Current Knowledge and Perspectives of Phage Therapy for Combating Refractory Wound Infections.

Wound infection is one of the most important factors affecting wound healing, so its effective control is critical to promote the process of wound healing. However, with the increasing prevalence of multi-drug-resistant (MDR) bacterial strains, the prevention and treatment of wound infections are now more challenging, imposing heavy medical and financial burdens on patients. Furthermore, the diminishing effectiveness of conventional antimicrobials and the declining research on new antibiotics necessitate the urgent exploration of alternative treatments for wound infections. Recently, phage therapy has been revitalized as a promising strategy to address the challenges posed by bacterial infections in the era of antibiotic resistance. The use of phage therapy in treating infectious diseases has demonstrated positive results. This review provides an overview of the mechanisms, characteristics, and delivery methods of phage therapy for combating pathogenic bacteria. Then, we focus on the clinical application of various phage therapies in managing refractory wound infections, such as diabetic foot infections, as well as traumatic, surgical, and burn wound infections. Additionally, an analysis of the potential obstacles and challenges of phage therapy in clinical practice is presented, along with corresponding strategies for addressing these issues. This review serves to enhance our understanding of phage therapy and provides innovative avenues for addressing refractory infections in wound healing.

Microbial detoxification of mycotoxins in food and feed.

Mycotoxins are metabolites produced by fungi growing in food or feed, which can produce toxic effects and seriously threaten the health of humans and animals. Mycotoxins are commonly found in food and feed, and are of significant concern due to their hepatotoxicity, nephrotoxicity, carcinogenicity, mutagenicity, and ability to damage the immune and reproductive systems. Traditional physical and chemical detoxification methods to treat mycotoxins in food and feed products have limitations, such as loss of nutrients, reagent residues, and secondary pollution to the environment. Thus, there is an urgent need for new detoxification methods to effectively control mycotoxins and treat mycotoxin pollution. In recent years, microbial detoxification technology has been widely used for the degradation of mycotoxins in food and feed because this approach offers the potential for treatment with high efficiency, low toxicity, and strong specificity, without damage to nutrients. This article reviews the application of microbial detoxification technology for removal of common mycotoxins such as Aflatoxin, Ochratoxin, Zearalenone, Deoxynivalenol, and Fumonisins, and discusses the development trend of this important technology.

Lung cancer coexisting with Papiliotrema flavescens infection diagnosed by next-generation sequencing: a case report.

BACKGROUND: Papiliotrema flavescens is a rare environmental yeast, which has been isolated from air, trees, kernels of wheat and corn, fermenting soya sauce, and cerebrospinal fluid of patient with AIDS. Additionally, it is also reported to cause subcutaneous infection in a dog. In this case, we describe primary lung adenocarcinoma coexisting with Papiliotrema flavescens infection in a female patient diagnosed by next-generation sequencing (NGS) technique, which is the first such reported case. CASE PRESENTATION: The patient was a 52-year-old female with recurrent cough for 3 months. Chest CT examination revealed a ground glass nodule of 17 * 23 * 18 mm in the right upper lung, and 3 new pulmonary nodules appeared around it 2 months later. The patient underwent right upper lobe lobectomy and pathology confirmed that the primary 2-cm-lesion in the right upper lobe was invasive lung adenocarcinoma, and two of the three surrounding lung nodules were pathologically suggestive of pulmonary fungal infection (not known in specific fungal types). Hence, the patient received empirical anti-fungal treatments with fluconazole 400 mg/day for a week and follow-up CT scanning showed no tumor progression and no relapse of fungal infection. The specific pathogen was eventually identified as Papiliotrema flavescens by the next-generation sequencing of pathogen. DISCUSSION AND CONCLUSION: We first reported that lung cancer coexisting with Papiliotrema flavescens infection in a female patient. The diagnosis of lung cancer with typical CT imaging features is relatively simple, while the diagnosis of lung cancer coexisting with rare fungal infection is challenging. NGS technique is an effective supplementary technique for clinical diagnosis of bacterial or fungal infectious diseases, enabling precise clinical decision-making and appropriate treatment. In this case, the lung cancer may result in a degree of immune suppression, at least locally, resulting in the formation of pulmonary fungal nodular lesions around the tumor.

