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Cancer Cell International Jun 2024To investigate the influence of LINC00665 on the development and immune evasion of lung cancer.
OBJECTIVE
To investigate the influence of LINC00665 on the development and immune evasion of lung cancer.
METHODS
Tumor tissues and corresponding adjacent tissues were collected from 84 lung cancer patients, categorized into non-metastatic (n = 58) and metastatic (n = 26) groups. LINC00665 expression in lung cancer and metastatic lung cancer tissues was assessed via qRT-PCR. Pearson correlation analysis was conducted to examine the correlation between LINC00665 and immune-modulating cytokines (TGF-β, IL-10, IL-1β, IFN-γ, IL-2, TNF-α). A549 and H1299 cells, with relatively high LINC00665 expression, were used for in vitro studies. Cells were transfected with LINC00665-targeting shRNA, and changes in proliferation, apoptosis, migration, invasion, and NK cell cytotoxicity were assessed. Downstream molecular mechanisms of LINC00665 were investigated using GEO database analysis, highlighting the association with HHLA2. LINC00665's role in promoting HHLA2 expression via binding with TCF7 was explored. In low LINC00665-expressing A549/H1299 cells, overexpression of HHLA2 was performed to evaluate effects on malignant behavior and NK cell sensitivity. A xenograft model was established for in vivo validation through tumor volume and weight measurements, Ki-67 immunoreactivity analysis, and flow cytometry analysis of CD107a + NK cells.
RESULTS
LINC00665, TCF7 mRNA, and HHLA2 mRNA expression levels were significantly higher in lung cancer tissues than adjacent tissues, with non-metastatic lung cancer showing higher expression than metastatic lung cancer. In metastatic lung cancer, LINC00665 positively correlated with immune-suppressive cytokines (TGF-β, IL-10, IL-1β) and negatively correlated with anti-tumor cytokines (IFN-γ, IL-2, TNF-α). LINC00665 knockdown significantly inhibited lung cancer cell growth and metastasis, promoting sensitivity to NK cells. Further analysis revealed that LINC00665 recruits transcription factor TCF7 to upregulate HHLA2 expression in lung cancer cells, thereby facilitating lung cancer development and immune escape.
CONCLUSION
LINC00665, through recruitment of TCF7 and upregulation of HHLA2, inhibits NK cell cytotoxicity, promoting the development and immune evasion of lung cancer.
PubMed: 38951802
DOI: 10.1186/s12935-024-03411-4 -
Molecular Systems Biology Jul 2024Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing...
Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing hands-on time and enhancing quantitative reproducibility. We introduced a scalable PL pipeline integrating automated enrichment of biotinylated proteins in a 96-well plate format. Combining this with optimized quantitative MS based on data-independent acquisition (DIA), we increased sample throughput and improved protein identification and quantification reproducibility. We applied this pipeline to delineate subcellular proteomes across various compartments. Using the 5HT serotonin receptor as a model, we studied temporal changes of proximal interaction networks induced by receptor activation. In addition, we modified the pipeline for reduced sample input to accommodate CRISPR-based gene knockout, assessing dynamics of the 5HT network in response to perturbation of selected interactors. This PL approach is universally applicable to PL proteomics using biotinylation-based PL enzymes, enhancing throughput and reproducibility of standard protocols.
PubMed: 38951684
DOI: 10.1038/s44320-024-00049-2 -
Scientific Reports Jul 2024To assess malnutrition contribution to the functional status and health related quality of life after hospitalization due to COVID-19 pneumonia, 66 selected adults...
To assess malnutrition contribution to the functional status and health related quality of life after hospitalization due to COVID-19 pneumonia, 66 selected adults referred for physical rehabilitation accepted to participate in the study; none of them required oxygen supply or had history of lung/musculoskeletal/neurological/immune/rheumatic disease or trauma, or contraindication for respiratory-function tests. At three evaluations, with 3 months in-between, assessments included: self-report of functional status, the St. George's Respiratory Questionnaire, spirometry, the 6-min-walk-test, the MRC-scale, the 30-s sit-to-stand-test, the timed-up-and-go-test, nutritional status, and ultrasound imaging (vastus medialis and diaphragm). At referral, patients had nutritional deficits with protein deficiency, which gradually improved; while muscle thickness (of both vastus medialis and diaphragm) increased, along with muscle strength and mobility (ANOVA, p < 0.05). Contrarywise, the distance covered during the 6-min-walk-test decreased (ANOVA, p < 0.05), with a negative influence from excess body mass. During rehabilitation, health-related quality of life and functional status improved, with negative influence from a history of tobacco use and referral delay, respectively. After hospitalization due to COVID-19, early diagnosis of both protein deficiency and decrease of skeletal muscle thickness could be relevant for rehabilitation, while pondering the negative impact of excess body mass on submaximal exercise performance.
