The severe cardiotoxicity of doxorubicin (Dox) significantly restricts its clinical application. Deubiquitinating enzymes (DUBs) have emerged as a research hotspot in cardiac pathophysiology due to their precise regulation of protein function, localization, and degradation. However, the specific role of ubiquitin-specific peptidase 20 (USP20) in doxorubicin-induced cardiomyopathy (DIC) remains poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to delineate the cell-type-specific expression pattern of USP20 in the heart and combined it with LC-MS/MS-coupled co-immunoprecipitation (co-IP) to identify its direct, endogenous substrate proteins in cardiomyocytes. Employing cardiomyocyte-specific Usp20-knockout (Usp20-CKO) mice, we demonstrated that USP20 deficiency profoundly exacerbates DIC by driving ferroptotic cell death. Mechanistically, the ubiquitin-specific protease domain of USP20 directly interacted with human antigen R (HuR). USP20 deubiquitinated HuR at lysine 154 by specifically cleaving K48-linked polyubiquitin chains, thereby preventing its proteasomal degradation and maintaining protein stability. Subsequently, the stabilized HuR bound to GPX4 mRNA, suppressing its degradation to mitigate ferroptosis and alleviate DIC. Furthermore, AAV9-mediated targeted overexpression of USP20 in cardiomyocytes significantly attenuated DIC severity. Crucially, this cardioprotective effect was completely abolished in cardiomyocyte-specific HuR-knockout (HuR-CKO) mice, establishing HuR as an indispensable downstream effector of USP20 in DIC. In summary, our findings demonstrate that USP20 inhibits ferroptosis and mitigates DIC by stabilizing HuR through targeted deubiquitination.

Objective:Uterine sarcomas and uterine carcinosarcomas are rare heterogeneous malignancies with poor prognosis. Though carcinosarcomas have been pathologically reclassified as dedifferentiated endometrial carcinomas, their highly aggressive clinical behavior merits combined analysis with uterine sarcomas. This study aimed to investigate the prognostic value of Ki-67 proliferation index in major histologic subtypes and identify an optimal cut-off value for risk stratification. Materials and Methods:We retrospectively enrolled 86 surgically treated primary uterine sarcoma and carcinosarcoma patients (2006-2019). Ki-67 labeling index was detected via immunohistochemistry. The optimal cut-off value for Ki-67 was determined using receiver operating characteristic (ROC) curve analysis. Overall survival (OS) and progression-free survival (PFS) were evaluated via Kaplan-Meier curves and Cox regression. Results:The optimal Ki-67 cut-off value was 32.5%. High Ki-67 expression (≥32.5%) was significantly associated with older age (P=0.001), postmenopausal status (P=0.002), and aggressive histological subtypes 0.760 (P<0.001). High Ki-67 group had worse 3-year PFS (18.5% vs 76.4%) (range, 22-73) and 3-year OS (25.5% vs 85.4%). Multivariate analysis confirmed high Ki-67 as an independent prognostic factor for poorer PFS and OS (P < 0.001). Larger tumor size (P < 0.001), postmenopausal status (PFS: P = 0.001; OS: P = 0.002), and high-risk histological type (P < 0.001) also remained significant. Notably, the 32.5% cut-off applies across major histological subtypes. Conclusion:Ki-67 index serves as an independent biomarker for uterine sarcoma and carcinosarcoma. The 32.5% cut-off effectively divide patients into low- and high-risk groups, with the latter demonstrating significantly inferior survival outcomes.

Phototherapy holds great potential for treating cancer and infections but faces limitations related to photosensitizer accumulation, tissue penetration, and diminished photo-conversion efficiency, particularly in deep-seated tumors and infections. Here, a biomimetic phototherapeutic nanodisc platform consisting of erythrocyte membranes and the photosensitizer IR780 is developed. With the advantages of the ultra-small size and exceptional biosafety of cell membrane-derived nanodiscs, this platform facilitates efficient accumulation and deep tissue penetration at disease sites. Upon near-infrared (NIR) irradiation, IR780 delivered via the nanodisc exhibits enhanced photothermal conversion efficiency, markedly inhibiting tumor growth in an orthotopic 4T1 breast cancer model and reducing bacterial load in a methicillin-resistant Staphylococcus aureus (MRSA) skin infection model. Furthermore, the nanodisc platform demonstrates outstanding biocompatibility in mice. In conclusion, this nanodisc system significantly extends the functional potential of cellular nanodiscs, presenting a promising strategy to address the challenges of photosensitizer delivery and biosafety in phototherapeutic applications.

