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AARS1-Mediated RUNX3 K193 Lactylation Enhances the Activation and Cytotoxicity of CD8+T Cells in Smoking-Related Emphysema.

Emphysema is the primary pathological feature of chronic obstructive pulmonary disease (COPD). The accumulation of CD8+T cells induces epithelial cell damage, thereby impairing the pulmonary alveolar niche. In this study, we demonstrated that CD8+T cell activation was associated with COPD progression. Furthermore, our data indicated that AARS1-mediated lactylation was involved in cigarette smoke extract (CSE)-induced CD8+T cell activation. Mechanistically, cigarette smoke (CS) exposure upregulated AARS1 levels in CD8+T cells. Elevated AARS1 catalyzed the transfer of a lactyl group to RUNX3 at

A new PD-1-specific nanobody enhances the antitumor activity of T-cells in synergy with dendritic cell vaccine.

Despite the many successes and opportunities presented by PD-1 blockade in cancer therapies, anti-PD-1 monoclonal antibodies still face multiple challenges. Herein we report a strategy based on a nanobody (Nb) to circumvent these obstacles. A new PD-1-blocking Nb (PD-1 Nb20) in combination with tumor-specific dendritic cell (DC)/tumor-fusion cell (FC) vaccine that aims to improve the activation, proliferation, cytokine secretion, and tumor cell cytotoxicity of CD8+ T-cells. This combination was found to effectively enhance the in vitro cytotoxicity of CD8+ T-cells to kill human non-small cell

Cancer CARtography: charting out a new approach to cancer immunotherapy.

Evaluation of: Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6(224), 224ra25 (2014). Recently, chimeric antigen receptor (CAR) T-cell immunotherapy has entered clinical trials in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. 19-28z CAR T cells express a fusion protein comprised of an anti-CD19 mAb fused with CD28 costimulatory and CD3-zeta-chain signaling domains. The current paper demonstrates that administration of 19-28z CAR T cells in patients with relap

Granulocyte differentiation arrest in HAX1-deficient cells, demonstrated in a new in vitro model of a certain phenotypic aspects of Kostmann disease, is caused by ineffective lipid droplet autophagy and fatty acids uptake.

Molecular mechanisms underlying congenital neutropenia in patients with HAX1 deficiency are not clear at the moment. HAX1 deficiency was shown to result in the arrest of neutrophil differentiation. Our studies of the effect of HAX1 deficiency on the proteomic and metabolic profiles of promyelocytic cells have led to the conclusion, supported by specific tests, that fatty acid metabolism is affected in HAX1 KO cells. The lipid droplet content is increased in HAX1 KO cells, pointing to the accumulation of fatty acids that are not metabolized. Studies of autophagosome function in HAX1 WT and KO c

Усиленная транскрипционная деятельность OCT4 заменит экзогенный SOX2 при перепрограммировании клеток.

Аденовиральная ранняя область 1A (E1A) — вирусный ген, который может способствовать распространению клеток и дедифференцированию клеток млекопитающих, необходимых для перепрограммирования соматических клеток в плюрипотентичное состояние. Было доказано, что E1A взаимодействует с OCT4 и, как следствие, увеличивает транскрипционную активность OCT4. Действительно, E1A и OCT4 достаточны для того, чтобы вернуть нейропитефильные гибриды в плюрипотентность, как показали предыдущие эксперименты с синтезом клеток. Однако роль, которую Э1А может играть в формировании индуцированных плюрипотентных стволов

Совпадение в аннотации оригинала
Adenoviral early region 1A (E1A) is a viral gene that can promote cellular proliferation and de-differentiation in mammalian cells, features … OCT4 are sufficient to revert neuroepithelial hybrids to pluripotency, as demonstrated in previous cell fusion experiments. However, the role that E1A might play in the generation of induced pluripotent stem cells (iPSCs) has not been investigated yet. In this report, we show that E1A can generate iPSCs in combination with OCT4 and KLF4, thus replacing exoge …

De novo formation of several features of a centromere following introduction of a Y alphoid YAC into mammalian cells.

