Positional differences in the micro- and ultra-structural variations of ray parenchyma cells during the transformation from sapwood to heartwood.

Ray parenchyma cells are involved in the initiation of heartwood formation. The position within a ray influences the timing of ray parenchyma cell differentiation and function; however, there is little information concerning the positional influence on the cellular changes of ray parenchyma cells from sapwood and heartwood. In this study, radial variations in morphology, size, and ultrastructure of ray parenchyma cells were studied by combined transmission electron microscopy and optical microscopy. Results showed that cellular traits of ray parenchyma cells in Populus tomentosa were all affected by both radial position in the secondary xylem and position within a ray. Specifically, radial variations in cellular traits were more evident in isolation cells, which were not adjacent to vessel elements. Both cell length and cell width/length ratio of isolation cells were bigger than contact cells, which contacted adjacent vessel elements via pits. Moreover, the secondary wall thickening and lignification of contact cells developed in the current-year xylem, much earlier than isolation cells. Secondary walls in contact cells were in a polylamellate structure with a protective layer on the inner side. No alteration in the ultrastructure of contact cells occurred in the sapwood-heartwood transition zone, except that most contact cells died. By contrast, in the transition zone, isolation cells still lived. A thin secondary wall began to deposit on the thick primary wall of isolation cells, with two isotropic layers on the inner side of the primary wall and secondary wall respectively being characteristic. Meanwhile, starch grains in isolation cells were depleted, and dark polyphenolic droplets lost their spherical shape and flowed together. Furthermore, the intercellular spaces of isolation cells became densified in the transition zone. Overall, cellular changes suggested that the positional information of ray parenchyma cells appeared to be an important factor in the transformation from sapwood to heartwood. Unlike contact cells, isolation cells were more elongated, specialized in radial transport, had a delayed formation of secondary walls, and were involved in the synthesis of heartwood substances. Our result promotes the elucidation of the involvement of xylem rays in heartwood formation.

Utilizing decellularized bio-membranes to optimize histopathological embedding of small tissues.

In recent years, minimally invasive biopsy techniques have been widely used to generate small tissue samples that require processing in clinical pathology. However, small paraffin-embedded tissues are prone to loss due to their small size. To prevent the loss of small tissues, researchers have employed nonbiological embedding materials for preembedding, but this approach can lead to cumbersome experimental procedures and increase the chances of tissue loss. This study aimed to develop a convenient decellularized embedding material derived from biological membrane tissues to effectively protect small tissues from loss during paraffin embedding. This study decellularized three types of fresh animal-derived membrane tissues and selected the small intestine as the most suitable decellularized raw material through attempts at softening, comparing physical properties, and using tissue as the starting material. Subsequently, small tissues from various tissue sources were embedded, followed by H&E staining, Masson staining, immunofluorescence staining, and immunohistochemical staining. The decellularized material derived from biomembrane tissues (DMBT) developed in this study can reduce the loss of small tissues without the need for preembedding, thereby shortening the embedding process. This provides a new pathological embedding tool for future laboratory and clinical research and work.•The fat layer of the pig's small intestine is scraped off, and chemical reagents are used to defat and decellularize it.•Chemical reagents are used to soften and make the pig's small intestine transparent, and the decellularized pig's small intestine is dried.•DMBT is used for embedding and staining the biological tissue.

The biological characteristics of DAstV molecular epidemiology and pathogenicity of duck astrovirus causing hepatitis in ducks and chickens in Southeast China.