Recurrent vulvovaginal candidiasis (RVVC) is an opportunistic infection predominantly caused by Candida albicans (C. albicans) and is particularly prevalent among individuals on immunosuppressants. Currently, there are no FDA-approved therapies for specifically controlling RVVC, mainly due to the need for therapeutics against RVVC that require both antifungal treatments to resolve active infections and strategies to prevent recurrence. This study introduces a biomimetic photoimmunotherapeutic nanoplatform consisting of an adjuvant-encapsulated polymeric core stabilized by a photosensitizer-loaded vaginal epithelial cell membrane coating to treat and protect against RVVC. With its cell membrane camouflaging, the nanoplatforms target and enhance adherence to the intravaginal site of C. albicans infection, allowing the nanoplatform to resist being flushed away by vaginal fluids. Upon subsequent near-infrared irradiation, the nanoplatform's targeted photothermal power effectively eliminates C. albicans while minimizing thermal damage to surrounding healthy tissue. Postphotothermal treatment, the generated C. albicans-based debris and candidalysin-captured nanoplatform (serving as a nanotoxoid), along with adjuvant, are processed by resident antigen-presenting cells to promote multiantigenic immunity. This response provides protection against secondary intravaginal C. albicans infection (RVVC model) and C. albicans-induced systemic infection even under immunosuppressive conditions (septicemia model). Notably, anti-C. albicans antibodies produced in the pretreated mice exhibit comparable affinity to clinically isolated C. albicans strains, indicating potential for clinical application. Overall, this study underscores the potential of the proposed photoimmunotherapeutic nanoplatform for the effective treatment and prevention of RVVC.

Anthracycline doxorubicin (DOX) remains the first-line chemotherapeutic drug for the efficient treatment of breast cancer, but its severe cardiotoxicity limits its long-term application in clinical tumor chemotherapy. Until now, the pathogenesis mechanism of DOX-induced cardiotoxicity (DIC) is still not fully understood. According to current studies, the oxidative stress caused by the imbalance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and mitochondrial dysfunction in myocardial cells are closely related to DIC. Presently, the usual technology to solve the DIC problem is to use a multifunctional nanoplatform to load DOX and obtain a new medicinal agent, thereby enhancing the efficacy of chemotherapeutic drugs and reducing toxic side effects. Herein, the present investigation employed the Mannich condensation reaction, initiated by L-cysteine and (-)-epigallocatechin-3-gallocarboxylate (EGCG), to synthesize EGCG Cys nanoformulation with both anti-tumor and anti-oxidant properties. The EGCG Cys were then employed as the DOX carrier to construct a novel chemotherapeutic drug, EGCG Cys(DOX), for high-efficiency breast cancer treatment. The tumor growth inhibition index of EGCG Cys(DOX) in tumor-bearing mice was 12.56

Blood transfusions save lives and improve health every day. Despite the matching of blood types being stricter than it ever has been, emergency transfusions among incompatible blood types are still inevitable in the clinic when there is a lack of acceptable blood types for recipients. Here to overcome this, a counter measure nanoplatform consisting of a polymeric core coated by a red blood cell (RBC) membrane is developed. With A-type or B-type RBC membrane camouflaging, the nanoplatform is capable of specifically capturing anti-A or anti-B IgM antibodies within B-type or A-type whole blood, thereby decreasing the corresponding IgM antibody levels and then allowing the incompatible blood transfusions. In addition to IgM, the anti-RBC IgG antibody in a passive immunization murine model can likewise be neutralized by this nanoplatform, leading to prolonged circulation time of incompatible donor RBCs. Noteworthily, nanoplatform made by expired RBCs (>42 days stored hypothermically) and then subjected to lyophilization does not impair their effect on antibody neutralization. Most importantly, antibody-captured RBC-NP do not exacerbate the risk of inflammation, complement activation, and coagulopathy in an acute hemorrhagic shock murine model. Overall, this biomimetic nanoplatform can safely neutralize the antibody to enable incompatible blood transfusion.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