The DNA sequence requirements for mammalian centromere function have been investigated by re-introducing human YAC clones containing either centromeric or non-centromeric sequences into hamster and human cells. All YACs integrated into the host chromosomes. In most cell lines produced by spheroplast fusion into hamster cells, intact copies of the YAC and a large amount of yeast DNA were found. Cell lines produced by lipofection into human cells usually contained simple structures without yeast DNA. YACs containing Y alphoid DNA reformed several of the properties of a centromere, including a cy

Acquired EML4-ALK fusion and BRAF V600G dual bypass activation following osimertinib resistance in lung adenocarcinoma and successful treatment with lorlatinib: a case report.

BACKGROUND: While osimertinib is the standard of care for EGFR-mutated advanced non-small cell lung cancer (NSCLC), acquired resistance is inevitable. Resistance mechanisms involving the simultaneous activation of dual bypass pathways, coupled with the complete loss of the primary EGFR mutation, are exceptionally rare and pose significant therapeutic challenges. CASE PRESENTATION: We report a clinically instructive case of a 64-year-old female with stage IV lung adenocarcinoma initially harboring an EGFR exon 19 deletion. She received uninterrupted first-line osimertinib for approximately fiv

Multichannel deep learning prediction of major pathological response after neoadjuvant immunochemotherapy in lung cancer: a multicenter diagnostic study.

OBJECTIVES: This study aimed to develop a pretreatment CT-based multichannel predictor integrating deep learning features encoded by Transformer models for preoperative diagnosis of major pathological response (MPR) in non-small cell lung cancer (NSCLC) patients receiving neoadjuvant immunochemotherapy. MATERIAL AND METHODS: This multicenter diagnostic study retrospectively included 332 NSCLC patients from four centers. Pretreatment computed tomography images were preprocessed and segmented into region of interest cubes for radiomics modeling. These cubes were cropped into four groups of two-

A solitary osteolytic lesion with pathological fracture in the cervical spine - a case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder. The treatment options vary depending on how many organs are involved and how extensive the disease is. In this report, a case of LCH with isolated 6th cervical vertebra (C6) collapse was presented. This case was treated with anterior corpectomy and instrumented fusion, followed by local radiotherapy (RT), with a good clinical outcome up to postoperative six months. CASE PRESENTATION: This was a 47-year-old female patient with a complaint of neck pain and bilateral shoulder pain for two months before consultation. She was init

PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120.

BACKGROUND: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. METHODS: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusi

A fusion protein comprising pneumococcal surface protein A and a pneumolysin derivate confers protection in a murine model of pneumococcal pneumonia.

PspA and pneumolysin are two important vaccine candidates, able to elicit protection in different models of pneumococcal infection. The high immunogenic potential of PspA, combined with a possible adjuvant effect of pneumolysin derivatives (due to their ability to interact with TLR-4) could greatly improve the immunogenicity and coverage of a protein-based pneumococcal vaccine. A chimeric protein including the N-terminal region of PspA in fusion with the pneumolysin derivative, PlD1, has been shown to induce high antibody levels against each protein, and protect mice against invasive challenge

Modular Platform for the Development of Recombinant Hemoglobin Scavenger Biotherapeutics.

Cell-free hemoglobin (Hb) is a driver of disease progression in conditions with intravascular or localized hemolysis. Genetic and acquired anemias or emergency medical conditions such as aneurysmal subarachnoid hemorrhage involve tissue Hb exposure. Haptoglobin (Hp) captures Hb in an irreversible protein complex and prevents its pathophysiological contributions to vascular nitric oxide depletion and tissue oxidation. Preclinical proof-of-concept studies suggest that human plasma-derived Hp is a promising therapeutic candidate for several Hb-driven diseases. Optimizing the efficacy and safety o

Transforaminal Posterior Approach Is Effective for Treatment of Lower Thoracic Spine Spondylodiscitis.

BackgroundPatients with lower-thoracic spine pathologies that affect anterior column stability and compress the neural tissues need anterior decompression and reconstruction. Anterior approaches result in long-term morbidities. Posterior laminectomy and fixation alone may not be sufficient to maintain spine stability.Questions/purposesTo evaluate the results of a posterior-only transforaminal thoracic interbody fusion approach for patients with thoracic disc space infection in terms of the improvement in neurologic status, resolution of infection, correction of kyphotic deformity, and assessme

Gene-by-environment interactions that disrupt mitochondrial homeostasis cause neurodegeneration in C. elegans Parkinson's models.