Metastatic Low-Grade Sarcoma with CARS-ALK Fusion Dramatically Responded to Multiple ALK Tyrosine Kinase Inhibitors: A Case Report with Comprehensive Genomic Analysis.

This article reports a case of advanced metastatic low-grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next-generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS-ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second-line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient's primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case. KEY POINTS: To our best knowledge, this is the first report of a very successful treatment with first- and second-line ALK tyrosine kinase inhibitors for CARS-ALK fusion-positive metastatic low-grade sarcoma. Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained. Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low-grade sarcoma case. A whole genome duplication event might have happened during tumorigenesis of this low-grade sarcoma case.

One-step time-resolved fluorescence microsphere immunochromatographic test strip for quantitative and simultaneous detection of DON and ZEN.

Deoxynivalenol (DON) and zearalenone (ZEN) are mycotoxins that contaminate a wide range of grains and crops. In this study, a one-step time-resolved single-channel immunochromatographic test strip based on europium ion polystyrene fluorescence microspheres was first developed for sensitive and quantitative detection of DON and ZEN. The concentration of the artificial antigen and the mass ratio of the monoclonal antibody to fluorescent microspheres for conjugation were optimized to simplify the sample addition process during immunochromatographic assay and improve the on-site detection efficiency. The limits of detection (LOD) of the single-channel immunochromatographic test strip for DON and ZEN detection were 0.17 and 0.54 µg/L, respectively. Meanwhile, the dual-channel immunochromatographic test strip was designed to simultaneously detect DON and ZEN, with LODs of 0.24 and 0.69 µg/L achieved for DON and ZEN, respectively. The developed test strips also yielded recovery results consistent with that obtained by LC-MS/MS for DON and ZEN detection in real samples of wheat and corn flour, confirming the practicability and reliability of the test strip. The developed immunochromatographic test strips realize quick and sensitive detection of DON and ZEN, exhibiting potential for broad applications in the point-of-care testing platform of multiple mycotoxins in agricultural products. Graphic abstract.

Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment.

RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid-polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t1/2 ∼ 8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.

Increased Expression and Prognostic Significance of BYSL in Melanoma.

We evaluated the BYSL content and underlying mechanism in melanoma (SKCM) overall survival (OS). In this study, we used a comprehensive approach combining bioinformatics tools, including miRNA estimation, quantitative real-time polymerase chain reaction (qRT-PCR) of miRNAs, E3 ligase estimation, STRING analysis, TIMER analysis, examination of associated upstream modulators, protein-protein interaction (PPI) analysis, as well as retrospective and survival analyses, alongside clinical sample validation. These methods were used to investigate the content of BYSL, its methylation status, its relation to patient outcome, and its immunologic significance in tumors. Our findings revealed that BYSL expression is negatively regulated by BYSL methylation. Analysis of 468 cases of SKCM RNA sequencing samples demonstrated that enhanced BYSL expression was associated with higher tumor grade. We identified several miRNAs, namely hsa-miR-146b-3p, hsa-miR-342-3p, hsa-miR-511-5p, hsa-miR-3690, and hsa-miR-193a-5p, which showed a strong association with BYSL levels. Furthermore, we predicted the E3 ubiquitin ligase of BYSL and identified CBL, FBXW7, FZR1, KLHL3, and MARCH1 as potential modulators of BYSL. Through our investigation, we discovered that PNO1, RIOK2, TSR1, WDR3, and NOB1 proteins were strongly associated with BYSL expression. In addition, we found a close association between BYSL levels and certain immune cells, particularly dendritic cells (DCs). Notably, we observed a significant negative correlation between miR-146b-3p and BYSL mRNA expression in SKCM sera samples. Collectively, based on the previously shown evidences, BYSL can serve as a robust bioindicator of SKCM patient prognosis, and it potentially contributes to immune cell invasion in SKCM.