A suspected outbreak of duck astrovirus (DAstV) disease occurred in a large Muscovy duck farm in Guangdong Province, China, in June 2022, which severely affected the production performance and health of Muscovy ducks. This study aimed to investigate the prevalence of DAstV disease in Southeast China. Herein, we employed semi-nested PCR ethodto screen 5203 swab and liver samples from 11 Muscovy duck farms in 5 provinces of China for the presence of DAstV. Among them, 1356 samples (26.06%, 1356/5203) tested positive for DAstV, out of which 11 DAstV strains were isolated after 10 generations of blind transmission through Leghorn male hepatoma (LMH) cells and performed their whole-genome sequencing. The alignment results showed that the 11 DAstV isolates exhibited relatively low homology (15.4%-75%) with the astrovirus isolates from other species published in GenBank, whereas their homology (nucleotide: 90.4%-99.99%; amino acid: 94%-99.8%) with the DAstV type 1 (DAstV-1) reference strain was higher, indicating considerable homology. The results indicated that DAstV-1 was the main pathogenic factor. Herein, we successfully recreated the clinical symptoms of natural infection in 28-day-old specific-pathogen-free (SPF) ducks using the DAstV-1-GDB-2022 strain. The primary clinical manifestations included liver enlargement, hemorrhaging, and disruptions in liver function. Additionally, we confirmed the cross-species transmission potential of DAstV-1, marking the first occurrence of clinical symptoms of DAstV in 28-day-old SPF chickens. Our findings provide new perspectives on the epidemiology and pathogenicity of DAstV-1 and may help in advancing the development of DAstV vaccines.

Incidence of medical adhesive-related skin injury: a reduction by changing posture.

OBJECTIVE: Medical adhesive-related skin injuries (MARSI), defined as skin damage associated with the use of medical adhesive products or devices, are a common and under-reported condition that compromises skin integrity. The prevention and management of MARSI that can occur around the needle insertion site of a chest wall implantable port in hospitalised patients with a tumour remain challenging issues. The aim of this study was to explore whether the incidence of MARSI could be reduced by changing the body position during dressing changes. METHOD: Participants were recruited between May 2019 and November 2020 in the oncology department of a tertiary hospital. Patients were randomly assigned to Group AB (supine followed by semi-recumbent position) and Group BA (semi-recumbent followed by supine position) with a standard intervening recovery interval of 21-28 days. Assessments for typical MARSI included itching, the combination of erythema and oedema, and blisters in the port area, and were graded according to the level of severity. RESULTS: The itch intensity was significantly lower in phase B (semi-recumbent) compared to phase A (supine) (2.35±1.985 versus 5.31±1.332, respectively; p<0.01). Similarly, the severity of erythema and oedema was less severe when comparing phase B to phase A: grade 0 (64.9% versus 10.5%, respectively); grade 1 (28.1% versus 19.3%, respectively); grade 2 (3.5% versus 7.0%, respectively); grade 3 (1.8% versus 45.6%, respectively); and grade 4 (1.8% versus 17.5%, respectively) (Z=5.703; p<0.01). Blisters were found far less frequently in phase B than phase A (1.8% versus 56.1%, respectively; p<0.01). CONCLUSION: The study provided statistically significant evidence that patients in a semi-recumbent position receiving dressing at a chest wall implantable port had fewer and less severe injection site MARSI than when in a supine position. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare.

The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics.

Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.

Medical image foundation models in assisting diagnosis of brain tumors: a pilot study.

OBJECTIVES: To build self-supervised foundation models for multicontrast MRI of the whole brain and evaluate their efficacy in assisting diagnosis of brain tumors. METHODS: In this retrospective study, foundation models were developed using 57,621 enhanced head MRI scans through self-supervised learning with a pretext task of cross-contrast context restoration with two different content dropout schemes. Downstream classifiers were constructed based on the pretrained foundation models and fine-tuned for brain tumor detection, discrimination, and molecular status prediction. Metrics including accuracy, sensitivity, specificity, and area under the ROC curve (AUC) were used to evaluate the performance. Convolutional neural networks trained exclusively on downstream task data were employed for comparative analysis. RESULTS: The pretrained foundation models demonstrated their ability to extract effective representations from multicontrast whole-brain volumes. The best classifiers, endowed with pretrained weights, showed remarkable performance with accuracies of 94.9, 92.3, and 80.4%, and corresponding AUC values of 0.981, 0.972, and 0.852 on independent test datasets in brain tumor detection, discrimination, and molecular status prediction, respectively. The classifiers with pretrained weights outperformed the convolutional classifiers trained from scratch by approximately 10% in terms of accuracy and AUC across all tasks. The saliency regions in the correctly predicted cases are mainly clustered around the tumors. Classifiers derived from the two dropout schemes differed significantly only in the detection of brain tumors. CONCLUSIONS: Foundation models obtained from self-supervised learning have demonstrated encouraging potential for scalability and interpretability in downstream brain tumor-related tasks and hold promise for extension to neurological diseases with diffusely distributed lesions. CLINICAL RELEVANCE STATEMENT: The application of our proposed method to the prediction of key molecular status in gliomas is expected to improve treatment planning and patient outcomes. Additionally, the foundation model we developed could serve as a cornerstone for advancing AI applications in the diagnosis of brain-related diseases.

