kong. Bone health status was assessed by fracture history, bone mineral density (BMD) measured by dual energy X-ray absorptiometry, and serum 25-hydroxy-vitamin D (25[OH]D) level. @*Results@#Thirty-two children were included (males, 12). The median age was 10.8 years. BMD assessments were performed in 17 patients (SMA type 1=2, type 2=8, type 3=7). Low BMD was observed in 16 out of 17 patients. Four had a history of long bone fractures and were started on bisphosphonates. SMA types, age at last visit, sex, ambulation, and 25(OH)D level were not associated with fracture history or BMD Z-scores. Only one fulfilled the 2019 International Society for Clinical Densitometry (ISCD) pediatric definition of osteoporosis, with both low BMD and a history of clinically significant fracture. @*Conclusions@#Children with SMA on disease-modifying treatments commonly had Low BMD and a history of fractures, but osteoporosis was uncommon according to the 2019 ISCD pediatric definition. A special definition of osteoporosis may be needed for this high-risk group.

Exploration and reform on education of applied talent in clinical laboratory technology in Guizhou Medical University under the background of "New Medicine" / 中华检验医学杂志

Objective:To explore the reform path of clinical laboratory technical talents training in local universities under the background of "New Medicine".Methods:The present situation of medical laboratory technical personnel training under the background of "New Medicine" was analyzed, and the teaching mode, teaching platform and practical teaching were reformed according to the reality of Guizhou Medical University.Results:An open education system of "healthcare-education collaboration and academia-industry alliances" and the talent training mode of "three-oriented drive, four-sided integration" had been formed, which improved the training quality and provided a large number of qualified medical laboratory technical undergraduate talents to the grass-roots of Guizhou Medical System.Conclusion:The reform and practice of applied talent training in Guizhou Medical University can be used as a reference for local colleges and universities to educate applied medical laboratory technical talents.

Smart Multistage "Trojan Horse"-Inspired Bovine Serum Albumin-Coated Liposomes for Enhancing Tumor Penetration and Antitumor Efficacy.

Poor antitumor drug penetration into tumor tissues is a global challenge in clinical cancer treatment. Here, we reported a smart multistage "Trojan Horse"-inspired bovine serum albumin (BSA)-coated liposome (HBM), including the mimics of capsid and secondary BSA-coated polymeric nanoparticles (NPs) for enhancing tumor penetration and antitumor efficacy. These drug-loaded polymeric NPs possess a capsid-like component, a well-distributed nanostructure (size: 190.1 ± 4.98 nm, PDI: 0.259), and an excellent drug loading content (15.85 ± 1.36%). Meaningfully, after the smart multistage BSA-coated liposome targeted the tumor tissue, the mimics of capsid were "taken off" under the condition of tumor-specific enzymes, releasing "Heart" BSA-modified secondary NPs to increase the ability to penetrate tumor cells for enhancing antitumor efficacy. As expected, the HBM efficiently achieves high drug penetration into PAN02 tumor cells. Moreover, compared to free DOX and HM (HBM without BSA) NPs, DOX/HBM NPs exhibited the strongest tumor penetration and the highest cytotoxicity against PAN02 tumor cells both in vitro (IC50 = 0.141 µg/mL) and in vivo. This smart multistage "Trojan Horse"-inspired BSA-coated liposome should provide a new hathpace for further development of polymeric NPs in clinical treatment.

Long noncoding RNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocyte apoptosis by regulating Rab2A-p53 axis.

