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Released from prison for a crime he didn't commit, an ex-con targets the same bank he was sent away for robbing.

Skin cancer is a significant global health concern, with melanoma being the most dangerous form, responsible for the majority of skin cancer-related deaths. Early detection of skin cancer is critical, as it can drastically improve survival rates. While deep learning models have achieved impressive results in skin cancer classification, there remain challenges in accurately distinguishing between benign and malignant lesions. In this study, we introduce a novel multi-scale attention-based performance booster inspired by the Vision Transformer (ViT) architecture, which enhances the accuracy of both ViT and convolutional neural network (CNN) models. By leveraging attention maps to identify discriminative regions within skin lesion images, our method improves the models’ focus on diagnostically relevant areas. Additionally, we employ ensemble learning techniques to combine the outputs of several deep learning models using majority voting. Our skin cancer classifier, consisting of ViT and EfficientNet models, achieved a classification accuracy of 95.05% on the ISIC2018 dataset, outperforming individual models. The results demonstrate the effectiveness of integrating attention-based multi-scale learning and ensemble methods in skin cancer classification.

Breast cancer (BC) metastasis remains a leading cause of female mortality. Neuropilin-1 (NRP-1) is a glycoprotein receptor that plays ligand-dependent roles in BC. Clinical studies indicate its correlation with metastatic disease; however, its functional role in BC metastasis remains uncertain. CRISPR-Cas9 was used to knockout the NRP-1 gene in MDA-MB-231 BC cells, and the effects on metastasis were determined using an orthotopic mouse engraftment model. NRP-1 expression in knockout cells was rescued using a recombinant cDNA with a silent mutation in the sgRNA target-adjacent PAM sequence. Differentially expressed genes between NRP-1 knockout and control cells were determined using whole-transcriptome sequencing and validated using real-time PCR. NRP-1KO cells showed a pronounced reduction in the metastasis to the lungs. KEGG pathway analysis of the transcriptome data revealed that PI3K and ECM receptor interactions were among the top altered pathways in the NRP-1KO cells. In addition, reduction in metastasis enhancers proteins, Integrin-β3 and Tenascin-C, and genes CCL20 and FN1 and upregulation of metastasis suppressor genes, ACVRL and GPX3 in NRP-1KO were detected. These findings provide evidence for a functional role for NRP-1 in BC metastasis, supporting further exploration of NRP-1 and the identified genes as targets in treating metastatic BC.

Background Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-β (TGF-β) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-β and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models. Methods BA is a first-in-class bifunctional inhibitor of TGF-β and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models. Results Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-β and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls. Conclusions Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.

Background Calpains are a family of calcium-dependent thiol proteases that participate in a wide variety of biological activities. In our recent study, calpain is increased in the sera of scleroderma or systemic sclerosis (SSc). However, the role of calpain in interstitial lung disease (ILD) has not been reported. ILD is a severe complication of SSc, which is the leading cause of death in SSc. The pathogenesis of SSc-related ILD remains incompletely understood. This study investigated the role of myeloid cell calpain in SSc-related ILD. Methods A novel line of mice with myeloid cell-specific deletion of Capns1 ( Capns1-ko ) was created. SSc-related ILD was induced in Capns1-ko mice and their wild-type littermates by injection 0.l mL of bleomycin (0.4 mg/mL) for 4 weeks. In a separate experiment, a pharmacological inhibitor of calpain PD150606 (Biomol, USA, 3 mg/kg/day, i.p.) daily for 30 days was given to mice after bleomycin injection on daily basis. At the end of the experiment, the animals were killed, skin and lung tissues were collected for the following analysis. Inflammation, fibrosis and calpain activity and cytokines were assessed by histological examinations and ELISA, and immunohistochemical analyses, western blot analysis and Flow cytometry analysis. Results Calpain activities increased in SSc-mouse lungs. Both deletion of Capns1 and administration of PD150606 attenuated dermal sclerosis as evidenced by a reduction of skin thickness and reduced interstitial fibrosis and inflammation in bleomycin model of SSc mice. These effects of reduced calpain expression or activity were associated with prevention of macrophage polarization toward M1 phenotype and consequent reduced production of pro-inflammatory cytokines including TNF-α, IL-12 and IL-23 in lung tissues of Capns1-ko mice with bleomycin model of SSc. Furthermore, inhibition of calpain correlated with an increase in the protein levels of PI3K and phosphorylated AKT1 in lung tissues of the bleomycin model of SSc mice. Conclusions This study for the first time demonstrates that the role of myeloid cell calpain may be promotion of macrophage M1 polarization and pro-inflammatory responses related PI3K/AKT1 signaling. Thus, myeloid cell calpain may be a potential therapeutic target for bleomycin model of SSc-related ILD.