Stromal-derived MAOB promotes prostate cancer growth and progression.

Prostate cancer (PC) develops in a microenvironment where the stromal cells modulate adjacent tumor growth and progression. Here, we demonstrated elevated levels of monoamine oxidase B (MAOB), a mitochondrial enzyme that degrades biogenic and dietary monoamines, in human PC stroma, which was associated with poor clinical outcomes of PC patients. Knockdown or overexpression of MAOB in human prostate stromal fibroblasts indicated that MAOB promotes cocultured PC cell proliferation, migration, and invasion and co-inoculated prostate tumor growth in mice. Mechanistically, MAOB induces a reactive stroma with activated marker expression, increased extracellular matrix remodeling, and acquisition of a protumorigenic phenotype through enhanced production of reactive oxygen species. Moreover, MAOB transcriptionally activates CXCL12 through Twist1 synergizing with TGFß1-dependent Smads in prostate stroma, which stimulates tumor-expressed CXCR4-Src/JNK signaling in a paracrine manner. Pharmacological inhibition of stromal MAOB restricted PC xenograft growth in mice. Collectively, these findings characterize the contribution of MAOB to PC and suggest MAOB as a potential stroma-based therapeutic target.

A cisplatin conjugate with tumor cell specificity exhibits antitumor effects in renal cancer models.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and is notorious for its resistance to both chemotherapy and small-molecule inhibitor targeted therapies. Subcellular targeted cancer therapy may thwart the resistance to produce a substantial effect. METHODS: We tested whether the resistance can be circumvented by subcellular targeted cancer therapy with DZ-CIS, which is a chemical conjugate of the tumor-cell specific heptamethine carbocyanine dye (HMCD) with cisplatin (CIS), a chemotherapeutic drug with limited use in ccRCC treatment because of frequent renal toxicity. RESULTS: DZ-CIS displayed cytocidal effects on Caki-1, 786-O, ACHN, and SN12C human ccRCC cell lines and mouse Renca cells in a dose-dependent manner and inhibited ACHN and Renca tumor formation in experimental mouse models. Noticeably, in tumor-bearing mice, repeated DZ-CIS use did not cause renal toxicity, in contrast to the CIS-treated control animals. In ccRCC tumors, DZ-CIS treatment inhibited proliferation markers but induced cell death marker levels. In addition, DZ-CIS at half maximal inhibitory concentration (IC50) sensitized Caki-1 cells to small-molecule mTOR inhibitors. Mechanistically, DZ-CIS selectively accumulated in ccRCC cells' subcellular organelles, where it damages the structure and function of mitochondria, leading to cytochrome C release, caspase activation, and apoptotic cancer cell death. CONCLUSIONS: Results from this study strongly suggest DZ-CIS be tested as a safe and effective subcellular targeted cancer therapy.

Glucocorticoids promote lung metastasis of pancreatic cancer cells through enhancing cell adhesion, migration and invasion.

Glucocorticoids (GCs) are the important stress hormones and widely prescribed as drugs. Although stress has been suggested as a promoter of tumor progression, the direct influence of GCs on metastasis of tumor is not fully understood. Metastasis is a major cause of death in pancreatic cancer patients. In the present study, we investigated the effect of GCs on progression of pancreatic cancer and elucidated the underlying mechanism. It was found that GCs significantly promote cell adhesion, migration, and invasion of pancreatic cancer cells in vitro and their lung metastasis in vivo. Further mechanistic studies showed that GCs notably up-regulate the expression of a trans-membrane glycoprotein, mucin 1 (MUC1) and increase the activation of AKT. Inhibiting MUC1 expression not only attenuates the activation of AKT, but also significantly reduces the promoting effects of GCs on cell adhesion, migration, invasion, and lung metastasis of pancreatic cancer cells. Moreover, GCs not only significantly up-regulate expression of Rho-associated kinase 1/2 (ROCK1/2) and matrix metalloproteinase 3 and 7 (MMP3/7), but also activate ROCK2, which are also involved in the pro-migratory and pro-invasive effects of GCs in pancreatic cancer cells. Taken together, our findings reveal that GCs promote metastasis of pancreatic cancer cells through complex mechanism. MUC1-PI3K/AKT pathway, ROCK1/2 and MMP3/7 are involved in the promoting effect of GCs on cell migration, invasion and metastasis in pancreatic cancer cells. These results suggest the importance of reducing stress and GCs administration in patients with pancreatic cancer to avoid an increased risk of cancer metastasis.