Topics: Humans; COVID-19; Quality of Life; Male; Female; Malnutrition; Middle Aged; Aged; Follow-Up Studies; Functional Status; Nutritional Status; SARS-CoV-2; Adult; Hospitalization; Muscle Strength; Surveys and Questionnaires
PubMed: 38951534
DOI: 10.1038/s41598-024-65698-7 -
Environmental Pollution (Barking, Essex... Jun 2024Associations between indoor air pollution from fine particulate matter (PM with aerodynamic diameter d < 2.5 μm) and human health are poorly understood. Here, we...
Associations between fine particulate matter, gene expression, and promoter methylation in human bronchial epithelial cells exposed within a classroom under Air-Liquid Interface.
Associations between indoor air pollution from fine particulate matter (PM with aerodynamic diameter d < 2.5 μm) and human health are poorly understood. Here, we analyse the concentration-response curves for fine and ultrafine PM, the gene expression, and the methylation patterns in human bronchial epithelial cells (BEAS-2B) exposed at the air-liquid interface (ALI) within a classroom in downtown Rome. Our results document the upregulation of aryl hydrocarbon receptor (AhR) and genes associated with xenobiotic metabolism (CYP1A1 and CYP1B1) in response to single exposure of cells to fresh urban aerosols at low fine PM mass concentrations within the classroom. This is evidenced by concentrations of ultrafine particles (UFPs, dp < 0.1 μm), polycyclic aromatic hydrocarbons (PAH), and ratios of black carbon (BC) to organic aerosol (OA). Additionally, an interleukin 18 (IL-18) down-regulation was found during periods of high human occupancy. Despite the observed gene expression dysregulation, no changes were detected in the methylation levels of the promoter regions of these genes, indicating that the altered gene expression is not linked to changes in DNA methylation and suggesting the involvement of another epigenetic mechanism in the gene regulation. Gene expression changes at low exposure doses have been previously reported. Here, we add the possibility that lung epithelial cells, when singly exposed to real environmental concentrations of fine PM that translate into ultra-low doses of treatment, may undergo epigenetic alteration in the expression of genes related to xenobiotic metabolism. Our findings provide a perspective for future indoor air quality regulations. We underscore the potential role of indoor UFPs as carriers of toxic molecules with low-pressure weather conditions, when rainfall and strong winds may favour low levels of fine PM.
PubMed: 38950846
DOI: 10.1016/j.envpol.2024.124471 -
The Lancet. Oncology Jun 2024Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and...
BACKGROUND
Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer.
METHODS
We conducted an open-label, first-in-human study of immunoPET-CT imaging with [Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741.
FINDINGS
Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort.
INTERPRETATION
DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies.
FUNDING
National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.
PubMed: 38950555
DOI: 10.1016/S1470-2045(24)00249-3 -
American Journal of Respiratory Cell... Jul 2024The relationship between the Programmed Death-Ligand 1 (PD-L1)/Programmed Death-1 (PD-1) pathway, lung inflammation, and clinical outcomes in acute respiratory distress...
The relationship between the Programmed Death-Ligand 1 (PD-L1)/Programmed Death-1 (PD-1) pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 (n = 59) and ARDS2 (n = 78)) or plasma samples alone (ARDS3 (n = 149)) collected from subjects with ARDS and tested for associations with mortality using multiple regression. We used mass cytometry to measure PD-L1/PD-1 expression and intracellular cytokine staining in cells isolated from bronchoalveolar lavage fluid (BALF) (n = 18) and blood (n = 16) from critically-ill subjects with or without ARDS enrolled from a fourth cohort. Higher plasma levels of sPD-L1 were associated with mortality in ARDS1, ARDS2, and ARDS3. In contrast, higher levels of sPD-L1 in the lung were either not associated with mortality (ARDS2) or were associated with survival (ARDS1). Alveolar PD-1 T cells had more intracellular cytokine staining compared with PD-1 T cells. Subjects without ARDS had a higher ratio of PD-L1 alveolar macrophages to PD-1 T cells compared with subjects with ARDS. We conclude that sPD-L1 may have divergent cellular sources and/or functions in the alveolar vs. blood compartments given distinct associations with mortality. Alveolar leukocyte subsets defined by PD-L1/PD-1 cell-surface expression have distinct cytokine secretion profiles, and the relative proportions of these subsets are associated with ARDS.
PubMed: 38950166
DOI: 10.1165/rcmb.2024-0201OC -
PloS One 2024The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal...