Background Current multiparametric MRI (mp-MRI) in routine clinical practice has poor-to-moderate diagnostic performance for transition zone prostate cancer. The aim of this study was to evaluate the potential diagnostic performance of novel 1 H magnetic resonance spectroscopic imaging (MRSI) using a semi-localized adiabatic selective refocusing (sLASER) sequence with gradient offset independent adiabaticity (GOIA) pulses in addition to the routine mp-MRI, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI) and quantitative dynamic contrast enhancement (DCE) for transition zone prostate cancer detection, localization and grading. Methods Forty-one transition zone prostate cancer patients underwent mp-MRI with an external phased-array coil. Normal and cancer regions were delineated by two radiologists and divided into low-risk, intermediate-risk, and high-risk categories based on TRUS guided biopsy results. Support vector machine models were built using different clinically applicable combinations of T2WI, DWI, DCE, and MRSI. The diagnostic performance of each model in cancer detection was evaluated using the area under curve (AUC) of the receiver operating characteristic diagram. Then accuracy, sensitivity and specificity of each model were calculated. Furthermore, the correlation of mp-MRI parameters with low-risk, intermediate-risk and high-risk cancers were calculated using the Spearman correlation coefficient. Results The addition of MRSI to T2WI + DWI and T2WI + DWI + DCE improved the accuracy, sensitivity and specificity for cancer detection. The best performance was achieved with T2WI + DWI + MRSI where the addition of MRSI improved the AUC, accuracy, sensitivity and specificity from 0.86 to 0.99, 0.83 to 0.96, 0.80 to 0.95, and 0.85 to 0.97 respectively. The (choline + spermine + creatine)/citrate ratio of MRSI showed the highest correlation with cancer risk groups (r = 0.64, p < 0.01). Conclusion The inclusion of GOIA-sLASER MRSI into conventional mp-MRI significantly improves the diagnostic accuracy of the detection and aggressiveness assessment of transition zone prostate cancer.

Wolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes and neurodegeneration, and is considered a prototype of human endoplasmic reticulum (ER) disease. Wolfram syndrome is caused by loss of function mutations of Wolfram syndrome 1 or Wolfram syndrome 2 genes, which encode transmembrane proteins localized to the ER. Despite its rarity, Wolfram syndrome represents the best human disease model currently available to identify drugs and biomarkers associated with ER health. Furthermore, this syndrome is ideal for studying the mechanisms of ER stress-mediated death of neurons and β cells. Here we report that the pathway leading to calpain activation offers potential drug targets for Wolfram syndrome and substrates for calpain might serve as biomarkers for this syndrome. Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 ( WFS1 ) and Wolfram syndrome 2 ( WFS2 ), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.

Background Limited understanding of the cancer biology of metastatic sites is a major factor contributing to poor outcomes in cancer patients. The regional lymph nodes are the most common site of metastasis in most solid cancers and their involvement is a strong predictor of relapse in breast cancer (BC). We have previously shown that ezrin, a cytoskeletal–membrane linker protein, is associated with lymphovascular invasion and promotes metastatic progression in BC. However, the efficacy of pharmacological inhibition of ezrin in blocking cancer cell migration and metastasis remains unexplored in BC. Methods We quantified ezrin expression in a BC tissue microarray ( n  = 347) to assess its correlation with risk of relapse. Next, we developed a quantitative intravital microscopy (qIVM) approach, using a syngeneic lymphatic reporter mouse tumor model, to investigate the effect of systemic ezrin inhibition on cancer cell migration and metastasis. Results We show that ezrin is expressed at significantly higher levels in lymph node metastases compared to matched primary tumors, and that a high tumor ezrin level is associated with increased risk of relapse in BC patients with regional disease. Using qIVM, we observe a subset of cancer cells that retain their invasive and migratory phenotype at the tumor-draining lymph node. We further show that systemic inhibition of ezrin, using a small molecule compound (NSC668394), impedes the migration of cancer cells in vivo. Furthermore, systemic ezrin inhibition leads to reductions in metastatic burden at the distal axillary lymph node and lungs. Conclusions Our findings demonstrate that the tumor ezrin level act as an independent biomarker in predicting relapse and provide a rationale for therapeutic targeting of ezrin to reduce the metastatic capacity of cancer cells in high-risk BC patients with elevated ezrin expression.