Doxorubicin (DOX) is an efficacious and widely used drug for human malignancy treatment, but its clinical application is limited due to side effects, especially cardiotoxicity. Our present study revealed that DOX could induce apoptosis in cardiomyocytes. Herein, we screened the dysregulated long noncoding RNAs (lncRNAs) in DOX-treated cardiomyocytes. Notably, overexpression of lncRNA NONMMUT015745 (lnc5745) could alleviate DOX-induced cardiomyocyte apoptosis both in vitro and in vivo. Conversely, silencing lnc5745 promotes cardiomyocyte apoptosis. Moreover, Rab2A, a direct target of lnc5745, possesses a protective effect in DOX-induced cardiotoxicity once knocked down. Importantly, we verified that the p53-related apoptotic signalling pathway was responsible for the lnc5745-mediated protective role against DOX-induced cardiomyocyte apoptosis. Mechanistically, Rab2A interacts with p53 and phosphorylated p53 on Ser 33 (p53 (Phospho-Ser 33)), promotes p53 phosphorylation, thereby activating the apoptotic pathway. Taken together, our results suggested that lnc5745 protects against DOX-induced cardiomyocyte apoptosis through suppressing Rab2A expression, modifying p53 phosphorylation, thereby regulating p53-related apoptotic signalling pathway. Our findings establish the functional mode of the lnc5745-Rab2A-p53 axis in DOX-induced cardiotoxicity. The development of new strategies targeting the lnc5745-Rab2A-p53 axis could attenuate DOX-induced cardiotoxicity, which is beneficial to its clinical anti-tumour application.

Sensitive naked-eye detection of telomerase activity based on exponential amplification reaction and lateral flow assay.

Telomerase is a promising diagnostic and prognostic biomarker for cancers. Sensitive, simple, and reliable telomerase activity detection is vital for cancer diagnosis. Herein, we developed an ultrasensitive visualized assay for telomerase activity that combined the exponential amplification reaction (EXPAR) and lateral flow assay for easy and quick signal readout, which we termed as a lateral flow readout-EXPAR (LFR-EXPAR) assay. In the LFR-EXPAR assay, telomerase elongation products initiate the exponential amplification reaction, the generated trigger hybridizes with the reporter to form the recognition site of the nicking enzyme, and the nicking enzyme cuts the reporter strand. The degradation of the reporter can be detected with a universal lateral flow dipstick and read out with the naked eye. After conducting a series of proof-of-concept investigations, the LFR-EXPAR assay was found to achieve a sensitivity comparable to that of a TRAP (telomere repeat amplification protocol) assay. The LFR-EXPAR assay can be used to realize ultrasensitive and point-of-care detection of telomerase without requiring specialized instruments, holding great promise for early cancer diagnosis.

Emerging function and clinical significance of extracellular vesicle noncoding RNAs in lung cancer.

Lung cancer (LC) is a commonly diagnosed cancer with an unsatisfactory prognosis. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that mediate cell-cell communication by transporting various biomacromolecules, such as nucleic acids, proteins, and lipids. Noncoding RNAs (ncRNAs), including microRNAs, circular RNAs, and long noncoding RNAs, are important noncoding transcripts that play critical roles in a variety of physiological and pathological processes, especially in cancer. ncRNAs have been verified to be packaged into EVs and transported between LC cells and stromal cells, regulating multiple LC malignant phenotypes, such as proliferation, migration, invasion, epithelial-mesenchymal transition, metastasis, and treatment resistance. Additionally, EVs can be detected in various body fluids and are associated with the stage, grade, and metastasis of LC. Herein, we summarize the biological characteristics and functions of EV ncRNAs in the biological processes of LC, focusing on their potential to serve as diagnostic and prognostic biomarkers of LC as well as their probable role in the clinical treatment of LC. EV ncRNAs provide a new perspective for understanding the mechanism underlying LC pathogenesis and development, which might benefit numerous LC patients in the future.

[Knockout of ribosomal genes bS22 and bL37 increases the sensitivity of mycobacteria to antibiotics].