Artificial Intelligence Applications in Glioma With 1p/19q Co-Deletion: A Systematic Review.

As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.

Uncovering potential diagnostic biomarkers of acute myocardial infarction based on machine learning and analyzing its relationship with immune cells.

BACKGROUND: Acute myocardial infarction (AMI) is a common cardiovascular disease. This study aimed to mine biomarkers associated with AMI to aid in clinical diagnosis and management. METHODS: All mRNA and miRNA data were downloaded from public database. Differentially expressed mRNAs (DEmRNAs) and differentially expressed miRNAs (DEmiRNAs) were identified using the metaMA and limma packages, respectively. Functional analysis of the DEmRNAs was performed. In order to explore the relationship between miRNA and mRNA, we construct miRNA-mRNA negative regulatory network. Potential biomarkers were identified based on machine learning. Subsequently, ROC and immune correlation analysis were performed on the identified key DEmRNA biomarkers. RESULTS: According to the false discovery rate < 0.05, 92 DEmRNAs and 272 DEmiRNAs were identified. GSEA analysis found that kegg_peroxisome was up-regulated in AMI and kegg_steroid_hormone_biosynthesis was down-regulated in AMI compared to normal controls. 5 key DEmRNA biomarkers were identified based on machine learning, and classification diagnostic models were constructed. The random forests (RF) model has the highest accuracy. This indicates that RF model has high diagnostic value and may contribute to the early diagnosis of AMI. ROC analysis found that the area under curve of 5 key DEmRNA biomarkers were all greater than 0.7. Pearson correlation analysis showed that 5 key DEmRNA biomarkers were correlated with most of the differential infiltrating immune cells. CONCLUSION: The identification of new molecular biomarkers provides potential research directions for exploring the molecular mechanism of AMI. Furthermore, it is important to explore new diagnostic genetic biomarkers for the diagnosis and treatment of AMI.

NTRK-rearranged spindle cell neoplasms: a clinicopathological and molecular study of 13 cases with peculiar characteristics at one of the largest institutions in China.

NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) represent an emerging group of rare tumours defined using molecular means. To the best of our knowledge, there have been no large series of reports about this tumour in the Chinese population in English full-text articles. Herein, we present 13 NTRK-RSCNs with peculiar characteristics. Ten of the 13 (77%) patients were children without sex differences. The tumour locations included six trunks, four extremities, two recta, and one small bowel. The histological morphology included four lipofibromatosis-like neural tumour (LPF-NT)-like, eight malignant peripheral nerve sheath tumours (MPNST)/fibrosarcoma-like, and one extremely rare myxofibrosarcoma-like pattern. Immunohistochemically, all cases were CD34, pan-TRK and TRK-A positive, SOX-10 negative, and H3K27me3 intact. S-100 protein expression was identified in 11 of 13 (85%) cases. Genetically, NTRK1 rearrangements were considered positive (7/13, 54%) or suspicious for positivity (6/13, 46%) by fluorescence in situ hybridisation. Next-generation sequencing and Sanger sequencing confirmed NTRK1 fusions with a variety of partner genes, including five LMNA, three TPM3, one SQSTM1, three novel CPSF6, IGR (downstream PMVK), and GAS2L1 genes. Interestingly, the last tumour concurrently harboured a second EWSR1-PBX1 fusion, which has never been reported. Four patients developed local recurrence and two of them suffered metastasis. In our study, NTRK-RSCNs had peculiar fusions that displayed unusual or complicated clinicopathological features. Histological clues and IHC helped streamline a small subset of potential candidates. Although FISH is a powerful technology for identifying NTRK rearrangements, RNA-/DNA-based NGS is recommended for highly suspected cases in which FISH signal patterns are not discernible as classic positive patterns, particularly if targeted therapy is considered.

