EXCLI Journal最新文献

Cutaneous Squamous Cell Carcinoma (cSCC) is a common and potentially fatal type of skin cancer that poses a significant threat to public health and has a high prevalence rate. Exposure to ultraviolet radiation on the skin surface increases the risk of cSCC, especially in those with genetic syndromes like xerodermapigmentosum and epidermolysis bullosa. Therefore, understanding the molecular pathogenesis of cSCC is critical for developing personalized treatment approaches that are effective in cSCC. This article provides a comprehensive overview of current knowledge of cSCC pathogenesis, emphasizing dysregulated signaling pathways and the significance of molecular profiling. Several limitations and challenges associated with conventional therapies, however, are identified, stressing the need for novel therapeutic strategies. The article further discusses molecular targets and therapeutic approaches, i.e., epidermal growth factor receptor inhibitors, hedgehog pathway inhibitors, and PI3K/AKT/mTOR pathway inhibitors, as well as emerging molecular targets and therapeutic agents. The manuscript explores resistance mechanisms to molecularly targeted therapies and proposes methods to overcome them, including combination strategies, rational design, and optimization. The clinical implications and patient outcomes of molecular-targeted treatments are assessed, including response rates and survival outcomes. The management of adverse events and toxicities in molecular-targeted therapies is crucial and requires careful monitoring and control. The paper further discusses future directions for therapeutic advancement and research in this area, as well as the difficulties and constraints associated with conventional therapies.

RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype. See also the graphical abstract(Fig. 1).

Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes.

Niosomes are drug delivery systems with widespread applications in pharmaceutical research and the cosmetic industry. Niosomes are vesicles of one or more bilayers made of non-ionic surfactants, cholesterol, and charge inducers. Because of their bilayer characteristics, similar to liposomes, niosomes can be loaded with lipophilic and hydrophilic cargos. Therefore, they are more stable and cheaper in preparation than liposomes. They can be classified into four categories according to their sizes and structures, namely small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs,), multilamellar vesicles (MLVs), and multivesicular vesicles (MVVs). There are many methods for niosome preparation, such as thin-film hydration, solvent injection, and heating method. The current study focuses on the preparation methods and pharmacological effects of niosomes loaded with natural and chemical anti-inflammatory compounds in kinds of literature during the past decade. We found that most research was carried out to load anti-inflammatory agents like non-steroidal anti-inflammatory drugs (NSAIDs) into niosome vesicles. The studies revealed that niosomes could improve anti-inflammatory agents' physicochemical properties, including solubility, cellular uptake, stability, encapsulation, drug release and liberation, efficiency, and oral bioavailability or topical absorption. See also the graphical abstract(Fig. 1).

Valve surgery is common in cardiac procedures, with fasteners like COR-KNOT® and hand-tied knots used for knot securing. This study compares their efficacy in valve surgery patients. We searched PubMed, SCOPUS, and Cochrane Central until August 2023. Outcomes assessed included aortic cross-clamp time (AXT), cardiopulmonary bypass (CPB) time, valvular regurgitation, mortality, prolonged ventilatory support, atrial fibrillation, postoperative left ventricular ejection fraction (LVEF), and renal failure. Subgroup analysis was performed for minimally invasive and open cardiac surgery. We used a random effects model for analysis. We included eight observational studies and two randomized controlled trials (RCTs) with a total of 1.411 participants. COR-KNOT significantly reduced AXT [MD -15.14, 95 % CI (-18.57, -11.70), P<0.00001] and CPB time [MD -12.38, 95 % CI (-14.99, -9.77), P<0.00001]. Valvular regurgitation [RR 0.40, 95 % CI (0.26, 0.61), P<0.0001] and need for prolonged ventilatory support [RR 0.29, 95 % CI (0.13, 0.65), P=0.003] were significantly lower with COR-KNOT. There were no significant differences in mortality [RR 0.39, 95 % CI (0.09, 1.69), P=0.44], atrial fibrillation [RR 1.03, 95 % CI (0.83, 1.27), P=0.81], LVEF changes [MD 0.05, 95 % CI (-1.37, 1.47), P = 0.95], or renal failure [RR 0.87, 95 % CI (0.16, 4.80), P = 0.87]. COR-KNOT devices reduce operative time and valvular regurgitation without increasing mortality or adverse outcomes. This supports their use in enhancing surgical efficiency and patient outcomes. However, ongoing discussions about suturing techniques, especially in minimally invasive procedures, highlight the need for further research and consensus among practitioners. See also the graphical abstract(Fig. 1).

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

Resistance band training (RBT) with functional electrical stimulation (FES) may be an effective exercise regimen for improving age-related motor impairments. This preliminary study investigated the potential effects of bimanual RBT with FES on upper limb motor functions in older adults. This study randomly assigned 22 elderly people to the bimanual RBT with FES (Bi-RBT+FES) group and the RBT without FES (Bi-RBT) group. All participants performed isometric hand-grip force control tasks in unimanual (dominant and non-dominant) and bimanual conditions before and after four weeks of exercise for each group. We quantified the mean force, force accuracy, force variability, and force regularity at two targeted force levels (i.e., 10 % and 40 % of maximum voluntary contraction; MVC) to estimate changes in force control capabilities. The results revealed that the Bi-RBT+FES group demonstrated a greater force accuracy in the dominant hand at 10 % of MVC after training. Non-dominant hands in the Bi-RBT+FES group increased force accuracy at 40 % of MVC and reduced force variability collapsed across two targeted force levels. Both groups showed a decrease in force regularity after training. These preliminary results indicate that Bi-RBT+FES may be a viable option to facilitate functional recovery of the upper limbs in older adults.

