Exploration of the prognostic effect of costimulatory genes in bladder cancer.

BACKGROUND: A prognostic model of bladder cancer was constructed based on costimulatory molecules, and its stability and accuracy were verified in different datasets. METHOD: The expression profile of bladder cancer RNA and the corresponding clinical data in The Cancer Genome Atlas (TCGA) database were analyzed employing computational biology, and a prognostic model was constructed for costimulating molecule-related genes. The model was applied in GSE160693, GSE176307, Xiangya_Cohort, GSE13507, GSE19423, GSE31684, GSE32894, GSE48075, GSE69795 and GSE70691 in TCGA dataset and Gene Expression Omnibus database. The role of costimulating molecules in bladder cancer tumor subtypes was also explored. By consistent cluster analysis, bladder cancer in the TCGA dataset was categorized into two subtypes: C1 and C2. The C1 subtype exhibited a poor prognosis, high levels of immune cell infiltration and significant enrichment of natural killer cells, T cells and dendritic cells in the C1 subtype. In addition, the ImmuneScore calculated by the ESTIMATE algorithm differed greatly between the two subtypes, and the ImmuneScore of the C1 subtype was greater than the C2 subtype in a significant manner. RESULTS: This study also assessed the relationship between costimulating molecules and immunotherapy response. The high-risk group responded poorly to immunotherapy, with significant differences in the amount of most immune cells between the two groups. Further, three indices of the ESTIMATE algorithm and 22 immune cells of the CIBERSORT algorithm were significantly correlated with risk values. These findings suggest the potential value of costimulating molecules in predicting immunotherapy response. CONCLUSION: A costimulatory molecule-based prognostic model for bladder cancer was established and validated across multiple datasets. This model introduces a novel mode for tailoring treatments to each individual with bladder cancer, and offers valuable insights for informed clinical choices. Simultaneously, this research also delved into the significance of costimulating molecules within distinct bladder cancer subtypes, shedding novel insights into improving immunotherapy strategies for the treatment of bladder cancer.

Therapeutic strategies targeting mechanisms of macrophages in diabetic heart disease.

Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

Circular MTHFD2L RNA-encoded CM-248aa inhibits gastric cancer progression by targeting the SET-PP2A interaction.

The available targeted therapies for gastric cancer (GC) are still limited, so it is important to discover novel molecules as potential treatment options. Proteins or peptides encoded by circular RNAs (circRNAs) are increasingly reported to play essential roles in malignancies. The aim of the present study was to identify an undiscovered protein encoded by circRNA and explore its key role and molecular mechanism in GC progression. CircMTHFD2L (hsa_circ_0069982) was screened and validated as a downregulated circRNA with coding potential. The protein encoded by circMTHFD2L, named CM-248aa, was identified for the first time by immunoprecipitation and mass spectrometry. CM-248aa was significantly downregulated in GC, while its low expression was associated with advanced tumor-node-metastasis (TNM) stage and histopathological grade. Low expression of CM-248aa could be an independent risk factor for poor prognosis. Functionally, CM-248aa, instead of circMTHFD2L suppressed the proliferation and metastasis of GC in vitro and in vivo. Mechanistically, CM-248aa competitively targeted the acidic domain of SET nuclear oncogene (SET) and acted as an endogenous inhibitor of the SET-protein phosphatase 2A interaction to promote dephosphorylation of AKT, extracellular signal-regulated kinase, and P65. Our discovery revealed that CM-248aa could be a potential prognostic biomarker and endogenous therapeutic option for GC.

Enabling Efficient Anchoring-Conversion Interface by Fabricating Double-Layer Functionalized Separator for Suppressing Shuttle Effect.