The pharmacological activities of dictamnine and fraxinellone have been well reported; however, only a few studies have focused on the pharmacokinetics and bioavailability of concomitant delivery of these drugs in vivo. To shed light on this neglected area, we developed a rapid and sensitive UPLC-MS/MS method that quantified the levels of dictamnine and fraxinellone simultaneously in rat plasma. This method was initiated by a one-step protein precipitation strategy to purify plasma samples collected from rats treated with either oral or intravenous administration of dictamnine and fraxinellone. The mobile phase contained acetonitrile and 0.1% formic acid at a steady flow rate of 0.6 mL/min. As a result, an excellent analyte peak resolution was achieved, and the entire process took only 3 min per sample. The results were indicative of the desired linearity (r2 ≥ 0.999), precision (RSD% was within 15%), accuracy (RE% was within 15%), recoveries (≥80.66 and 68.15% for dictamnine and fraxinellone, respectively) and matrix effects (≥94.66 and 91.37% for dictamnine and fraxinellone, respectively). Additionally, the detectable limits of these two compounds were both low even when they reached 5 ng/mL. Taken together, these findings contribute to a better understanding of the pharmacokinetics and bioavailability properties of concomitant delivery of dictamnine and fraxinellone.

An effective therapeutic strategy to treat vulvovaginal candidiasis (VVC) that is mainly caused by Candida albicans (C. albicans) infection is highly desirable. While Amphotericin B (AmB) has demonstrated promise, its precise localization to C. albicans burden at vaginal sites is oftentimes limited by the high fluidity microenvironment of the vagina, which can compromise treatment efficacy. To overcome this issue, a biomimetic AmB delivery system is developed, in which AmB preloaded polymeric cores are cloaked with vaginal epithelial cells membrane (VM-ANP). With its cell membrane coating, VM-ANP naturally targets and strongly binds with C. albicans, thus resisting the self-cleaning of vaginal fluid. Besides its long retention property, VM-ANP could penetrate deeply in vaginal tissue to achieve its full antifungal potential by attaching to hidden C. albicans. It is shown that both C. albicans suspension and biofilm biomass could be effectively inhibited by the VM-ANP in vitro. In a C. albicans intravaginal infection model, treatment with VM-ANP results in significantly decreased fungal challenges both in vaginal tissue and fluid. Overall, such biomimetic strategy adds the merit of natural cell membrane into the targeted delivery of drug in treating VVC, which also serves as a promising platform against vaginitis-related pathogens.

Doxorubicin (DOX) is a commonly used chemotherapy drug widely applied in various cancers such as breast cancer, leukemia, and sarcomas. However, its usage is limited by cardiotoxicity. Additionally, the cardiac toxicity of DOX accumulates with dose and duration, making it imperative to identify therapeutic targets for DOX-induced cardiomyopathy (DIC). It has been reported that miRNAs are involved in the progression of DIC. Mir-34a-5p has been identified as an early diagnostic marker for DIC. While studies have shown the involvement of mir-34a-5p in DIC apoptosis, it has not been validated in animal models, nor has the potential improvement of DIC by inhibiting mir-34a-5p been confirmed. Autophagy and pyroptosis are key factors in the development of DIC and can serve as therapeutic targets for its treatment. In this study, we found that mir-34a-5p was upregulated in the heart after DOX treatment and that the inhibition of mir-34-5p reduced autophagy and pyroptosis in DIC. We also found that the inhibition of mir-34a-5p inhibited pyroptosis by regulating autophagy and reducing mitochondrial reactive oxygen species. Moreover, we identified Sirtuin3 (Sirt3) as a target gene of mir-34a-5p using a double-luciferase reporter assay. overexpression Sirt3 reduced pyroptosis by alleviating autophagy. Our research findings suggest that inhibiting mir-34a-5p has a beneficial role in alleviating autophagy and pyroptosis in DIC. This provides therapeutic prospects for treating DIC.

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

This retrospective study was conducted in 27 patients with malignant transformation of mature cystic teratoma（MT-MCT）and 125 ovarian teratoma patients with torsion who underwent surgery in the First Affiliated Hospital of Wenzhou Medical University from 2008 to 2019. The incidence of MT-MCT in this study was 0.79%. The 3-year overall survival (OS) rate was 69.6 ± 9.6%. The 3-year progression-free survival (PFS) rate was 58.3 ± 9.6%. Kaplan-Meier survival analysis indicated that patients with squamous cell carcinoma (SCC) had significantly shorter OS compared with non-SCC patients. Older age (OR 1.076, 95% CI 1.041-1.111), higher platelet (PLT) level (OR 1.012, 95% CI 1.005-1.020) and lower neutrophil-to-lymphocyte ratio (NLR) level (OR 0.794, 95% CI 0.647-0.915) were independent predictors of MT-MCT. The area under the curve (AUC) for the combined use of age, PLT count and NLR was 0.921 (95% confidence interval 0.877-0.964; p < 0.001), with a sensitivity of 92.6% and a specificity of 80.8%.

