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Clinicopathological and prognostic significance of programmed cell death ligand 1 expression in patients diagnosed with breast cancer: meta-analysis.

Br J Surg 2021 May 8. Epub 2021 May 8.

Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.

Background: Uncertainty exists regarding the clinical relevance of programmed cell death ligand 1 (PD-L1) expression in breast cancer. This systematic review and meta-analysis evaluated the clinicopathological and prognostic role of PD-L1 in breast cancer.

Methods: A systematic review was performed in accordance with PRISMA guidelines. Read More

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Cocaine-induced projection-specific and cell type-specific adaptations in the nucleus accumbens.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Cocaine craving, seeking, and relapse are mediated, in part, by cocaine-induced adaptive changes in the brain reward circuits. The nucleus accumbens (NAc) integrates and prioritizes different emotional and motivational inputs to the reward system by processing convergent glutamatergic projections from the medial prefrontal cortex, basolateral amygdala, ventral hippocampus, and other limbic and paralimbic brain regions. Medium spiny neurons (MSNs) are the principal projection neurons in the NAc, which can be divided into two major subpopulations, namely dopamine receptor D1- versus D2-expressing MSNs, with complementing roles in reward-associated behaviors. Read More

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Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China.

Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor β (LXRβ) is expressed in astrocytes, and LXRβ global knockout mice shows impaired synaptic formation. In order to define the role of LXRβ in astrocytes, we used a conditional Cre-loxP system to specifically remove LXRβ from astrocytes. Read More

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Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment.

NPJ Precis Oncol 2021 May 7;5(1):37. Epub 2021 May 7.

Department of Basic Medical Science, School of Medicine, Tsinghua University, Beijing, China.

The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression of immunotherapy prognostic marker genes (IPMGs) in these pathways can predict the patient survival with high accuracy not only in the TCGA cohort (89. Read More

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Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex.

Sci Rep 2021 May 7;11(1):9803. Epub 2021 May 7.

Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Angiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Read More

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Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma.

Sci Rep 2021 May 7;11(1):9766. Epub 2021 May 7.

Disease Biology Lab, SSSIHL-Agilent Center for Excellence in Multiomics and Cell Sciences, Dept. of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, Anantapur, Andhra Pradesh, 515 134, India.

Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO datasets to identify features unique to POAG. Read More

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The oncogenic E3 ligase TRIP12 suppresses epithelial-mesenchymal transition (EMT) and mesenchymal traits through ZEB1/2.

Cell Death Discov 2021 May 7;7(1):95. Epub 2021 May 7.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.

Thyroid hormone receptor interactor 12 (TRIP12) is an E3 ligase most notably involved in the proteolytic degradation of the tumor suppressor p14ARF. Through this process, it is proposed that TRIP12 plays an oncogenic role in tumor initiation and growth. However, its role in other cancer processes is unknown. Read More

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ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss.

Cell Death Dis 2021 May 7;12(5):458. Epub 2021 May 7.

Laboratory of Retinal Cell Biology, Tokyo, Japan.

Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. Read More

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Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.

Thorax 2021 May 7. Epub 2021 May 7.

Department of Pulmonary Medicine, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands

Introduction: Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology.

Methods: Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton's tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Read More

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Toll9 from functions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals.

Proc Natl Acad Sci U S A 2021 May;118(19)

Guangdong Laboratory for Lingnan Modern Agriculture, Laboratory of Insect Molecular Biology and Biotechnology, Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, 510642 Guangzhou, China;

Toll/Toll-like receptors (TLRs) are key regulators of the innate immune system in both invertebrates and vertebrates. However, while mammalian TLRs directly recognize pathogen-associated molecular patterns, the insect Toll pathway is thought to be primarily activated by binding Spätzle cytokines that are processed from inactive precursors in response to microbial infection. Phylogenetic and structural data generated in this study supported earlier results showing that Toll9 members differ from other insect Tolls by clustering with the mammalian TLR4 group, which recognizes lipopolysaccharide (LPS) through interaction with myeloid differentiation-2 (MD-2)-like proteins. Read More

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SARS-CoV-2 spike protein stabilized in the closed state induces potent neutralizing responses.

J Virol 2021 May 7. Epub 2021 May 7.

Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.

The majority of SARS-CoV-2 vaccines in use or advanced development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described against both open and closed conformations. Read More

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ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2.