Gooderoside A from Anoectochilus elatus attenuates acute and chronic pains by inhibiting NO/cGMP and IRAK4/IRAK1/TAK1 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus elatus Lindl. was traditionally used for pain treatment and Gooderoside A (GA) was regarded as its principal constituent. AIM OF THE STUDY: To investigate whether GA can be responsible for the antinociceptive activity of A. elatus and explore its underlying mechanism. MATERIALS AND METHODS: Acetic acid-induced abdominal writhing and tail flick tests were employed to evaluate the antinociceptive activity of ethanolic extract of A. elatus (EEA) and GA. Formalin test was used to ascertain the antinociceptive pattern of GA. Entobarbital sodium induced sleep test was adopted to exclude its hypnotic effect, while open-field test was performed to rule out its motor impairment effect. Chronic constriction injury (CCI)-induced neuropathic pain in rats was developed to evaluate its efficacy on neuropathic pain, and BV-2 cells were used to explore the underlying mechanism. RESULTS: EEA and GA, significantly inhibited chemical and thermal nociception. GA suppressed nociception in formalin test in both phase I and II, whereas methylene blue and L-NAME partially reversed its efficacy. GA located inner and slightly blocked sodium channel current, and did not show any hypnotic effect or motor impairment effect. Crucially, GA markedly attenuated chronic neuropathic pain in rats, inhibited the phosphorylation of IRAK4, IRAK1 and TAK1, and suppressed MAPKs pathway in BV-2 cells. CONCLUSION: GA relieved acute and chronic pains in vivo. The mechanism of action involves the blocking of NO/cGMP and IRAK4/IRAK1/TAK1 pathways. These results suggested GA may be a promising candidate for antinociceptive drug development.

Interdigital-type antifungal socks for prevention and treatment of tinea pedis.

BACKGROUND: Interdigital tinea pedis is the most common type of foot infection, which is often treated by topical or systemic antifungals. Due to the increase in antifungal resistance, antifungal socks are becoming potential alternatives for the daily management of tinea pedis. METHODS: In this study, antifungal fibres were adopted to produce interdigital hygiene socks to split the third and fourth toe seams of the feet. In vitro antifungal activity was first examined to verify the effectiveness of the socks. Preventive efficacy against tinea pedis was then evaluated among healthy participants, followed by therapeutic effect detection in patients diagnosed with tinea pedis by analysing the improvement in total symptom scores (TTS). RESULTS: The interdigital-type hygiene socks exhibited apparent antifungal activities in vitro. An in vivo study demonstrated significant preventive effects against tinea pedis for interdigital socks compared to plain socks (P = 0.011) and a lower TTS than noninterdigital (P = 0.04) or plain socks (P < 0.0001). Moreover, interdigital socks showed a total effectiveness rate of 72.9% in patients with tinea pedis, with most of the symptoms alleviated. CONCLUSION: Interdigital-type hygiene socks not only exhibited in vitro antifungal activities but also showed significant prophylactic and therapeutic effects against interdigital tinea pedis in vivo.

New insight into the role of fibroblasts in the epithelial immune microenvironment in the single-cell era.