Lithium-sulfur batteries (LiSBs) with high energy density still face challenges on sluggish conversion kinetics, severe shuttle effects of lithium polysulfides (LiPSs), and low blocking feature of ordinary separators to LiPSs. To tackle these, a novel double-layer strategy to functionalize separators is proposed, which consists of Co with atomically dispersed CoN4 decorated on Ketjen black (Co/CoN4@KB) layer and an ultrathin 2D Ti3C2Tx MXene layer. The theoretical calculations and experimental results jointly demonstrate metallic Co sites provide efficient adsorption and catalytic capability for long-chain LiPSs, while CoN4 active sites facilitate the absorption of short-chain LiPSs and promote the conversion to Li2S. The stacking MXene layer serves as a microscopic barrier to further physically block and chemically anchor leaked LiPSs from the pores and gaps of the Co/CoN4@KB layer, thus preserving LiPSs within efficient anchoring-conversion reaction interfaces to balance the accumulation of "dead S" and Li2S. Consequently, with an ultralight loading of Co/CoN4@KB-MXene, the LiSBs exhibit amazing electrochemical performance even under high sulfur loading and lean electrolyte, and the outperforming performance for lithium-selenium batteries (LiSeBs) can also be achieved. This work exploits a universal and effective strategy of a double-layer functionalized separator to regulate the equilibrium adsorption-catalytic interface, enabling high-energy and long-cycle LiSBs/LiSeBs.

Dissociable brainstem functional connectivity changes correlate with objective and subjective vigilance decline after total sleep deprivation in healthy male subjects.

The maintenance of vigilance relies on the activation of the cerebral cortex by the arousal system centered on the brainstem. Previous studies have suggested that both objective and subjective vigilance are susceptible to sleep deprivation. This study aims to explore the alterations in brainstem arousal system functional connectivity (FC) and its involvement in these two types of vigilance decline following total sleep deprivation (TSD). Thirty-seven healthy male subjects underwent two counterbalanced resting-state fMRI scans, once in rested wakefulness (RW) and once after 36 h of TSD. The pontine tegmental area and caudal midbrain (PTA-cMidbrain), the core regions of the brainstem arousal system, were chosen as the seeds for FC analysis. The difference in PTA-cMidbrain FC between RW and TSD conditions was then investigated, as well as its associations with objective vigilance measured by psychomotor vigilance task (PVT) and subjective vigilance measured by Stanford Sleepiness Scale. The sleep-deprived subjects showed increased PTA-cMidbrain FC with the thalamus and cerebellum and decreased PTA-cMidbrain FC with the occipital, parietal, and sensorimotor regions. TSD-induced increases in PVT reaction time were negatively correlated with altered PTA-cMidbrain FC in the dorsolateral prefrontal cortex, extrastriate visual cortex, and precuneus. TSD-induced increases in subjective sleepiness were positively correlated with altered PTA-cMidbrain FC in default mode regions including the medial prefrontal cortex and precuneus. Our results suggest that different brainstem FC patterns underlie the objective and subjective vigilance declines induced by TSD.

Patient stratification based on urea cycle metabolism for exploration of combination immunotherapy in colon cancer.

BACKGROUND: Owing to the low ratio of patients benefitting from immunotherapy, patient stratification becomes necessary. An accurate patient stratification contributes to therapy for different tumor types. Therefore, this study aimed to subdivide colon cancer patients for improved combination immunotherapy. METHODS: We characterized the patients based on urea cycle metabolism, performed a consensus clustering analysis and constructed a risk model in the cancer genome atlas cohort. Colon cancer patients were further categorized into two tags: clusters, and risk groups, for the exploration of combination immunotherapy. In addition to external validation in the Gene Expression Omnibus datasets, several images of immunohistochemistry were used for further validation. RESULTS: Patient characterization based on urea cycle metabolism was related to immune infiltration. An analysis of consensus clustering and immune infiltration generated a cluster distribution and identified patients in cluster 1 with high immune infiltration levels as hot tumors for immunotherapy. A risk model of seven genes was constructed to subdivide the patients into low- and high-risk groups. Validation was performed using a cohort of 731 colon cancer patients. Patients in cluster 1 had a higher immunophenoscore (IPS) in immune checkpoint inhibitor therapy, and those other risk groups displayed varying sensitivities to potential combination immunotherapeutic agents. Finally, we subdivided the colon cancer patients into four groups to explore combination immunotherapy. Immunohistochemistry analysis showed that protein expression of two genes were upregulated while that of other two genes were downregulated or undetected in cancerous colon tissues. CONCLUSION: Using subdivision to combine chemotherapy with immunotherapy would not only change the dilemma of immunotherapy in not hot tumors, but also promote the proposition of more rational personalized therapy strategies in future.

Life cycle environmental and economic comparison of thermal utilization of refuse derived fuel manufactured from landfilled waste or fresh waste.