In recent years, two novel proteins in the ribosomes of mycobacteria have been discovered by cryo-electron microscopy. The protein bS22 is located near the decoding center of the 30S subunit, and the protein bL37 is located near the peptidyl transferase center of the 50S subunit. Since these two proteins bind to conserved regions of the ribosome targeted by antibiotics, it is speculated that they might affect the binding of related drugs to these targets. Therefore, we knocked out the genes encoding these two proteins in wild-type Mycolicibacterium smegmatis mc2155 through homologous recombination, and then determined the growth curves of these mutants and their sensitivity to related antibiotics. The results showed that compared with the wild-type strain, the growth rate of these two mutants did not change significantly. However, mutant ΔbS22 showed increased sensitivity to capreomycin, kanamycin, amikacin, streptomycin, gentamicin, paromomycin, and hygromycin B, while mutant ΔbL37 showed increased sensitivity to linezolid. These changes in antibiotics sensitivity were restored by gene complementation. This study hints at the possibility of using ribosomal proteins bS22 and bL37 as targets for drug design.

Circular RNAs act as regulators of autophagy in cancer.

Circular RNAs (circRNAs) are a large class of noncoding RNAs that are emerging as critical regulators of various cellular processes that are involved in the physiopathological mechanism of many human diseases, such as cardiovascular disease, atherosclerosis, diabetes mellitus, and carcinogenesis. Autophagy is a conserved and catabolic cellular process that degrades unfolded, misfolded, or damaged protein aggregates or organelles to maintain cellular homeostasis under physiological and pathological conditions. Increasing evidence has shown a link between circRNAs and autophagy that is closely related to the occurrence and development of human diseases, including cancer. In this review, we highlight recent advances in understanding the functions and mechanisms of circRNAs in the regulation of autophagy in cancer. These autophagy-related circRNAs contribute to cancer development and progression in various types of human cancer by activating or inhibiting autophagy. Cumulative research on the relationship between circRNAs and autophagy regulation provides critical insight into the essential role that circRNAs play in carcinogenesis and suggests new targets for tumor therapy.

The Emerging Roles of Autophagy-Related MicroRNAs in Cancer.

Autophagy is a conserved catabolic process involving the degradation and recycling of damaged biomacromolecules or organelles through lysosomal-dependent pathways and plays a crucial role in maintaining cell homeostasis. Consequently, abnormal autophagy is associated with multiple diseases, such as infectious diseases, neurodegenerative diseases and cancer. Currently, autophagy is considered to be a dual regulator in cancer, functioning as a suppressor in the early stage while supporting the growth and metastasis of cancer cells in the later stage and may also produce therapeutic resistance. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by silencing targeted mRNA. MiRNAs have great regulatory potential for several fundamental biological processes, including autophagy. In recent years, an increasing number of studies have linked miRNA dysfunction to the growth, metabolism, migration, metastasis, and responses of cancer cells to therapy. Therefore, the study of autophagy-related miRNAs in cancer will provide insights into cancer biology and lead to the development of novel anti-cancer strategies. In the present review, we summarise the current knowledge of miRNA dysregulation during autophagy in cancer, focusing on the relationship between autophagy and miRNAs, and discuss their involvement in cancer biology and cancer treatment.

Systematically Displaying the Pathogenesis of Keratoconus via Multi-Level Related Gene Enrichment-Based Review.

Keratoconus (KC) is an etiologically heterogeneous corneal ectatic disorder. To systematically display the pathogenesis of keratoconus (KC), this study reviewed all the reported genes involved in KC, and performed an enrichment analysis of genes identified at the genome, transcription, and protein levels respectively. Combined analysis of multi-level results revealed their shared genes, gene ontology (GO), and pathway terms, to explore the possible pathogenesis of KC. After an initial search, 80 candidate genes, 2,933 transcriptional differential genes, and 947 differential proteins were collected. The candidate genes were significantly enriched in extracellular matrix (ECM) related terms, Wnt signaling pathway and cytokine activities. The enriched GO/pathway terms of transcription and protein levels highlight the importance of ECM, cell adhesion, and inflammatory once again. Combined analysis of multi-levels identified 13 genes, 43 GOs, and 12 pathways. The pathogenic relationships among these overlapping factors maybe as follows. The gene mutations/variants caused insufficient protein dosage or abnormal function, together with environmental stimulation, leading to the related functions and pathways changes in the corneal cells. These included response to the glucocorticoid and reactive oxygen species; regulation of various signaling (P13K-AKT, MAPK and NF-kappaB), apoptosis and aging; upregulation of cytokines and collagen-related enzymes; and downregulation of collagen and other ECM-related proteins. These undoubtedly lead to a reduction of extracellular components and induction of cell apoptosis, resulting in the loosening and thinning of corneal tissue structure. This study, in addition to providing information about the genes involved, also provides an integrated insight into the gene-based etiology and pathogenesis of KC.