J Virol 2021 May 7. Epub 2021 May 7.

CSIRO Health & Biosecurity, Australian Centre for Disease Preparedness, Private bag 24, Geelong 3220, Victoria, Australia

The human protein-coding gene (inflammation and lipid regulator with UBA-like and NBR1-like domains, previously C6orf106) was identified as a proviral factor for Hendra virus infection and recently characterised to function an inhibitor of type-I interferon expression. Here, we have utilised RNA-seq to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of Caco-2 cells. We find that inhibition of ILRUN expression by RNA interference alters transcription profile of numerous cellular pathways, including upregulation of the SARS-CoV-2 entry receptor and several other members of the renin-angiotensin aldosterone system. Read More

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The integrin signaling network promotes axon regeneration via the Src-ephexin-RhoA GTPase signaling axis.

J Neurosci 2021 May 7. Epub 2021 May 7.

Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan

Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase-ROCK (Rho-associated coiled-coil kinase)-regulatory non-muscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Read More

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Galectin-9 Targets NLRP3 for Autophagic Degradation to Limit Inflammation.

J Immunol 2021 May 7. Epub 2021 May 7.

Department of Immunology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China;

NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in a variety of inflammatory disorders, and its activation should be tightly controlled to avoid detrimental effects. NLRP3 protein expression is considered as the rate-limiting step for NLRP3 inflammasome activation. In this study, we show that galectin-9 (encoded by ) attenuated NLRP3 inflammasome activation by promoting the protein degradation of NLRP3 in primary peritoneal macrophages of C57BL/6J mice. Read More

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Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma.

J Immunother Cancer 2021 May;9(5)

Providence Cancer Institute, Portland, Oregon, USA

Background: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone.

Methods: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Read More

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IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy.

J Immunother Cancer 2021 May;9(5)

Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA

Background: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression. Read More

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Immune cell composition and functional marker dynamics from multiplexed immunohistochemistry to predict response to neoadjuvant chemotherapy in the WSG-ADAPT-TN trial.

J Immunother Cancer 2021 May;9(5)

West German Study Group, Moenchengladbach, Germany.

Background: The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored.

Methods: Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression. Read More

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Predicting anti-PD-1 responders in malignant melanoma from the frequency of S100A9+ monocytes in the blood.

J Immunother Cancer 2021 May;9(5)

Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Stockholm, Sweden

Background: While programmed cell death receptor 1 (PD-1) blockade treatment has revolutionized treatment of patients with melanoma, clinical outcomes are highly variable, and only a fraction of patients show durable responses. Therefore, there is a clear need for predictive biomarkers to select patients who will benefit from the treatment.

Method: To identify potential predictive markers for response to PD-1 checkpoint blockade immunotherapy, we conducted single-cell RNA sequencing analyses of peripheral blood mononuclear cells (PBMC) (n=8), as well as an in-depth immune monitoring study (n=20) by flow cytometry in patients with advanced melanoma undergoing treatment with nivolumab at Karolinska University Hospital. Read More

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Combination anti-PD1 and ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders.

J Immunother Cancer 2021 May;9(5)

Department of Medical Oncology, Westmead and Blacktown Hospital, New South Wales, New South Wales, Australia

Background: Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases. Read More

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Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas.

J Immunother Cancer 2021 May;9(5)

Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

Background: Pediatric high-grade gliomas (pHGGs) are among the most common and incurable malignant neoplasms of childhood. Despite aggressive, multimodal treatment, the outcome of children with high-grade gliomas has not significantly improved over the past decades, prompting the development of innovative approaches.

Methods: To develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of oncolytic adenoviruses (OAs) by testing the combination with a gene-therapy approach using a bispecific T-cell engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2), conveyed by a replication-incompetent adenoviral vector (EphA2 adenovirus (EAd)). Read More

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CAR Linker Length Modulates CD22-Targeted CAR T-cell Efficacy in ALL.

Authors:

Cancer Discov 2021 May 7. Epub 2021 May 7.

The chimeric antigen receptor (CAR) linker affected CAR T-cell results in acute lymphoblastic leukemia. Read More

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Sphingosine 1-phosphate, a potential target in neovascular retinal disease.

Br J Ophthalmol 2021 May 7. Epub 2021 May 7.