The skin is exposed to environmental challenges and contains heterogeneous cell populations such as epithelial cells, stromal cells, and skin-resident immune cells. As the most abundant type of stromal cells, fibroblasts have been historically considered silent observers in the immune responses of the cutaneous epithelial immune microenvironment (EIME), with little research conducted on their heterogeneity and immune-related functions. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have overcome the limitations of bulk RNA sequencing and help recognize the functional and spatial heterogeneity of fibroblasts, as well as their crosstalk with other types of cells in the cutaneous EIME. Recently, emerging single-cell sequencing data have demonstrated that fibroblasts notably participate in the immune responses of the EIME and impact the initiation and progression of inflammatory skin diseases. Here, we summarize the latest advances in the role of fibroblasts in the cutaneous EIME of inflammatory skin diseases and discuss the distinct functions and molecular mechanisms of activated fibroblasts in fibrotic skin diseases and non-fibrotic inflammatory skin diseases. This review help unveil the multiple roles of fibroblasts in the cutaneous EIME and offer new promising therapeutic strategies for the management of inflammatory skin diseases by targeting fibroblasts or the fibroblast-centered EIME.

Integrating Chinese Herbs and Western Medicine for New Wound Dressings through Handheld Electrospinning.

In this nanotechnology era, nanostructures play a crucial role in the investigation of novel functional nanomaterials. Complex nanostructures and their corresponding fabrication techniques provide powerful tools for the development of high-performance functional materials. In this study, advanced micro-nanomanufacturing technologies and composite micro-nanostructures were applied to the development of a new type of pharmaceutical formulation, aiming to achieve rapid hemostasis, pain relief, and antimicrobial properties. Briefly, an approach combining a electrohydrodynamic atomization (EHDA) technique and reversed-phase solvent was employed to fabricate a novel beaded nanofiber structure (BNS), consisting of micrometer-sized particles distributed on a nanoscale fiber matrix. Firstly, Zein-loaded Yunnan Baiyao (YB) particles were prepared using the solution electrospraying process. Subsequently, these particles were suspended in a co-solvent solution containing ciprofloxacin (CIP) and hydrophilic polymer polyvinylpyrrolidone (PVP) and electrospun into hybrid structural microfibers using a handheld electrospinning device, forming the EHDA product E3. The fiber-beaded composite morphology of E3 was confirmed through scanning electron microscopy (SEM) images. Fourier-transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analysis revealed the amorphous state of CIP in the BNS membrane due to the good compatibility between CIP and PVP. The rapid dissolution experiment revealed that E3 exhibits fast disintegration properties and promotes the dissolution of CIP. Moreover, in vitro drug release study demonstrated the complete release of CIP within 1 min. Antibacterial assays showed a significant reduction in the number of adhered bacteria on the BNS, indicating excellent antibacterial performance. Compared with the traditional YB powders consisting of Chinese herbs, the BNS showed a series of advantages for potential wound dressing. These advantages include an improved antibacterial effect, a sustained release of active ingredients from YB, and a convenient wound covering application, which were resulted from the integration of Chinese herbs and Western medicine. This study provides valuable insights for the development of novel multiscale functional micro-/nano-composite materials and pioneers the developments of new types of medicines from the combination of herbal medicines and Western medicines.

Tri-Layer Core-Shell Fibers from Coaxial Electrospinning for a Modified Release of Metronidazole.

Polymers are the backbone of drug delivery. Electrospinning has greatly enriched the strategies that have been explored for developing novel drug delivery systems using polymers during the past two decades. In this study, four different kinds of polymers, i.e., the water-soluble polymer poly (vinyl alcohol) (PVA), the insoluble polymer poly(ε-caprolactone) (PCL), the insoluble polymer Eudragit RL100 (ERL100) and the pH-sensitive polymer Eudragit S100 (ES100) were successfully converted into types of tri-layer tri-polymer core-shell fibers through bi-fluid coaxial electrospinning. During the coaxial process, the model drug metronidazole (MTD) was loaded into the shell working fluid, which was an emulsion. The micro-formation mechanism of the tri-layer core-shell fibers from the coaxial emulsion electrospinning was proposed. Scanning electron microscope and transmission electron microscope evaluations verified the linear morphology of the resultant fibers and their obvious tri-layer multiple-chamber structures. X-ray diffraction and Fourier transform infrared spectroscopy measurements demonstrated that the drug MTD presented in the fibers in an amorphous state and was compatible with the three polymeric matrices. In vitro dissolution tests verified that the three kinds of polymer could act in a synergistic manner for a prolonged sustained-release profile of MTD in the gut. The drug controlled-release mechanisms were suggested in detail. The protocols reported here pioneer a new route for creating a tri-layer core-shell structure from both aqueous and organic solvents, and a new strategy for developing advanced drug delivery systems with sophisticated drug controlled-release profiles.