Parkinson's disease (PD) is a complex multifactorial disorder where environmental factors interact with genetic susceptibility. Accumulating evidence suggests that mitochondria have a central role in the progression of neurodegeneration in sporadic and/or genetic forms of PD. We previously reported that exposure to a secondary metabolite from the soil bacterium, Streptomyces venezuelae, results in age- and dose-dependent dopaminergic (DA) neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. Initial characterization of this environmental factor indicated that neurodegeneration

Translational Multimodality Neuroimaging.

BACKGROUND: Recently high-resolution, noninvasive, multimodality in-vivo molecular imaging with PET, SPECT, CT and MRI, employing fusion algorithms has revolutionized personalized medicine. However, novel discovery of specific radiopharmaceuticals (RPs) for the accurate diagnosis and effective treatment of progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, drug addiction, and other cognitive impairments still remains a significant challenge. OBJECTIVE: The primary objective of this review is to highlight the clinical significance of multimodalit

Toremifene interacts with and destabilizes the Ebola virus glycoprotein.

Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes

Combining DR5 activation with FGFR1 and VEGFR2 inhibition via an engineered TRAIL-based multimodal fusion protein for dual antitumor and antivascular activity in gastric and colorectal cancer models.

Targeting both tumor cells and microenvironment is a promising anticancer strategy. FGFR1 and VEGFR2 represent important drivers of tumor progression and angiogenesis. We engineered multitarget proteins by fusing DR5‑specific TRAIL DR5-B with SRH and P9 peptides antagonizing VEGFR2 and FGFR1, respectively. SRH-DR5-B, DR5-B-P9, and SRH-DR5-B-P9 fusions demonstrated nanomolar affinity for receptors DR5, VEGFR2, and FGFR1 and reduced viability of FGFR1-positive gastric (MKN-45) and colon (HCT116, COLO 205) adenocarcinoma cells. DR5‑B-P9 and SRH‑DR5‑B‑P9 decreased phospho‑FGFR1 levels in FGF2‑stim

A call for standardization: Evaluating different methodologies to induce in vitro foreign body giant cell formation for biomaterials research and design.

Foreign body giant cells (FBGCs) are crucial in the foreign body reaction at the biomaterial-tissue interface, forming through the fusion of cells from the monocyte/macrophage lineage and performing functions such as material degradation and fibrous encapsulation. Yet, their presence and role in biomaterials research is only slowly unveiled. This review analyzed existing FBGC literature identified through a search string and sources from FBGC articles to evaluate the most commonly used methods and highlight the challenges in establishing a standardized protocol. Our findings revealed a fragmen

Coexistence of acute myeloid leukemia with a complex chromosomal translocation and monoclonal gammopathy of undetermined significance: A case report and literature review.

Acute myeloid leukemia (AML) with chromosomal translocation t(8;21)(q22;q22.1) is a rare subtype, accounting for 4-8% of all cases of AML. Despite its rarity, it has a favorable outcome. The translocation event culminates in the formation of the Runt-related transcription factor 1 (RUNX1)::RUNX1 partner transcriptional co-repressor 1 (RUNX1T1) fusion protein, which is implicated in hematopoietic differentiation and maturation. Furthermore, monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of monoclonal immunoglobulins in the blood or urine, serum M prot

Cytomorphologic features of intraductal salivary gland carcinoma: A multi-institutional study of 13 FNA cases with histologic, molecular, and clinical correlations.

BACKGROUND: Intraductal carcinoma of the salivary gland (IDC) is a rare cancer with potential actionable targets, including RET fusions. Histologic and molecular features of IDC were recently reported, but cytomorphologic data are limited. In the largest multi-institutional fine-needle aspiration (FNA) series, the authors describe the cytomorphologic features of 13 IDC cases with available clinical, radiologic, histopathologic, and molecular data. METHODS: The cases included 13 FNAs for 9 low-grade (LG) IDCs and 4 high-grade (HG) IDCs with corresponding histopathology and available molecular,