School of Pharmacy, University College Cork, Cork, Ireland

Neovascular ocular diseases (such as age-related macular degeneration, diabetic retinopathy and retinal vein occlusion) are characterised by common pathological processes that contribute to disease progression. These include angiogenesis, oedema, inflammation, cell death and fibrosis. Currently available therapies target the effects of vascular endothelial growth factor (VEGF), the main mediator of pathological angiogenesis. Read More

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Structural insights into integrin αβ opening by fibronectin ligand.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.

Integrin αβ is a major fibronectin receptor critical for cell migration. Upon complex formation, fibronectin and αβ undergo conformational changes. While this is key for cell-tissue connections, its mechanism is unknown. Read More

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Rare case of a duodenal de novo dedifferentiated gastrointestinal stromal tumour.

BMJ Case Rep 2021 May 7;14(5). Epub 2021 May 7.

Department of Medical Oncology, HealthCare Global Enterprises Ltd, Bangalore, Karnataka, India.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Dedifferentiation in these tumours occurs rarely, and when it does occurs most commonly after prolonged treatment with imatinib. We report the case of a 64-year-old man who presented with a mass of 8×7×3 cm dimensions involving the duodenum and head of the pancreas. Read More

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Receptor Activator of NF Kappa B (RANK) Expression Indicates Favorable Prognosis in Patients with Muscle-invasive Bladder Cancer.

Eur Urol Focus 2021 May 4. Epub 2021 May 4.

Department of Urology, University Hospital, Tübingen, Germany; Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Clinical Trials Unit, Studienpraxis Urologie, Nürtingen, Germany. Electronic address:

Background: Receptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown.

Objective: To assess the relevance of RANK expression in patients with MIBC. Read More

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Expression and localization of apelin and its receptor in the testes of diabetic mice and its possible role in steroidogenesis.

Cytokine 2021 May 4:155554. Epub 2021 May 4.

Department of Zoology, Mizoram University, Aizawl, Mizoram 796 004, India. Electronic address:

Type 1 diabetes mellitus (T1DM) is a metabolic disorder with severe hyperglycemia, one of the complications of which is testicular dysfunctions, androgen deficiency and decreased male fertility. In the diabetic testes, the expression and signaling pathways of leptin and a number of other adipokines are significantly changed. However, there is no information on the localization and expression of adipokine, apelin and its receptor (APJ) in the diabetic testes, although there is information on the involvement of apelin in the regulation of reproductive functions. Read More

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ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling.

J Exp Clin Cancer Res 2021 May 7;40(1):158. Epub 2021 May 7.

Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Hongkou District, Shanghai, 200080, China.

Background: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin-RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). Read More

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A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2.

World J Surg Oncol 2021 May 7;19(1):142. Epub 2021 May 7.

Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan.

Background: No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group.

Methods: Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Read More

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Thoracic radiotherapy and concurrent almonertinib for unresectable stage III EGFR-mutated non-small-cell lung cancer: a phase 2 study.

BMC Cancer 2021 May 7;21(1):511. Epub 2021 May 7.

Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, People's Republic of China.

Background: Concurrent chemo-radiotherapy remains the standard treatment in unresectable stage III non-small-cell lung cancer (NSCLC) patients. Several studies have shown a potential value of concurrent epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with thoracic radiotherapy in EGFR-mutated population, but a high risk of radiation pneumonitis raised a major concern. This study intends to explore the safety and efficacy of concurrent almonertinib, a new third-generation EGFR-TKI, with radiotherapy in locally advanced EGFR-mutated NSCLC patients. Read More

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The cytotoxic conjugate of highly internalizing tetravalent antibody for targeting FGFR1-overproducing cancer cells.

Mol Med 2021 May 7;27(1):46. Epub 2021 May 7.

Faculty of Biotechnology, Department of Protein Engineering, University of Wroclaw, Joliot-Curie 14a, 50-383, Wroclaw, Poland.

Background: Antibody drug conjugates (ADCs) represent one of the most promising approaches in the current immuno-oncology research. The precise delivery of cytotoxic drugs to the cancer cells using ADCs specific for tumor-associated antigens enables sparing the healthy cells and thereby reduces unwanted side effects. Overexpression of fibroblast growth factor receptor 1 (FGFR1) has been demonstrated in numerous tumors and thereby constitutes a convenient molecular target for selective cancer treatment. Read More

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