One-step extraction and simultaneous quantitative fluorescence immunochromatography strip for AFB1 and Cd detection in grain.

AFB1 and heavy metal Cd are two common pollutants during grain storage. The rapid detection of grains before they enter the granary is particularly important. Hence, rapidly, accurately, and sensitively screening contaminated grains, simplifying the detection process, and reducing detection costs are necessary. In this study, linear ranges of time-resolved fluorescence microsphere - immunochromatographic test strip (TRFM-ICTS) detection were 0.01-30 ng/mL (AFB1) and 0.01-60 ng/mL (Cd), and the IC50 values were 0.536 ng/mL (AFB1) and 3.331 ng/mL (Cd). In the TRFM-ICTS sample addition experiment, the recovery rates were all between 90% and 110%. The coefficient of variation was less than 8% in the actual sample detection process of grain. We have established a one-step extraction method for AFB1 and Cd in grains to achieve simultaneous detection in one extraction. In addition, TRFM-ICTS could be stored for at least 12 months, providing technical support for the realization of commercial production.

AZIN1 RNA editing alters protein interactions, leading to nuclear translocation and worse outcomes in prostate cancer.

The transcript encoding Antizyme Inhibitor 1 (AZIN1) is frequently edited in various cancers, and this editing is associated with enhanced tumor aggressiveness. After comparison of wild-type AZIN1 (wtAZIN1) and edited AZIN1 (edAZIN1, which contains a Ser367Gly substitution), we report differential binding of edAZIN1 to a small set of proteins; specifically, edAZIN1 binds to alpha-smooth muscle actin (ACTA2), gamma actin 1 (ACTG1), and myosin9, whereas wtAZIN1 does not. This binding enables nuclear translocation of edAZIN1. In contrast to overexpression of edAZIN1 and, to a lesser extent, (editable) wtAZIN1, overexpression of an uneditable AZIN1 allele does not promote a cellular phenotype associated with increased tumorigenicity. In patients, both editing and nuclear localization of AZIN1 are common and are associated with tumor aggressiveness, i.e., a higher Gleason score, higher genomic instability, and a shorter progression-free survival time. In conclusion, the data indicate that binding of edAZIN1 to the actin/myosin9 complex supports its nuclear translocation, leading to enhanced cellular aggressiveness, and is associated with worse prostate cancer outcomes.

Genome-wide CRISPR/Cas9 library screen identifies PCMT1 as a critical driver of ovarian cancer metastasis.

BACKGROUND: The development of lethal cancer metastasis depends on the dynamic interactions between cancer cells and the tumor microenvironment, both of which are embedded in the extracellular matrix (ECM). The acquisition of resistance to detachment-induced apoptosis, also known as anoikis, is a critical step in the metastatic cascade. Thus, a more in-depth and systematic analysis is needed to identify the key drivers of anoikis resistance. METHODS: Genome-wide CRISPR/Cas9 knockout screen was used to identify critical drivers of anoikis resistance using SKOV3 cell line and found protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) as a candidate. Quantitative real-time PCR (qRT-PCR) and immune-histochemistry (IHC) were used to measure differentially expressed PCMT1 in primary tissues and metastatic cancer tissues. PCMT1 knockdown/knockout and overexpression were performed to investigate the functional role of PCMT1 in vitro and in vivo. The expression and regulation of PCMT1 and integrin-FAK-Src pathway were evaluated using immunoprecipitation followed by mass spectrometry (IP-MS), western blot analysis and live cell imaging. RESULTS: We found that PCMT1 enhanced cell migration, adhesion, and spheroid formation in vitro. Interestingly, PCMT1 was released from ovarian cancer cells, and interacted with the ECM protein LAMB3, which binds to integrin and activates FAK-Src signaling to promote cancer progression. Strikingly, treatment with an antibody against extracellular PCMT1 effectively reduced ovarian cancer cell invasion and adhesion. Our in vivo results indicated that overexpression of PCMT1 led to increased ascites formation and distant metastasis, whereas knockout of PCMT1 had the opposite effect. Importantly, PCMT1 was highly expressed in late-stage metastatic tumors compared to early-stage primary tumors. CONCLUSIONS: Through systematically identifying the drivers of anoikis resistance, we uncovered the contribution of PCMT1 to focal adhesion (FA) dynamics as well as cancer metastasis. Our study suggested that PCMT1 has the potential to be a therapeutic target in metastatic ovarian cancer.