This paper analyses environmental and economic performance of thermal utilization technologies of two different refuse derived fuel (RDF) manufactured from landfilled waste or fresh municipal waste, including incineration of landfilled RDF (I-LRDF), gasification of landfilled RDF (G-LRDF), replacement of partial coal by landfilled RDF for the cement industry (C-LRDF), incineration of municipal RDF (I-MRDF), and replacement of partial coal by municipal RDF for the cement industry (C-MRDF). The preference among the RDF utilization options is identified from the standpoints of various stakeholders by integrating the life cycle assessment (LCA) and techno-economic analysis (TEA) with the analytic hierarchy process (AHP) and technique for order preference by similarity to ideal solution (TOPSIS) approaches. RDF thermal utilization technologies bring an economic profit of $17.29∼$35.77 per ton of waste. Especially, I-LRDF has the worst effect on ecosystem quality and human health and can yield the greatest economic profit of $35.77 per ton of landfilled waste, while I-MRDF has the least impact on environment. In terms of the five RDF thermal utilization technologies, I-MRDF has the best comprehensive performance from the perspectives of different stakeholders. The improvement of the RDF thermal utilization efficiency is the most critical factor affecting the economic benefits for all cases.

A new insight into the mechanism for cytosolic lipid droplet degradation in senescent leaves.

Leaf senescence involves lipid droplet (LD) degradation that produces toxic fatty acids, but little is known about how the toxic metabolites are isolated from the rest of the cellular components. Our ultramicroscopic characterization of cytosolic LD degradation in central vacuole-absent cells and central vacuole-containing cells of senescent watermelon leaves demonstrated two degradation pathways: the small vacuole-associated pathway and the central vacuole-associated pathway. This provided an insight into the subcellular mechanisms for the isolation of the fatty acids derived from LDs. The central vacuole-containing cells, including mesophyll cells and vascular parenchyma cells, adopted the central vacuole-associated pathway, indicated by the presence of LDs in the central vacuole, which is believed to play a crucial role in scavenging toxic metabolites. The central vacuole-absent intermediary cells, where senescence caused the occurrence of numerous small vacuoles, adopted the small vacuole-associated pathway, evidenced by the occurrence of LDs in the small vacuoles. The assembly of organelles, including LDs, small vacuoles, mitochondria and peroxisome-like organelles, occurred in the central vacuole-absent intermediary cell in response to leaf senescence.

Volatilization characteristics and risk evaluation of heavy metals during the pyrolysis and combustion of rubber waste without or with molecular sieves.

The volatilization characteristics and risk evaluation of heavy metals (As, Cd, Co ,Cr, Cu, Ni, Pb, Zn, and Ti) during pyrolysis and combustion of rubber waste with or without molecular sieves (MS) were studied. The addition of MS during pyrolysis inhibited the volatilization of As and promoted the volatilization of Ni and Co, while during combustion it inhibited the volatilization of Pb, Zn and promoted the volatilization of Cu. For Cd, Cr, Ni, Zn and Ti, their volatilization rates during pyrolysis were significantly higher than those during combustion, whereas for As and Cu, the volatilization rates during pyrolysis were lower than those during combustion. Risk evaluation of gaseous heavy metals was exhibited based on the Potential Ecological Risk Index (RI) method. The potential ecological risk during combustion was generally lower than that during pyrolysis. The research results provide important information of heavy metals control during waste thermal treatment.

[Effect of Hypoxia Inducible Factor-1 Alpha on Brain Metastasis from Lung Cancer and Its Mechanism].