Breast Cancer MCF-7 Cells Acquire Heterogeneity during Successive Co-Culture with Hematopoietic and Bone Marrow-Derived Mesenchymal Stem/Stromal Cells.

During disease progression and bone metastasis, breast tumor cells interact with various types of bystander cells residing in the tumor microenvironment. Such interactions prompt tumor cell heterogeneity. We used successive co-culture as an experimental model to examine cancer-bystander cell interaction. RMCF7-2, a clone of the human breast cancer MCF-7 cells tagged with a red fluorescent protein, was tracked for morphologic, behavioral, and gene expression changes. Co-cultured with various types of hematopoietic cells, RMCF7-2 adopted stable changes to a rounded shape in suspension growth of red fluorescent cells, from which derivative clones displayed marked expressional changes of marker proteins, including reduced E-cadherin and estrogen receptor α, and loss of progesterone receptor. In a successive co-culture with bone marrow-derived mesenchymal stem/stromal cells, the red fluorescent clones in suspension growth changed once more, adopting an attachment growth, but in diversified shapes. Red fluorescent clones recovered from the second-round co-culture were heterogeneous in morphology, but retained the altered marker protein expression while displaying increased proliferation, migration, and xenograft tumor formation. Interaction with bystander cells caused permanent morphologic, growth behavioral, and gene expressional changes under successive co-culture, which is a powerful model for studying cancer cell heterogeneity during breast cancer progression and metastasis.

Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. NRP2 silencing restricted NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is transcriptionally inhibited by AR, and in turn suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Collectively, these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.

Novel vandetanib derivative inhibited proliferation and promoted apoptosis of cancer cells under normoxia and hypoxia.

Over-expressions of epidermal growth factor receptor and vascular endothelial growth factor receptor were frequently associated with the metastasis of solid tumors. Vandetanib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor and vascular endothelial growth factor receptor, was broadly effective in treating a variety of human solid tumors. The compelling evidence that hypoxia is involved in tumor resistance to cancer therapy. Hypoxia-inducible factor (HIF-1α), a major transcription factor in response to hypoxia, has been considered as a promising specific target for cancer therapy. We reported a stronger vandetanib derivative, compound 39, which was more potently decreased viability of A549, HT-29, MCF-7, HepG2, and HeLa cells than its parent compound vandetanib. Remarkable hypoxia-selectivity was observed in A549 cells (IC50 = 1.55 ± 0.23 µM under normoxia and 0.31 ± 0.06 µM under hypoxia, respectively) and HT-29 cells (IC50 = 12.89 ± 2.15 µM under normoxia and 3.47 ± 0.79 µM under hypoxia, respectively). The apoptosis of A549 and HT-29 cells induced by compound 39 were detected by flow cytometry. Western blot analysis demonstrated that compound 39 significantly down-regulated the anti-apoptotic B-cell lymphoma-2 (BCL-2) protein and up-regulated the expression of pro-apoptotic BCL2-Associated X (Bax) protein as well as promoted the cleavage of poly (ADP-ribose) polymerase PARP. HIF-1α was down-regulated by compound 39 in A549 and HT-29 cells under hypoxia. We also found that the depletion of intracellular Reduced Glutathione (GSH) as well as production of Reactive Oxygen Species (ROS) were critical for compound 39-mediated cell death.

KRT13 promotes stemness and drives metastasis in breast cancer through a plakoglobin/c-Myc signaling pathway.

