Malignancy-associated ischemic stroke: Implications for diagnostic and therapeutic workup.

BACKGROUND: Patients with malignancies have an increased risk of suffering ischemic stroke via several mechanisms such as coagulation dysfunction and other malignancy-related effects as well as iatrogenic causes. Moreover, stroke can be the first sign of an occult malignancy, termed as malignancy-associated ischemic stroke (MAS). Therefore, timely diagnostic assessment and targeted management of this complex clinical situation are critical. FINDINGS: Patients with both stroke and malignancy have atypical ages, risk factors, and often exhibit malignancy-related symptoms and multiple lesions on neuroimaging. New biomarkers such as eicosapentaenoic acid and blood mRNA profiles may help in distinguishing MAS from other strokes. In terms of treatment, malignancy should not be considered a contraindication, given comparable rates of recanalization and complications between stroke patients with or without malignancies. CONCLUSION: In this review, we summarize the latest developments in diagnosing and managing MAS, especially stroke with occult malignancies, and provide new recommendations from recently emerged clinical evidence for diagnostic and therapeutic workup strategies.

Source-free domain adaptive segmentation with class-balanced complementary self-training.

Unsupervised domain adaptation (UDA) plays a crucial role in transferring knowledge gained from a labeled source domain to effectively apply it in an unlabeled and diverse target domain. While UDA commonly involves training on data from both domains, accessing labeled data from the source domain is frequently constrained, citing concerns related to patient data privacy or intellectual property. The source-free UDA (SFUDA) can be promising to sidestep this difficulty. However, without the source domain supervision, the SFUDA methods can easily fall into the dilemma of "winner takes all", in which the majority category can dominate the deep segmentor, and the minority categories are largely ignored. In addition, the over-confident pseudo-label noise in self-training-based UDA is a long-lasting problem. To sidestep these difficulties, we propose a novel class-balanced complementary self-training (CBCOST) framework for SFUDA segmentation. Specifically, we jointly optimize the pseudo-label-based self-training with two mutually reinforced components. The first class-wise balanced pseudo-label training (CBT) explicitly exploits the fine-grained class-wise confidence to select the class-wise balanced pseudo-labeled pixels with the adaptive within-class thresholds. Second, to alleviate the pseudo-labeled noise, we propose a complementary self-training (COST) to exclude the classes that do not belong to, with a heuristic complementary label selection scheme. We evaluated our CBCOST framework on both 2D and 3D cross-modality cardiac anatomical segmentation tasks and brain tumor segmentation tasks. Our experimental results showed that our CBCOST performs better than existing SFUDA methods and yields similar performance, compared with UDA methods with the source data.

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth.

CXCR7 is an atypical chemokine receptor that recruits ß-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke.

Neutrophils play critical roles in the evolving of brain injuries following ischemic stroke. However, how they impact the brain repair in the late phase after stroke remain uncertain. Using a prospective clinical stroke patient cohort, we found significantly increased cathelicidin antimicrobial peptide (CAMP) in the peripheral blood of stroke patients compared to that of healthy controls. While in the mouse stroke model, CAMP was present in the peripheral blood, brain ischemic core and significantly increased at day 1, 3, 7, 14 after middle cerebral artery occlusion (MCAO). CAMP-/- mice exhibited significantly increased infarct volume, exacerbated neurological outcome, reduced cerebral endothelial cell proliferation and vascular density at 7 and 14 days after MCAO. Using bEND3 cells subjected to oxygen-glucose deprivation (OGD), we found significantly increased angiogenesis-related gene expression with the treatment of recombinant CAMP peptide (rCAMP) after reoxygenation. Intracerebroventricular injection (ICV) of AZD-5069, the antagonist of CAMP receptor CXCR2, or knockdown of CXCR2 by shCXCR2 recombinant adeno-associated virus (rAAV) impeded angiogenesis and neurological recovery after MCAO. Administration of rCAMP promoted endothelial proliferation and angiogenesis and attenuated neurological deficits 14 days after MCAO. In conclusion, neutrophil derived CAMP represents an important mediator that could promote post-stroke angiogenesis and neurological recovery in the late phase after stroke.

Ferroptosis: the vulnerability within a cancer monster.

Treatment-resistant cancer, such as neuroendocrine prostate cancer (NEPC), is a lethal disease with limited therapeutic options. RB1 is a tumor suppressor gene that is lost in a majority of NEPC tumors. In this issue of the JCI, Wang and colleagues examined how RB1 loss may sensitize cancer cells to ferroptosis inducers through elevation of ACSL4, a key enzyme that promotes lipid peroxidation and triggers ferroptosis. We discuss a high potential of RB1-deficient cells to undergo ferroptosis due to the elevation of ACSL4. This is normally kept in check by abundant expression of GPX4, an antioxidant enzyme, in cancer cells. This balance, however, is tilted by GPX4 inhibitors, leading to massive ferroptosis. We highlight possible therapeutic strategies that exploit this inherent vulnerability for targeting RB1-deficient, treatment-resistant cancer.

FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A.

Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFß signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.

The levels, prevalence and related factors of compassion fatigue among oncology nurses: a systematic review and meta-analysis.

BACKGROUND: Compassion fatigue is described as the phenomenon of exhaustion and dysfunction in healthcare workers resulting from prolonged exposure to work-related stress and compassion stress. Oncology nurses are at high risk for compassion fatigue. AIMS: Our study aims to estimate the levels, prevalence and related factors of compassion fatigue dimension in oncology nurses. DESIGN: Systematic review and meta-analysis. METHOD: Ten electronic databases were conducted in the systematic review and meta-analysis. Time frame of the searches is from inception up to 31 January 2020. The research team independently conducted study selection, quality assessments, data extractions and analysis of all included studies. The means, standard deviations and prevalence of three dimensions of compassion fatigue were pooled using random-effects meta-analysis. The PRISMA guideline was used to report the systematic review and meta-analysis. PROSPERO registration number: CRD42020205521. RESULTS: The systematic review included 21 studies, involving 6533 oncology nurses across 6 different countries. In our studies, the pooled mean scores of compassion satisfaction (CS), burnout (BO) and secondary traumatic stress (STS) were 35.47 (95% CI: 33.54-37.41), 24.94 (95% CI: 23.47-26.41) and 24.48 (95% CI: 23.36-25.60), respectively; the pooled prevalence of "low" rates of CS, "high" rates of BO and STS were 20% (CI 13%-28%), 22% (CI 18%-26%) and 22% (CI 17%-28%), respectively; furthermore, geographical regions (Asia) significantly affect the prevalence of compassion fatigue among oncology nurses. The compassion fatigue variables considered were demographic (age, marital status, education background, health condition and gender), work-related (job satisfaction, income satisfaction, years of working experience, professional title, position and work environment) and other variables (social support, coping strategy, self-compassion, professional cognition and psychological training). CONCLUSION: Oncology nurses were at "moderate" level of compassion satisfaction, burnout and secondary traumatic stress, and 22% of oncology nurses suffered from "high" risk of compassion fatigue. Hospital administrators should develop interventions to address compassion fatigue phenomenon, and enhance the mental health of oncology nurses and nursing care results. RELEVANCE TO CLINICAL PRACTICE: Oncology unit warrants special attention, and oncology nurses are at high risk for compassion fatigue. However, the reported prevalence rates and oncology nurses with different characteristics vary considerably. The review provides a preliminary framework for nursing administrators to develop interventions to address compassion fatigue phenomenon, and enhance the psychological health of oncology nurses.

Velvet antler polypeptide partially rescue facet joint osteoarthritis-like phenotype in adult ß-catenin conditional activation mice.

BACKGROUND: Wnt/ß-catenin signaling pathway is closely related to osteoarthritis. In our preliminary study, ß-catenin conditional activation (cAct) mice that specifically over-express ß-catenin gene in cartilage chondrocyte exhibits osteoarthritis-like phenotype in the lumbar disc and knee joint. Therefore, we used the mice to model FJ-OA and test the potential curative effect of Velvet Antler Polypeptide (VAP) on this mice model. METHODS: We tested the effect of VAP on ß-catenin conditional activation mice, and used Cre negative littermates as controls. Micro-CT, histology and histomorphometry analysis were performed to evaluate the curative effect of VAP on mice facet joint-like phenotype. Expression of ß-catenin and collagen II was detected by immunohistochemistry (IHC) and western-blot., MMP13, ADAMTS4 and ADAMTS5 was detected by immunofluorescence (IF). RT-PCR analysis was preformed to detect mRNA expression of cartilage degrading enzymes, such as MMP13, ADAMTS4 and ADAMTS5. RESULTS: Results of micro-CT (µCT) analysis showed that VAP could partially reverse lumbar disc osteophyte formation observed in ß-catenin(ex3)Col2ER mice. Histology data revealed VAP partially improved facet joint cartilage tissue invades. Histomorphometry analysis showed an increase in total cartilage area after VAP treatment. IHC show that VAP reduced ß-catenin protein levels and moderately up-regulated collagen II protein levels. RT-PCR and IF data showed that VAP down-regulated the expression of extracellular matrix synthesis (ECM) degradation enzymes MMP13, ADAMTS4 and ADAMTS5. CONCLUSION: Taken together, VAP may modulate ECM by inhibits MMP13, ADAMTS4 and ADAMTS5 via Wnt /ß-catenin signaling pathway. Velvet Antler Polypeptide may be a potential medicine for FJ-OA.

Serum miRNAs are potential biomarkers for the detection of disc degeneration, among which miR-26a-5p suppresses Smad1 to regulate disc homeostasis.