OBJECTIVE: To study the relationship between hypoxia and the hypoxia inducible factor-1α (HIF-1α) from lung cancer cells, to reveal the possible mechanism of brain metastases of lung cancer. METHODS: The hypoxia model of A549 lung cancer cells was established. After hypoxia culture of A549 cells for 0.5, 2, 4, 8, 12 and 24 h (normal oxygen culture at the same time point was set as the control group), the mass concentration of HIF-1α in A549 lung cancer cell culture medium were determined by ELISA. Transwell chamber was used to construct an in vitro blood brain barrier model, was treated with A549 lung cancer cell culture medium after different time points of hypoxia, Tran endothelial resistance (TER) change of blood-brain barrier model in instrument, to reflect the changes of blood-brain barrier permeability in vitro; A549 lung cancer cells in the culture medium were counted under Transwell room. A549 lung cancer cells with hypoxia at different time points injected into Wistar rats via tail vein, Western blot method was used to menstruate expression of tight junction associated protein Claudin-5 in the brain tissues, Evans blue to detect the change of blood brain barrier permeability in rats. RESULTS: Compared with the control group, the HIF-1α mass concentration in the cell culture solution of A549 increased, the in vitro blood-brain barrier model TER decreased, and the cell number of A549 that passed through transwell into the lower chamber increased (all P<0.05) after hypoxia 2 h, the above effect was most obvious when hypoxia 8 h (all P<0.01). After hypoxia 24 h, it was restored to the control group level. In the in vivo experiment of rats, compared with the control group, the mass percent of Evans blue in rat brain tissues increased after A549 cell culture solution with hypoxia 2 h was injected via caudal vein, meaning increased the permeability of rat blood brain barrier, while the expression of Claudin-5 protein in rat brain tissues decreased (all P<0.05). The effect was most obvious when A549 cell culture solution with hypoxia 8 h was injected into rat tail vein (P<0.01 ). Ejectionof hypoxia 24 h A549 cell culture solution yielded the same effects as those in the control group. CONCLUSION: Hypoxia can induce the increase of HIF-1α in lung cancer cells. The increase of HIF-1α results in the decrease of Claudin-5 expression and increase of blood-brain barrier permeability, leading to lung cancer cells metastasis into the brain.

ERCC polymorphisms and prognosis of patients with osteosarcoma.

Osteosarcoma is the most common primary bone malignancy in children and teenagers, and its clinical outcome remains poor. Previous studies have investigated the association between excision repair cross-complementing (ERCC) and prognosis of osteosarcoma patients, but their results were inconsistent. We aimed to clarify the associations between ERCC polymorphisms and osteosarcoma prognosis by using meta-analysis. We searched relevant studies in PubMed, Embase, coupled with Chinese National Knowledge Infrastructure (CNKI) in human osteosarcoma published prior to April, 2014. Hazard ratios (HR) together with their 95 % confidence intervals (95 % CI) were used to measure the relationship between ERCC mutations and prognosis in patients with osteosarcoma. Pooled results showed that polymorphism of ERCC2 Lys751Gln was associated with the overall survival of osteosarcoma (GG vs. AA, HR = 0.40; 95 % CI 0.18-0.86), and ERCC5 His46His mutation was associated with the event-free survival of osteosarcoma (CC vs. TT, HR = 0.37; 95 % CI 0.15, 0.93). In addition, there is no evidence of association on ERCC1 Asn118Asn, ERCC1 Gln504Lys, and ERCC2 Asp312Asn polymorphisms with prognosis in osteosarcoma. In summary, the ERCC2 Lys751Gln and ERCC5 His46His polymorphisms might influence osteosarcoma prognosis.

Emulsion cross-linked chitosan/nanohydroxyapatite microspheres for controlled release of alendronate.

Sustained delivery of growth factors has emerged as an essential requirement for bone tissue engineering applications for the treatment of various kinds of bone defects. Chitosan (CH) has attracted particular attention for drug delivery and bone tissue engineering because of its favorable biocompatibility and biodegradability. In this study, a composite microsphere system containing CH and nanohydroxyapatite (nHA)-alendronate (AL) particles was fabricated by employing both emulsification and cross-linking strategies. The microspheres were characterized for their surface morphology, composition, size distribution, drug loading efficiency and release properties. The results showed that loading efficiency and sustained release of hydrophilic AL were significantly improved, which is ideal for locally sustained release in the bone microenvironment. In vitro osteogenic studies showed that the microspheres could enhance the osteogenic activity of rabbit adipose-derived stem cells. In conclusion, the CH/nHA-AL composite microspheres exhibit promising properties as a candidate for local treatment for bone defects.

[Surgical correction of post-traumatic thoracolumbar kyphotic deformity with posterior transpedicular limited osteotomy technique].