Acceptability of adding a non-contrast abdominal CT scan to screen for kidney cancer and other abdominal pathology within a community-based CT screening programme for lung cancer: A qualitative study.
OBJECTIVES
The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal malignancies to community-based CT screening for lung cancer within the Yorkshire Lung Screening Trial (YLST). This study explored the acceptability of the combined screening approach to participants and healthcare professionals (HCPs) involved in the trial.
METHODS
We conducted semi-structured interviews with eight HCPs and 25 participants returning for the second round of scanning within YLST, 20 who had taken up the offer of the additional abdominal CT scan and five who had declined. Transcripts were analysed using thematic analysis, guided by the Theoretical Framework of Acceptability.
RESULTS
Overall, combining the offer of a non-contrast abdominal CT scan alongside the low-dose thoracic CT was considered acceptable to participants, including those who had declined the abdominal scan. The offer of the additional scan made sense and fitted well within the process, and participants could see benefits in terms of efficiency, cost and convenience both for themselves as individuals and also more widely for the NHS. Almost all participants made an instant decision at the point of initial invitation based more on trust and emotions than the information provided. Despite this, there was a clear desire for more time to decide whether to accept the scan or not. HCPs also raised concerns about the burden on the study team and wider healthcare system arising from additional workload both within the screening process and downstream following findings on the abdominal CT scan.
CONCLUSIONS
Adding a non-contrast abdominal CT scan to community-based CT screening for lung cancer is acceptable to both participants and healthcare professionals. Giving potential participants prior notice and having clear pathways for downstream management of findings will be important if it is to be offered more widely.
Topics: Humans; Tomography, X-Ray Computed; Lung Neoplasms; Male; Female; Middle Aged; Early Detection of Cancer; Aged; Kidney Neoplasms; Qualitative Research; Patient Acceptance of Health Care; Mass Screening
PubMed: 38950010
DOI: 10.1371/journal.pone.0300313 -
Molecular Imaging and Radionuclide... Jun 2024We present the case of a patient with newly diagnosed high-risk prostate cancer. The patient underwent nephrectomy for renal cell carcinoma (RCC) in 2009. The...
We present the case of a patient with newly diagnosed high-risk prostate cancer. The patient underwent nephrectomy for renal cell carcinoma (RCC) in 2009. The prostate-specific membrane antigen (PSMA) scan revealed a primary tumor with seminal vessel involvement, PSMA-positive regional lymph nodes, several nodular lung lesions with mild PSMA uptake, PSMA-positive mediastinal lymph nodes, and a PSMA-positive mass in the pancreatic head. Ultrasound-guided biopsy was performed for the pancreatic lesions revealing metastasis from a RCC. Simultaneous treatment for prostate cancer and metastatic RCC was initiated. To separate metastatic sites for both primaries, we attempted to use fluorodeoxyglucose positron emission tomography/computed tomography, which was moderately positive for the pancreatic mass but not for the other locations. RCC is a Ga PSMA-positive tumor; the synchronous combination of RCC with prostate cancer can be confusing and requires more complex clinical interpretation.
PubMed: 38949477
DOI: 10.4274/mirt.galenos.2023.90582 -
Journal of Family Medicine and Primary... May 2024Corona virus disease (COVID-19) initially appeared to be an exclusively respiratory ailment. While that is true in a vast majority of the cases, its evolution and later...
Corona virus disease (COVID-19) initially appeared to be an exclusively respiratory ailment. While that is true in a vast majority of the cases, its evolution and later evidence have shown that it can afflict virtually any organ system in the human body after first gaining entry through the respiratory tract. The COVID-19 vaccines were one of the turning points in the campaign to control the COVID-19 pandemic. However, after their extensive use all over the world, it has emerged that they can cause some dangerous collateral damage. We, herein, report the case of a 58-year-old woman who presented to us with signs and symptoms of acute intestinal obstruction 4 months after receiving her first dose of Covishield vaccination for COVID-19. Her blood tests showed a high D-dimer and normal platelet count. She was previously admitted to the hospital with an acute abdomen 3 months back. A contrast-enhanced computed tomography (CECT) scan of the abdomen done then had revealed thrombi in the aorta and inferior mesenteric and splenic arteries. She was started on low-molecular-weight heparin and discharged on tablet Warfarin after clinical improvement. CECT abdomen done during her present admission revealed a proximal small bowel stricture with dilated proximal and collapsed distal loops. She underwent a laparoscopic jejuno-ileal resection anastomosis. During the post-operative period, a repeat CECT abdomen done to evaluate multiple episodes of vomiting revealed pulmonary embolism in the lower chest cuts. A venous Doppler revealed extensive deep venous thrombosis of the left lower limb. A thrombophilia profile diagnosed anti-phospholipid antibody syndrome, an exacerbation of which was likely precipitated by the COVID-19 vaccine.