BACKGROUND: Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Keratin 13 (KRT13) plays an important role in breast cancer progression and metastasis. The objective of this study is to elucidate the mechanism by which KRT13 promotes breast cancer growth and metastasis. METHODS: The function and mechanisms of KRT13 in breast cancer progression and metastasis were assessed by overexpression and knockdown followed by examination of altered behaviors in breast cancer cells and in xenograft tumor formation in mouse mammary fat pad. Human breast cancer specimens were examined by immunohistochemistry and multiplexed quantum dot labeling analysis to correlate KRT13 expression to breast cancer progression and metastasis. RESULTS: KRT13-overexpressing MCF7 cells displayed increased proliferation, invasion, migration and in vivo tumor growth and metastasis to bone and lung. Conversely, KRT13 knockdown inhibited the aggressive behaviors of HCC1954 cells. At the molecular level, KRT13 directly interacted with plakoglobin (PG, γ-catenin) to form complexes with desmoplakin (DSP). This complex interfered with PG expression and nuclear translocation and abrogated PG-mediated suppression of c-Myc expression, while the KRT13/PG/c-Myc signaling pathway increased epithelial to mesenchymal transition and stem cell-like phenotype. KRT13 expression in 58 human breast cancer tissues was up-regulated especially at the invasive front and in metastatic specimens (12/18) (p < 0.05). KRT13 up-regulation in primary breast cancer was associated with decreased overall patient survival. CONCLUSIONS: This study reveals that KRT13 promotes breast cancer cell growth and metastasis via a plakoglobin/c-Myc pathway. Our findings reveal a potential novel pathway for therapeutic targeting of breast cancer progression and metastasis.

Epidemiological investigation of duck adenovirus 3 in southern China, during 2018-2020.

RESEARCH HIGHLIGHTSFirst report of the epidemiology of duck adenovirus 3 infection in China.Mutant DAdV-3 strains (truncated ORF67) became predominant.

Novel Mitochondria-Based Targeting Restores Responsiveness in Therapeutically Resistant Human Lung Cancer Cells.

Cisplatin and tyrosine kinase inhibitors (TKI) are recommended to treat non-small cell lung cancer (NSCLC). However, ubiquitously acquired drug resistance in patients with NSCLC diminishes their therapeutic efficacy. Strategies for overcoming cisplatin and TKI resistance are an unmet medical need. We previously described a group of near-infrared heptamethine carbocyanine fluorescent dyes, referred to as DZ, with tumor-homing properties via differentially expressed organic anion-transporting polypeptides on cancer cells. This group of organic dyes can deliver therapeutic payloads specifically to tumor cells in the form of a chemical conjugate. We synthesized DZ-simvastatin (DZ-SIM) initially to target cholesterol biosynthesis in lung cancer cells. DZ-SIM killed both cisplatin-sensitive and cisplatin-resistant as well as EGFR-TKI-sensitive and EGFR-TKI-resistant lung cancer cells. This conjugate specifically accumulated in and effectively inhibited the growth of xenograft tumors formed by NSCLC cells resistant to first-generation (H1650) and third-generation (PC9AR) EGFR TKIs. DZ-SIM induced cell death by targeting mitochondrial structure and function. We concluded that DZ-SIM could be a promising novel therapy for overcoming drug resistance in patients with NSCLC.

Isolation and characterization of a novel chicken astrovirus in China.

Chicken astrovirus (CAstV) is associated with kidney disease and visceral gout, runting and stunting syndrome, and white chick hatchery disease, causing economic losses to the poultry industry worldwide. In this study, 55.6% of 36 clinical samples from Guangdong province in China were positive for CAstV, but negative for other common enteric viruses, including avian nephritis virus, infectious bronchitis virus, fowl adenovirus Group I, Newcastle disease virus, chicken parvovirus, reovirus, and rotavirus by PCRs and RT-PCRs. A CAstV strain, named GD202013, was isolated from Guangdong province in south China, and was identified by CAstV RT-PCR. A whole genome sequence analysis demonstrated that GD202013 shares 76.0 to 88.1% identity with 24 reference strains in GenBank. Phylogenetic analysis, based on whole genome and capsid protein, showed that GD202013 is more closely related to 2 US strains (GA2011/US/2011 and 4175/US/2011) belonging to subgroup Bii. Recombination analysis indicated that GD202013 is a recombinant strain formed by 3 strains: a major parent strain CkP5/US/2016, and 2 minor parent strains (GA2011/US/2011 and G059/PL/2014). In addition, the chicken embryo infection experiment demonstrated that GD202013 causes hatchability reduction, growth depression, and death of embryos. Macroscopic and microscopic lesions in the liver, kidney and small intestine were observed in the dead-in-shell embryos. This is the first report of the novel CAstV infection in China.

Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer.

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1-AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA-AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. SIGNIFICANCE: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.