Epithelioid hemangioendotheliomas of the spine: clinical characters with middle and long-term follow-up under surgical treatments.

Epithelioid hemangioendothelioma, an aggressive vascular tumor has the rarity of morbidity that arises in the spine. There were few cases reported in literatures in recent years, and little was known about this disease. A review study of the patient files in our constitutions between 1996 and 2006 showed that five patients were treated for spinal epithelioid hemangioendothelioma. Although only five patients, this study attempts to bring more informations about this rare lesion. This patient group included two males and three females. The lesions located in the cervical (case 1) or thoracic (case 2-4) or lumbar spine (case 5). Treatments included: laminectomy and cytoreductive surgery followed by external beam irradiation (one patient), expanded resection in piece meal with postoperative external beam irradiation (three patients), and total en bloc resection alone (one patient). Reconstruction of the spinal stability was performed in four patients. Follow-up period ranged from 25 to 72 months, averaged 47.4 months. The neurologic function of patients got a satisfactory progress except the paraplegic patient at diagnosis. The patient who received laminectomy and cytoreductive surgery followed by external beam irradiation still presented with tumor local progress, metastasis, and she died at 34 months after operation. No local recurrence or distant metastasis was detected in the other four patients. Epithelioid hemangioendothelioma of the spine is so rare in clinic as a primary aggressive vascular tumor. Based on our experience, a valid expanded resection of the tumor with adjunct radiation therapy or total en bloc excision may present with acceptable results.

An unusual case of pigmented villonodular synovitis 14 years after total hip arthroplasty.

Pigmented villonodular synovitis (PVNS) is a rare benign proliferation lesion of the synovium of the joint, bursa, and the tendon sheath. We report here a case of PVNS in a 78-year-old woman 14 years after she underwent total arthroplasty of her right hip. Diffuse PVNS was detected in her right hip during surgery to replace her prosthesis, which had loosened. Macroscopically, the surface of the resected tissue was black and composed of papillae and nodules. Histologically, the tissue consisted of proliferative synoviocytes with black pigment in the cytoplasm. Beneath the synoviocytes were foamy cells. Pathologic analysis confirmed the diagnosis of PVNS with black pigment and the presence of hemosiderin. This indicates that implantation of the prosthesis might have caused the lesion or might have caused its proliferation.

Hormone Receptor Status May Impact the Survival Benefit Between Medullary Breast Carcinoma and Atypical Medullary Carcinoma of the Breast: A Population-Based Study.