Disc degeneration is a common clinical condition in which damaged discs cause chronic pain; however, a laboratory diagnosis method for its detection is not available. As circulating miRNAs have potential as biomarkers, their application in disc degeneration has not been explored. Here, we prepared serum miRNAs from a mouse disc degeneration model and performed miRNA-Seq and quantitative PCR to characterize disc degeneration-associated miRNAs. We identified three miRNAs, including miR-26a-5p, miR-122-5p and miR-215-5p, undergoing perturbation during the pathogenesis of disc degeneration. Specifically, the levels of miR-26a-5p in the serum demonstrated steady increases in the model of disc degeneration, compared with those in the pre-injury samples of younger age or compared with normal controls of the same age but without disc degeneration, whereas the miRNAs miR-122-5p and miR-215-5p exhibited lower expression in post-injury samples than in their counterparts without the surgery. Moreover, we found that miR-26a-5p targets Smad1 expression, and Smad1 negatively regulates Vegfa expression in disc cells, and thus, miR-26a-5p promotes disc degeneration. In summary, we established a method that consistently profiles circulating miRNAs and identified multiple miRNAs as promising biomarkers for disc degeneration, among which miR-26a-5p enhances VEGF expression during disc degeneration through targeting Smad1 signalling.

Wnt/ß-catenin signaling plays a key role in the development of spondyloarthritis.

Spondyloarthritis (SpA) is a group of diseases consisting of psoriatic arthritis (PsA), reactive arthritis, arthritis related to inflammatory bowel disease (a subgroup of juvenile idiopathic arthritis), and ankylosing spondylitis (the prototype of SpA). Axial bone formation and the combination of concurrent erosion and new bone formation are specific characteristics of SpA disease. The use of antiproinflammatory cytokines, such as inhibitors of tumor necrosis factor α (TNF-α), appears to be the greatest advance in the treatment of SpA over the past 20 years. However, TNF-α blockers do not halt new bone formation. Recent clinical observations and animal studies demonstrate that Wnt signaling proteins and natural Wnt inhibitors, such as DKK1 and sclerostin, are likely to play important roles in the process of ankylosis in SpA, and could potentially serve as therapeutic targets for the treatment of SpA.

High expression of UBD correlates with epirubicin resistance and indicates poor prognosis in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is prone to recurrence and metastasis with worse prognosis. Epirubicin-based chemotherapy is of great importance for patients with TNBC, but resistance to epirubicin severely limits the application of this drug and this has emerged as a major problem in the treatment of TNBC. The ubiquitin protein D (UBD) molecule has often been considered a tumor oncogene, and has been shown to promote the recurrence and metastasis of malignant tumor cells. Since the role of UBD in epirubicin resistance and its prognostic value in TNBC have not been reported, the study reported here was designed to identify the epirubicin-resistance molecule and clarify the related biomarker for TNBC prognosis. METHODS: UBD plasmid was transfected into MDA-MB-231 cells, and the cells were exposed to epirubicin to observe the ability of UBD in epirubicin resistance. UBD expression was also detected in 78 breast cancer tissues by immunohistochemistry. Statistical methods were used to study the relationship between UBD expression and epirubicin resistance in TNBC treatment. Kaplan-Meier survival analysis was used to determine the correlation between UBD expression and TNBC patients' prognostic parameters. RESULTS: UBD expression was found increased in breast cancer tissues. Forced UBD expression was found to have a relationship with TNBC epirubicin resistance in vitro. High expression of UBD was found in TNBC, compared with in non-TNBC, and this played a positive role in epirubicin resistance and indicated the poor prognosis of TNBC treatment. CONCLUSION: UBD may play an important role in epirubicin resistance in TNBC. UBD has the potential to be a novel biomarker in TNBC chemoresistance and may be a promising therapeutic target for TNBC patients.

Prognostic function of Ki-67 for pathological complete response rate of neoadjuvant chemotherapy in triple-negative breast cancer.

AIMS AND BACKGROUND: Triple-negative breast cancer (TNBC) has fluctuating pathological complete response (pCR) rates to neoadjuvant chemotherapy (NAC) according to published reports. Biomarkers predicting pCR rates of NAC would improve TNBC patients' outcomes. We conducted a meta-analysis to estimate the prognostic function of Ki-67 in relation to pCR rates of NAC in TNBC. METHODS AND STUDY DESIGN: Relevant publications in the literature from January 2006 to March 2013 were selected by searching PubMed, SpringerLink, Web of Science, Scopus and the Cochrane Library. The quality of prognostic studies was evaluated according to the standard reported by Hayden et al. Relative risk (RR) and 95% confidence interval (CI) were used to estimate the prognostic function of Ki-67 for pCR rates in TNBC. The fail-safe number was used to detect possible publication bias. Review Manager and MIX software was used to merge extracted data. RESULTS: The pCR rate of TNBC with high Ki-67 expression was 3.36 times that of low Ki-67 expression TNBC. The merged RR was 3.36 (95% CI: 1.61-7.02) and the fail-safe number was 34. No obvious publication bias but heterogeneity of the case series was detected. CONCLUSIONS: Ki-67 was a predictor of pCR rates to NAC in TNBC.