Crowd anomaly detection is crucial in enhancing surveillance and crowd management. This paper proposes an efficient approach that combines spatial and temporal visual descriptors, sparse feature tracking, and neural networks for efficient crowd anomaly detection. The proposed approach utilises diverse local feature extraction methods, including SIFT, FAST, and AKAZE, with a sparse feature tracking technique to ensure accurate and consistent tracking. Delaunay triangulation is employed to represent the spatial distribution of features in an efficient way. Visual descriptors are categorised into individual behaviour descriptors and interactive descriptors to capture the temporal and spatial characteristics of crowd dynamics and behaviour, respectively. Neural networks are then utilised to classify these descriptors and pinpoint anomalies, making use of their strong learning capabilities. A significant component of our study is the assessment of how dimensionality reduction methods, particularly autoencoders and PCA, affect the feature set’s performance. This assessment aims to balance computational efficiency and detection accuracy. Tests conducted on benchmark crowd datasets highlight the effectiveness of our method in identifying anomalies. Our approach offers a nuanced understanding of crowd movement and patterns by emphasising both individual and collective characteristics. The visual and local descriptors facilitate high-level analysis by closely relating to semantic information and crowd behaviour. The analysis observed shows that this approach offers an efficient framework for crowd anomaly detection, contributing to improved crowd management and public safety. The proposed model achieves accuracy of 99.5 %, 96.1%, 99.0% and 88.5% in the UMN scenes 1, 2, and 3 and violence in crowds datasets, respectively.

Key Points The fps/fes (Fujinami poultry sarcoma/feline sarcoma) and fer (Fes-related protein) proto-oncogenes encode distinct members of the non-receptor/cytoplasmic protein-tyrosine kinase family. Retroviral fps / fes alleles encode Gag–Fps/Fes fusion proteins, which are constitutively active kinases that can cause cellular transformation in vitro and tumours in vivo . The role of cellular Fps/Fes and Fer kinases is still unclear. Cellular Fps/Fes and Fer kinases consist of an amino-terminal Fps/Fes/Fer/CIP4 homology (FCH) domain — which might have a role in microfilament association — followed by three regions of predicted coiled-coils (which seem to regulate oligomerization), a central Src-homology-2 (SH2) domain (which mediates association with phosphotyrosine-containing peptide motifs) and a carboxy-terminal catalytic domain. Transgenic overexpression of retroviral or activated mutant fps / fes alleles resulted in several malignancies and hyperplasias in some tissues. These observations underscored the potential involvement of Fps/Fes in human cancer and indicate roles for regulation of cellular proliferation. Fps/Fes and Fer kinases are implicated in signalling downstream of the receptors for several cytokines, growth factors and immunoglobin (Ig)-receptors; however, the precise molecular roles are not well understood. Some recent observations of Fps/Fes and Fer activation downstream from IgE receptors on mast cells and the glycoprotein VI collagen receptor on platelets indicates that they might serve redundant biochemical roles. Studies using targeted germ-line null or loss-of-function mouse models of Fps/Fes have shown that this kinase is not required for haematopoiesis. However, many subtle phenotypes show an involvement that might be redundant with another kinase. This is further supported by more pronounced defects in mice that lack both Fps/Fes and Fer kinase activities. Other studies with targeted mouse models show that both Fps/Fes and Fer are involved in the regulation of inflammatory responses and innate immunity. Mice that lack either Fps/Fes or Fer kinase activity show enhanced sensitivity to endotoxin challenge and defects in the regulation of inflammatory cell functions, including mast-cell migration and leukocyte extravasation. Although the molecular functions of Fps/Fes and Fer kinases are still unknown, there is mounting evidence for a role in regulation of cell–cell and cell–matrix interactions, possibly through regulating rearrangement of the cytoskeleton and cross-talk between integrins and other receptor systems, such as adherens junctions or receptors for growth factors and cytokines. Fps/Fes and Fer are the only known members of a distinct subfamily of the non-receptor protein-tyrosine kinase family. Recent studies indicate that these kinases have roles in regulating cytoskeletal rearrangements and inside–out signalling that accompany receptor–ligand, cell–matrix and cell–cell interactions. Genetic analysis using transgenic mouse models also implicates these kinases in the regulation of inflammation and innate immunity.