Objective The aim of this study is to develop a rapid and sensitive UPLC-MS/MS approach to determine the sophoridine (SOP) level in rat plasma and the pharmacokinetics of the substance. Significance Sophoridine is used as an anti-inflammatory, anti-virus, anti-microbial, and anti-tumor alkaloid. It is essential to explore specific detection methods for the quantitative analysis of SOP in the blood circulation. Methods The rat plasma samples were prepared by one-step protein precipitation with acetonitrile. Subsequently, the samples were separated by chromatography using a UPLC BEH C18 reversed-phase with an initial mobile phase of methanol and 0.1% formic acid aqueous solution. The gradient elution was performed at a fixed flow rate of 0.4 mL/min, and multiple reaction monitoring (MRM) mode with an electrospray positive ionization source was employed to detect the transitions of m/z 249.1 -> 84.2 for SOP and m/z 264.3 -> 69.8 for dendrobine (IS). The entire process required 3.5 min for each sample. Results A linear correlation was established over the range of 2-2000 ng/mL (r (2)>= 0.9954) for SOP in rat plasma with a lower limit of quantification (LLOQ) at 2 ng/mL. The range of accuracy was tested between 94.90% and 100.80%, and the relative standard deviations (RSDs) toward both intra- and inter-day precision were <10%. Thus, this method was successfully applied to a pharmacokinetic study, and the subsequent results demonstrated a low absolute bioavailability of 2.32%. Conclusion The present study established a reliable method that quantified the SOP concentration in rat plasma after administering a dose of 2 mg/kg intravenously or 20 mg/kg orally.

The treatments for advanced non-small cell lung cancer (NSCLC) patients have been improved by developing tyrosine kinase inhibitors (TKIs) as targeted therapies. Oncogenic gene fusions resulting from structural DNA rearrangements have been proposed as a unique class of oncogenic drivers and therapeutic targets. Currently approved TKIs mainly focused on a few well-known fusion genes such as anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1). Fusions involving neuregulin 1 gene (NRG1) have been recently described in a small portion of solid tumors as actionable oncogenic drivers, leading to the activation of the erythroblastic leukemia viral oncogene homolog (ErbB)-mediated pathway. Therefore, gene fusions containing NRG1 could serve as a therapeutic candidate for ErbB-targeted treatment. In the present study, we report a lung adenocarcinoma patient harboring the CD74-NRG1 fusion, which was identified by next-generation sequencing (NGS). The patient received the irreversible pan-ErbB inhibitor, afatinib, as first-line treatment and showed a significant treatment response with a progression-free survival of 8 months. After progressive disease (PD), the second NGS did not identify novel genetic alterations that emerged after afatinib resistance. Our case supports the use of ErbB-targeted treatment for NRG1 fusion-positive NSCLC. Further studies are warranted to understand treatment effects and acquired resistance of afatinib in NGR1 fusion-positive patients.

Object To evaluate the effects of ultrasound-guided fine-needle aspiration with or without negative pressure (FNA+P or FNA-P) on diagnosis of thyroid nodules. Methods A prospective randomized study was performed. Patients (n=1374, female=1094, 79.6%, male=280, 20.4%, age=48.7±12.5 yr) with thyroid nodules were randomly divided into FNA-P (n=774, 56.3%) and FNA+P (600, 43.7%) groups. Thyroid nodules were diagnosed by FNA-P or FNA+P, in the left (n=640, 46.6%) and right (n=734, 53.4%). Results The thyroid nodules were diagnosed as microcalcification (n=751, 54.7%), coarse calcification (n=404, 29.4%), peripheral calcification (n=101, 7.4%) and mixed micro + coarse calcification (n=118, 8.6%). Based on Bethesda classification criteria, the thyroid nodules were cataloged as type I (n=217,15.8%), II (n=467, 34.0%), III (n=151, 11.0%), V (n=333, 24.2%), and VI (n=206, 15.0%). There were no significant differences between experimental groups diagnosed by FNA-P or FNA+P. Conclusion The results suggest that fine-needle aspiration with or without negative pressure does not significantly affect the sensitivity of thyroid nodule diagnosis.