Osteoarthritis (OA) is a degenerative joint disease that occurs with aging. In its late phases, it is determined by the loss of chondrocytes and the breakdown of the extracellular matrix, resulting in pain and functional impairment. Interleukin-1 beta (IL-1β) is increased in the injured joints and contributes to the OA pathobiology by inducing chondrocyte apoptosis and up-regulation of matrix metalloproteinases (MMPs). Here, we aimed to understand whether minocycline could protect chondrocytes against the IL-1β-induced effects. The human C28/I2 chondrocyte cell line was treated with IL-1β or IL-1β plus minocycline. Cell viability/toxicity, cell cycle progression, and apoptosis were assessed with MMT assay and flow cytometry. Expression of apoptotic genes and MMPs were evaluated with qRT-PCR and western blotting. IL-1β showed a significant cytotoxic effect on the C28/I2 chondrocyte cells. The minocycline effective concentration (EC₅₀) significantly protected the C28/I2 cells against the IL-1β-induced cytotoxic effect. Besides, minocycline effectively lowered IL-1β-induced sub-G1 cell population increase, indicating the minocycline anti-apoptotic effect. When assessed by real-time PCR and western blotting, the minocycline treatment group showed an elevated level of Bcl-2 and a significant decrease in the mRNA and protein expression of the apoptotic markers Bax and Caspase-3 and Matrix metalloproteinases (MMPs) such as MMP-3 and MMP-13. In conclusion, IL-1β promotes OA by inducing chondrocyte death and MMPs overexpression. Treatment with minocycline reduces these effects and decreases the production of apoptotic factors as well as the MMP-3 and MMP-13. Minocycline might be considered as an anti-IL-1β therapeutic supplement in the treatment of osteoarthritis. See also the graphical abstract(Fig. 1).

Celecoxib, a selective COX-2 inhibitor, and non-selective anti-inflammatory drug, is commonly prescribed as the first-line analgesic for osteoarthritis, rheumatoid arthritis, and certain acute pain cases. It is mainly preferred for its lower risk of gastrointestinal adverse effects. However, it also carries risks, including renal and liver toxicity, anaphylaxis, and Stevens-Johnson syndrome. A rare but severe cutaneous adverse reaction associated with celecoxib is Acute Generalized Exanthematous Pustulosis (AGEP), characterized by extensive nonfollicular sterile pustules on an erythematous background, fever, and neutrophilic leukocytosis. AGEP is a rare condition with an incidence rate of 1-5 cases per million per year in the general population. It is primarily triggered by drugs, with antibiotics accounting for over 90 % of cases. Here, we present the case of a 44-year-old female who presented with a sudden, rapidly progressive, painful, pruritic rash all over her body with associated leukocytosis. A skin biopsy confirmed the presence of a pustular rash. The patient reported taking Celebrex (celecoxib) for worsening arthritis two weeks prior to symptom onset. The patient was diagnosed with Celecoxib-induced AGEP based on clinical and histopathological features. Treatment involved steroid therapy and discontinuation of NSAIDs (non-steroidal anti-inflammatory drugs). Encouragingly, the patient's rash improved within three days. Our case report aims to raise awareness of AGEP as a side effect of NSAIDs. Although AGEP is not typically serious, it can be fatal in elderly patients. Therefore, prompt identification and immediate cessation of the culprit drug is crucial.

Swallowing problems are frequent in Parkinson's disease (PD). The aim of this study was to determine the effectiveness of combined transcranial Direct Current Stimulation (tDCS) and Conventional Dysphagia Therapy (CDT) on dysphagia in PD patients. Twenty PD patients with dysphagia were randomized into two groups: combination therapy (anodal tDCS plus CDT) and sham tDCS combined with CDT. Anodal or sham tDCS, bilaterally over the pharyngeal motor cortex, was applied with one mA during the first 20 min (real) or 30 s (sham) of CDT, which was delivered for 30 min. Both groups received twice-daily treatment sessions within two weeks. Swallowing functions were evaluated before, immediately, and one month after the intervention via the Penetration-Aspiration Scale (PAS), and the Swallowing Disorder Questionnaire (SDQ) as the primary outcome measures, and the Dysphagia Handicap Index (DHI) as the secondary outcome measure. The results showed a significant improvement of PAS scores from baseline to post-intervention and baseline to follow-up in both groups without significant differences between groups (t=0.03, p=0.973, and t=1.27, p=0.22 for post-intervention and follow-up time points, respectively). The results showed a significant reduction of SDQ and DHI scores in both groups after the intervention, but the magnitude of the change was significantly larger in the anodal tDCS group at the post-intervention (ta=2.58, pa=0.019 and tb=2.96, pb=0.008) and follow-up (ta=2.65, pa=0.016 and tb=2.97, pb=0.008) time points. This study provides preliminary evidence that bi-hemispheric anodal tDCS combined with CDT enhances swallowing functions in patients with Parkinson's disease more than CDT alone.