OBJECTIVE: To evaluate the clinical outcome of surgical management for post-traumatic thoracolumbar kyphotic deformity with single-stage posterior transpedicularlimited osteotomies. METHODS: From March 2007 to May 2010, 17 patients with post-traumatic thoracolumbar kyphotic deformity treated with posterior limited transpedicular osteotomy were admitted. The preoperative Cobb angle was 41°-62°(52.5° ±6.4°). Sagittal balance was evaluated by the standing lateral films measuring the C7 plumb line distance (C7 PLD) from the posterior superior corner of S1. The C7 PLD was 18-58 (41.2 ±12.4) mm in the sagittal plane. The preoperative oswestry disability index (ODI) was 42-50 (45.7 ±2.7), and the average preoperative visual analogue scale (VAS) was 8-10 (8.8 ±0.7). The American Spinal Injury Association (ASIA) impairment scale was used to assess the neurological deficits, and grade C in 1 patient, grade D in 7 and grade E in 9 patients. The operation time, blood loss, complications, post-operative Cobb angle, ODI and VAS score at the follow-up were collected and analyzed. RESULTS: The average duration of postoperative follow-up was 24-53 (34.5 ±7.1) months. The operation time was 180-400 (287.1 ±65.9) min, with an blood loss of 350-1 300 (838.2 ±276.4) mL. The postoperative kyphotic angle was 3°-12° (6.1° ±3.0°), and it was 7.5° ±2.6° at the final follow-up evaluation. The postoperative C7PLD was (3.6 ±3.9) mm and it was (3.4 ±2.3) mm at the final follow-up evaluation. Postoperatively, the ASIA impairment scale was grade D in 4 and grade E in 13 patients. At the final follow-up ODI and VAS were reduced to an average of 5.2 ±2.4 and 2.4 ±1.0, respectively. Cerebrospinal fluid leakage was found in 2 patients, deep wound infection in 1, and intercostal neuralgia in 2. All the complications were relieved after conservative medical therapy. One patient received additional surgery at postoperative 12 weeks due to breakage of posterior implants. Another screw pullout case was treated with reinsertion of larger screws at postoperative 4 months. Solid fusion was confirmed by plain film and CT scan in all patients within 1 year after the surgery. CONCLUSION: Single-staged posterior transpedicular limited osteotomies is safe and effective to correct post-traumatic thoracolumbar kyphotic deformity.

Triple Effects of the Physicochemical Interaction between Water and Copper and Their Influence on Microcutting.

Water has been recognized in promoting material removal, traditionally ascribed to friction reduction and thermal dissipation. However, the physicochemical interactions between water and the workpiece have often been overlooked. This work sheds light on how the physicochemical interactions that occur between water (H2O) and copper (Cu) workpiece influence material deformations during the cutting process. ReaxFF molecular dynamics simulations were employed as the primary method to study the atomistic physical and chemical interactions between the applied medium and the workpiece. Upon contact with the Cu surface, H2O dissociated into OH- ions, H+ ions, and traces of O2- ions. The OH- and O2- ions chemically reacted with Cu to form bonds that weakened the Cu-Cu bonds by elongation, while the H+ ions gained electrons and diffused into the Cu lattice as H- ions. The weakening of surface Cu bonds promoted plastic deformation and reduced the difficulty of material removal. Meanwhile, further addition of H2O molecules saw a plateau in hydrolysis and more dominance of H2O physical adsorption on Cu, which weakens the elongation of Cu-Cu bonds. While the ideal case for atomic-scale material removal was found with an optimal number of 240 H2O molecules, the presented Cu material state with more H2O molecules could account for the observations in microcutting. The constricted nature of physical adsorption and hydrogen ion diffusion in the surface layer prevented the propagation of dislocations through the surface, which subsequently caused pinning points to be closer together during chip formation as observed by smaller chip fold widths on the microscale. Theoretical and experimental analysis identified the importance of accounting for physicochemical interactions between surface media and the workpiece when considering material deformations at micronanoscale.

Case report: A highly active refractory myasthenia gravis with treatment of telitacicept combined with efgartigimod.

There is always a lack of effective treatment for highly active refractory generalized myasthenia gravis (GMG). Recently, telitacicept combined with efgartigimod significantly reduces circulating B cells, plasma cells, and immunoglobulin G, which brings promising therapeutic strategies. We report a case of a 37-year-old female patient with refractory GMG, whose condition got significant improvement and control with this latest treatment after multiple unsuccessful therapies of immunosuppressants. The new combination deserves further attention in the therapeutic application of myasthenia gravis.