BACKGROUND: A rare subtype of breast cancer, atypical medullary carcinoma of the breast (AMCB), shows a highly adverse prognosis compared to medullary carcinoma of the breast (MBC). The current study aimed to establish a correlated nomogram for the identification of the prognostic factors of AMCB and MBC. METHODS: Kaplan-Meier and Cox regression analyses were applied to data acquired from the Surveillance, Epidemiology and End Results (SEER) database for 2004 to 2013 to analyse tumour characteristics and overall survival. Propensity score matching (PSM) analysis was performed to determine the overall survival (OS) among those with AMCB and MBC. A predictive nomogram was created, and the concordance index (C-index) was used to predict accuracy and discriminative ability. RESULTS: A total of 2,001 patients from the SEER database were diagnosed with MBC between 2004 and 2013, including 147 patients diagnosed with AMCB. The number of diagnoses gradually increased in both groups. Cox analysis of multivariate and Kaplan-Meier analysis showed that older age (HR = 3.005, 95% CI 1.906-4.739) and later stage were significantly associated with poor prognosis, while cancer-directed surgery was an independent protective factor (HR = 0.252, 95% CI 0.086-0.740). In the HR-negative stratification analysis, older age (HR = 2.476, 95% CI 1.398-4.385), later stage and histological type (HR=0.381, 95% CI 0.198-0.734) were found to be independent prognostic factors for low standard survival. The log-rank analysis demonstrated significantly worse prognostic factors for patients with AMCB than for those with MBC (P = 0.004). A nomogram (C-index for survival = 0.75; 95% CI 0.69-0.81) was established from four independent prognostic factors after complete identification. CONCLUSIONS: MBC is rare, and cancer-directed surgery, older age, and later stage are independently linked with prognosis. In the HR negative population, AMCB patients show a worse survival gain than those with MBC.

Non-apoptotic function of caspase-8 confers prostate cancer enzalutamide resistance via NF-κB activation.

Caspase-8 is a unique member of caspases with a dual role in cell death and survival. Caspase-8 expression is often lost in some tumors, but increased in others, indicating a potential pro-survival function in cancer. By analyzing transcriptome of enzalutamide-resistant prostate cancer cells, we found that resistance was conferred by a mild caspase-8 upregulation that in turn led to NF-κB activation and the subsequent upregulation of the downstream IL-8. Mechanistically, we found that the pro-survival and enzalutamide-resistance-promoting features of caspase-8 were independent of its proteolytic activity, using a catalytically-inactive caspase-8 mutant. We further demonstrated that caspase-8 pro-apoptotic function was inhibited via cFLIP binding. Moreover, high caspase-8 expression was correlated with a worse prognosis in prostate cancer patients. Collectively, our work demonstrates that enzalutamide-resistance is mediated by caspase-8 upregulation and the consequent increase in NF-κB/IL-8 mediated survival signaling, highlighting caspase-8 and NF-κB as potential therapeutic targets to overcome enzalutamide-resistance in CRPC.

Integrated Transcriptomic Analysis Reveals a Distinctive Role of YAP1 in Extramedullary Invasion and Therapeutic Sensitivity of Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy. There are no standard therapeutic guidelines for extramedullary invasion (EM). We performed a retrospective integrated transcriptomic analysis based on GEO, TCGA, and Oncomine datasets with a total of over 2,500 cases enrolled. GSVA analysis was performed on GSE24080. The external validation cohorts include GSE9782, GSE2658, MMRF-COMPASS, and Oncomine. The data of MGUS to relapsed MM were acquired from GSE6477, GSE5900, and Oncomine. The data of EM were acquired from GSE39683 and GSE66291. Single-cell level transcriptome data of MM and EM were acquired from GSE106218. GSVA analysis revealed that 559 cases could be divided into 2 groups based on the expression of oncogenic pathways with prognostic significances. Group 1 with a specific phenotype of YAP1-MYC+ exhibited an unpromising prognosis. The univariate analysis revealed YAP1 as a tumor suppressor in MM. The activity of DNA repair, glycolysis, and oxidative phosphorylation was significantly higher in YAP1-MYC+ MM, which is in concordance with EM myeloma cells based on single-cell analysis. Furthermore, we discovered that YAP1-MYC+ MM patients exhibited an improved response for IMiD treatment. Collectively, YAP1-MYC+MM patients might suffer a worse prognosis and stronger propensity for EM progression.