Mucosal melanoma (MM) occurs in non-cutaneous mucosal sites, e.g., the head and neck or the lower genital tract; it is a rare and aggressive neoplasm with a poor prognosis. To date, few prognostic markers of MM have been well-defined. The aim of this study is to clarify the prognostic value of the cell-cycle regulatory proteins (CDK4, pRb and CyclinD1, p16) which are associated with the p16(INK4a)-CDK4-pRb pathway in MM. A total of 54 MM samples were obtained from biopsy specimens, and the expressions of the cell-cycle regulatory proteins (CDK4, pRb and CyclinD1, p16) were assessed by immunohistochemistry. A Mantel-Cox regression analysis was performed to investigate the association of these proteins with the overall survival of MM patients. Increased CDK4 expression was significantly associated with reduced survival at three years (P = 0.022). Increased CDK4 protein expression may be a helpful prognostic indicator for the management of these patients who infiltrate into the p16(INK4a)-CDK4-pRb pathway. In addition, we found that those patients with low expression of CDK4 were significantly older (P < 0.05) compared to the patients with high expression of CDK4.

Purpose: Combining siRNA and other chemotherapeutic agents into one nanocarrier can overcome the multidrug resistance (MDR) phenomenon by synergistically MDR relative genes silencing and elevated chemotherapeutic activity. Most of these systems are typically fabricated through complicated procedures, which involves materials preparation, drug loading and modifications. Herein, the purpose of this study is to develop a new and fast co-delivery system of siRNA and doxorubicin for potentially synergistic cancer treatment. Methods: The co-delivery system is constructed conveniently by a stable complex consisting of doxorubicin bound to siRNA via intercalation firstly, followed by interacting with (3-Aminopropyl)triethoxysilane (APTES) electrostatically and Tetraethyl orthosilicate (TEOS) co-condensed, and the characterizations of the resultant nanocarrier are also investigated. Furthermore, this study evaluates the synergistic anti-cancer efficacy in MCF-7/MDR cells after treatment of siRNA and doxorubicin 'two in one' nanocarriers. Results: We establish a new and fast method to craft a co-delivery system of siRNA and doxorubicin with controllable and nearly uniform size, and the entire fabrication process only costs in about 10 minutes. The resultant co-delivery system presents high loading capacities of siRNA and doxorubicin, and the encapsulated doxorubicin plays a pH-responsive control release. Further, biological functionality tests of the synthesized co-delivery nanocarriers show high inhibition of P-gp protein encoded by MDR-1 gene in MCF-7/MDR cells (a variant of human breast cancer cell line with drug resistance) after transfection of these nanocarriers carrying MDR-1 siRNA and doxorubicin simultaneously, which sensitize the MCF-7/MDR cells to doxorubicin, overall leading to improved cell suppression. Conclusion: Collectively, this co-delivery system not only serves as potent therapeutics for synergistic cancer therapy, it also may facilitate the bench-to-bedside translation of combinatorial delivery system as a robust drug nanocarrier by allowing for fabricating a simply and fast nanocarrier for co-delivery of siRNA and doxorubicin with predictable high production rate.

Background Abhydrolase domain containing 5 (ABHD5) functions as a tumor suppressor in colorectal and prostate cancers. The aim of this study was to investigate the roles of ABHD5 in endometrial cancer. Materials and methods ABHD5 expression was detected in clinical samples by immunohistochemical staining. Cell proliferation and invasion were evaluated with the Cell Counting Kit-8 and Transwell assay, respectively. Western blotting was performed to analyze protein expression. Glucose uptake was assessed by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose. Lactate production was detected by a lactate assay kit. Results In the present study, ABHD5 was overexpressed in endometrial cancer tissues, and its expression was closely correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. In addition, we observed that the knockdown of ABHD5 inhibited cell proliferation, invasion, glucose uptake and lactate production in HEC-1A cells, which expressed high levels of ABHD5. Conversely, the opposite effects were observed when ABHD5 was ectopically expressed in Ishikawa cells, which had low levels of ABHD5. Furthermore, the changes in glycolysis regulators (enolase 1 [ENO1], glucose transporter 1 [GLUT1] and lactate dehydrogenase A [LDHA]) and epithelial-to-mesenchymal transition-related proteins (E-cadherin and Snail) in HEC-1A cells with ABHD5 knockdown were consistent with the effects of ABHD5 on glycolysis and cell invasion. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was increased, while the phosphorylated AKT (p-AKT) was decreased when ABHD5 was downregulated. Notably, treatment with the allosteric AKT inhibitor MK-2206 completely abolished the effects caused by ABHD5 overexpression in Ishikawa cells. Finally, ABHD5 knockdown potently suppressed tumor growth in vivo. Conclusion Overall, these results suggest that ABHD5 may play an oncogenic role in endometrial cancer via the AKT pathway.