Surface functional groups on nanoplastics delay the recovery of gut microbiota after combined exposure to sulfamethazine in marine medaka (Oryzias melastigma).

Nanoplastics can interact with antibiotics, altering their bioavailability and the ensuing toxicity in marine organisms. It is reported that plain polystyrene (PS) nanoplastics decrease the bioavailability and adverse effects of sulfamethazine (SMZ) on the gut microbiota in Oryzias melastigma. However, the influence of surface functional groups on the combined effects with SMZ remains largely unknown. In this study, adult O. melastigma were fed diet amended with 4.62 mg/g SMZ and 3.65 mg/g nanoplastics (i.e., plain PS, PS-COOH and PS-NH2) for 30 days (F0-E), followed by a depuration period of 21 days (F0-D). In addition, the eggs produced on the last day of exposure were cultured under standard protocols without further exposure for 2 months (F1 fish). The results showed that the alpha diversity or the bacterial community of gut microbiota did not differ among the SMZ + PS, SMZ + PS-COOH, and SMZ + PS-NH2 groups in the F0-E and F1 fish. Interestingly, during the depuration, a clear recovery of gut microbiota (e.g., increases in the alpha diversity, beneficial bacteria abundances and network complexity) was found in the SMZ + PS group, but not for the SMZ + PS-COOH and SMZ + PS-NH2 groups, indicating that PS-COOH and PS-NH2 could prolong the toxic effect of SMZ and hinder the recovery of gut microbiota. Compared to plain PS, lower egestion rates of PS-COOH and PS-NH2 were observed in O. melastigma. In addition, under the simulated fish digest conditions, the SMZ-loaded PS-NH2 was found to desorb more SMZ than the loaded PS and PS-COOH. These results suggested that the surface -COOH and -NH2 groups on PS could influence their egestion efficiency and the adsorption/desorption behavior with SMZ, resulting in a long-lasting SMZ stress in the gut during the depuration phase. Our findings highlight the complexity of the carrier effect and ecological risk of surface-charged nanoplastics and the interactions between nanoplastics and antibiotics in natural environments.

Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis.

The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor-infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre- and post-NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan-Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long-term survival in patients with advanced GC. Furthermore, tumor-infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD-L1)-positive tumors was 31% (32/104) pre-NACT and 49% (51/104) post-NACT, and almost all patients with elevated PD-L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.

MicroRNAs in osteosarcoma: diagnostic and therapeutic aspects.

MicroRNAs (miRNAs) are small RNA molecules, which can interfere with the expression of several genes and act as gene regulator. miRNAs have been proved as a successful diagnostic and therapeutic tool in several cancers. In this review, the differential expression of miRNAs in osteosarcoma and their possibility to be used as diagnostic and therapeutic tools have been discussed. Osteosarcoma is the most common primary bone tumor that mainly affects children and adolescents. The current treatment of osteosarcoma remains difficult, and osteosarcoma causes many deaths because of its complex pathogenesis and resistance to conventional treatments. Several studies demonstrated that the differential expression patterns of miRNAs are a promising tool for the diagnosis and treatment of osteosarcoma. Although some aspect of the mechanism of action of miRNAs in controlling osteosarcoma has been identified (e.g., targeting the Notch signaling pathway), it is far beyond to the clear understanding of miRNA targets in osteosarcoma. Identification of the specific target of miRNAs may aid molecular targets for drug development and future relief of osteosarcoma.

Targeting the autophagy-lysosomal pathway in Huntington disease: a pharmacological perspective.

The autophagy-lysosomal pathway (ALP) is the major biological pathway responsible for clearing intracellular protein aggregates, therefore a promising target for treating diseases featuring the accumulation of aggregation-prone proteins, such as Huntington disease (HD). However, accumulating evidence indicated that targeting ALP to treat HD is pharmacologically challenging due to the complexity of autophagy and the autophagy defects in HD cells. Here in this mini-review, we summarized the current challenges in targeting ALP in HD and discussed a number of latest findings on aggrephagy and targeted protein degradation, which we believe will provide potential new targets and new strategies for treating HD via ALP.