Autophagy in cardiovascular diseases: role of noncoding RNAs.

Cardiovascular diseases (CVDs) remain the world's leading cause of death. Cardiomyocyte autophagy helps maintain normal metabolism and functioning of the heart. Importantly, mounting evidence has revealed that autophagy plays a dual role in CVD pathology. Under physiological conditions, moderate autophagy maintains cell metabolic balance by degrading and recycling damaged organelles and proteins, and it promotes myocardial survival, but excessive or insufficient autophagy is equally deleterious and contributes to disease progression. Noncoding RNAs (ncRNAs) are a class of RNAs transcribed from the genome, but most ncRNAs do not code for functional proteins. In recent years, increasingly, various ncRNAs have been identified, and they play important regulatory roles in the physiological and pathological processes of organisms, as well as in autophagy. Thus, determining whether ncRNA-regulated autophagy plays a protective role in CVDs or promotes their progression can help us to develop ncRNAs as therapeutic targets in autophagy-related CVDs. In this review, we briefly summarize the regulatory roles of several important ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the autophagy of various CVDs to provide a theoretical basis for the etiology and pathogenesis of CVDs and develop novel therapies to treat CVDs.

The piRNA CHAPIR regulates cardiac hypertrophy by controlling METTL3-dependent N6-methyladenosine methylation of Parp10 mRNA.

PIWI-interacting RNAs (piRNAs) are abundantly expressed during cardiac hypertrophy. However, their functions and molecular mechanisms remain unknown. Here, we identified a cardiac-hypertrophy-associated piRNA (CHAPIR) that promotes pathological hypertrophy and cardiac remodelling by targeting METTL3-mediated N6-methyladenosine (m6A) methylation of Parp10 mRNA transcripts. CHAPIR deletion markedly attenuates cardiac hypertrophy and restores heart function, while administration of a CHAPIR mimic enhances the pathological hypertrophic response in pressure-overloaded mice. Mechanistically, CHAPIR-PIWIL4 complexes directly interact with METTL3 and block the m6A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3ß and inhibits its kinase activity, which results in the accumulation of nuclear NFATC4 and the progression of pathological hypertrophy. Hence, our findings reveal that a piRNA-mediated RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy and that the CHAPIR-METTL3-PARP10-NFATC4 signalling axis could be therapeutically targeted for treating pathological hypertrophy and maladaptive cardiac remodelling.

In-Built N+ Pocket Electrically Doped Tunnel FET With Improved DC and Analog/RF Performance.

In this paper, we present an in-built N+ pocket electrically doped tunnel FET (ED-TFET) based on the polarity bias concept that enhances the DC and analog/RF performance. The proposed device begins with a MOSFET like structure (n-p-n) with a control gate (CG) and a polarity gate (PG). The PG is biased at -0.7 V to induce a P+ region at the source side, leaving an N+ pocket between the source and the channel. This technique yields an N+ pocket that is realized in the in-built architecture and removes the need for additional chemical doping. Calibrated 2-D simulations have demonstrated that the introduction of the N+ pocket yields a higher ION and a steeper average subthreshold swing when compared to conventional ED-TFET. Further, a local minimum on the conduction band edge (EC) curve at the tunneling junction is observed, leading to a dramatic reduction in the tunneling width. As a result, the in-built N+ pocket ED-TFET significantly improves the DC and analog/RF figure-of-merits and, hence, can serve as a better candidate for low-power applications.