The aim of this study was to investigate mechanisms of nitrofurantoin resistance and epidemiological characteristics in Escherichia coli clinical isolates. From a total of 1444 E. coli clinical isolates collected from our hospital in 2015, 18 (1.2%) nitrofurantoin-resistant E. coli isolates were identified with nitrofurantoin minimum inhibitory concentrations (MICs) ranging from 128 µg/mL to ≥512 µg/mL. The prevalence of the nfsA gene in nitrofurantoin-resistant, -intermediate and -susceptible isolates was 88.9%, 88.9% and 100%, respectively, and the prevalence of the nfsB gene was 66.7%, 61.1% and 100%, respectively. Eight nitrofurantoin-resistant isolates and two nitrofurantoin-intermediate isolates possessed oqxAB genes. In nitrofurantoin-resistant isolates, mutations in NfsA (the majority of mutated sites were I117T and G187D, accounting for 38.9%) and/or NfsB were detected, whereas only NfsA mutations were found in intermediate isolates and no sequence changes were detected in susceptible isolates. A ≥4-fold decrease in MIC was observed in eight nitrofurantoin-resistant isolates following addition of the efflux pump inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP). The mean expression level of oqxB in nitrofurantoin-resistant isolates increased ca. 7-fold compared with intermediate isolates. Multilocus sequence typing (MLST) categorised the 18 nitrofurantoin-resistant isolates into 11 different sequence types. Pulsed-field gel electrophoresis (PFGE) analysis revealed that homology among the nitrofurantoin-resistant isolates was low and sporadic. In conclusion, mutations in nfsA and nfsB were the main mechanisms leading to nitrofurantoin resistance, and overexpression of the oqxAB gene might help to further increase the MIC of nitrofurantoin.

Abstract Objective: To evaluate the efficacy and safety of percutaneous polidocanol injection (PPI) in treatment of predominantly cystic thyroid nodules. Materials and methods: This prospective study included 111 patients with 122 benign predominantly cystic thyroid nodules inducing pressure symptoms or cosmetic problems. The nodules were randomized to a single aspiration with (n = 61) or without (n = 61) subsequent PPI and followed up after 1, 3, 6, and 12 months. Ten patients (12 nodules) declined to follow up after aspiration in group 2. Nodule volumes, symptoms scores, and cosmetic scores were evaluated before and after treatment. The therapeutic success rate and safety of PPI for treatment of predominantly cystic thyroid nodules were also evaluated. Results: In the PPI group, the nodule volumes were reduced from 13.67 ± 9.90 to 2.60 ± 2.66 (p < .001). Therapeutic success rate (nodule volume reduction >50%) was obtained in 57 of 61 (93.44%) nodules in the PPI group, compared to seven of 49 (14.29%) in the aspiration group (p < .001). In the aspiration group, the nodule volume was not significantly reduced. The reduction in symptom scores was significantly higher in the PPI group (from 3.60 ± 1.65 to 1.60 ± 1.19) than in the aspiration group (from 3.62 ± 1.89 to 3.30 ± 1.06) (p < .001, between groups). The reduction in cosmetic scores showed a significant difference between groups (p < .001). In total, 4.92% of patients (3/61) in the PPI group and 85.71% (42/49) in the aspiration group showed recurrence during the follow-up period. There was a significant difference in the recurrence rate between groups (p < .001). No major side-effects occurred. Conclusions: US-guided PPI of benign recurrent predominantly cystic thyroid nodules is effective and safe. PPI is an important alternative to benign recurrent predominantly cystic thyroid nodules.