PubMed: 38948557
DOI: 10.4103/jfmpc.jfmpc_1006_23 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To experimentally validate the effects of a self-developed heat-stable thickening agent on the textual characteristics of enteral nutrition solutions of standard...
OBJECTIVE
To experimentally validate the effects of a self-developed heat-stable thickening agent on the textual characteristics of enteral nutrition solutions of standard concentration and its applicability in improving dysphagia.
METHODS
A gradient of different doses of the self-developed thickening agent (1.0 g, 1.5 g, 2.0 g, 2.5 g, and3.0 g) and three commonly used commercial thickeners were mixed with 23.391 g of a complete nutrition formula powder dissolved in 85 mL of purified water to prepare 100 mL standard concentration nutrition solutions. The textual parameters (cohesiveness, viscosity, thickness, and hardness) of these nutrition solutions were measured using a texture analyzer at various temperature gradients (20 ℃, 40 ℃, 60 ℃, and 80 ℃) to compare their thermal stability. A dysphagia rat model was created via epiglottectomy to explore the effects of the thickener on lung tissue damage scores and levels of inflammatory markers. The rats were divided into a test intervention group, a positive control group, a negative control group, and a blank control group (no surgery and normal feeding after fasting for one day), with 15 rats in each group. After fasting for one day post-surgery, the test intervention group was fed with the standard concentration nutrition solution thickened with the self-developed thickener, while the positive control group was given a standard concentration nutrition solution thickened with product 3, and the negative control group was fed a normal diet. All groups were fed for two weeks with food dyed with food-grade green dye. General conditions, body mass, and food intake were observed and recorded. After two weeks, abdominal aorta blood was collected, and heart, liver, spleen, lung, and kidney tissues were harvested and weighed to calculate the lung tissue organ coefficient. The organ conditions were evaluated using routine H&E staining, and lung damage was semi-quantitatively analyzed based on the Mikawa scoring criteria. Blood supernatants were collected to measure the total serum protein and albumin levels to determine the nutritional status of the rats. The expression of and genes in lung tissues was measured by RT-qPCR. IL-6 and TNF-α protein expression levels in lung tissues, lung tissue homogenate, and serum were measured by ELISA. The aspiration incidence rate was calculated.
RESULTS
Within the dosage range of 1.0 g to 3.0 g, the self-developed thickener in the test samples exhibited superior thermal stability in cohesiveness compared to the three commercially available thickeners, with a statistically significant difference (<0.01). The differences in the thermal stability of viscosity and hardness between the self-developed thickener and the three commercially available thickeners were not statistically significant. The viscosity stability was optimal for the self-developed thickener, followed by the commercially available thickeners 1 and 3, with thickeners 2 being the least stable, though the differences were not statistically significant (>0.05). Product 1 showed the best thermal stability in thickness, followed by the self-developed thickener and product 2, while the product 3 exhibited the worst performance, with the difference being statistically significant (<0.01). The self-developed thickener had the best thermal stability in hardness at temperatures ranging from 20℃ to 80 ℃, followed by products 1 and 2, with product 3 being the least stable. However, the differences were not statistically significant (>0.05). Animal experiment results indicated that the body weight gain in the positive control group and the test intervention group was lower than that in the blank and negative control groups (<0.01). The spleen coefficient of the intervention group was lower than that of the positive control group and the blank control group (<0.01), while the heart, liver, and kidney coefficients were lower than those of the blank control group (<0.01). The differences in the lung coefficient of the intervention group and those of the other three groups were no statistically significant. Levels of TP and ALB in the test intervention group, the positive control group, and the negative control group were all lower than those in the blank control group, with statistically significant differences (<0.01). ELISA results showed that serum IL-6 levels in the blank and test intervention groups were lower than those in the negative and positive control groups (<0.05), while the difference in the other indicators across the four groups were not statistically significant (>0.05). There were no statistically significant differences among the four groups in terms of lung tissue damage pathology scores, or in the levels of and gene expression in lung tissues. The aspiration incidence rate was 0% in all groups.
CONCLUSION
The self-developed enteral nutrition thickening agent demonstrated excellent thermal stability and swallowing safety. Further research to explore its application in patients with dysphagia is warranted.
Topics: Animals; Rats; Deglutition Disorders; Enteral Nutrition; Rats, Sprague-Dawley; Deglutition; Male; Lung; Hot Temperature; Viscosity
PubMed: 38948293
DOI: 10.12182/20240560203