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Bioinformatics (Oxford, England) Jun 2024Charting cellular trajectories over gene expression is key to understanding dynamic cellular processes and their underlying mechanisms. While advances in single-cell...
BACKGROUND
Charting cellular trajectories over gene expression is key to understanding dynamic cellular processes and their underlying mechanisms. While advances in single-cell RNA-sequencing technologies and computational methods have pushed forward the recovery of such trajectories, trajectory inference remains a challenge due to the noisy, sparse, and high-dimensional nature of single-cell data. This challenge can be alleviated by increasing either the number of cells sampled along the trajectory (breadth) or the sequencing depth, i.e. the number of reads captured per cell (depth). Generally, these two factors are coupled due to an inherent breadth-depth tradeoff that arises when the sequencing budget is constrained due to financial or technical limitations.
RESULTS
Here we study the optimal allocation of a fixed sequencing budget to optimize the recovery of trajectory attributes. Empirical results reveal that reconstruction accuracy of internal cell structure in expression space scales with the logarithm of either the breadth or depth of sequencing. We additionally observe a power law relationship between the optimal number of sampled cells and the corresponding sequencing budget. For linear trajectories, non-monotonicity in trajectory reconstruction across the breadth-depth tradeoff can impact downstream inference, such as expression pattern analysis along the trajectory. We demonstrate these results for five single-cell RNA-sequencing datasets encompassing differentiation of embryonic stem cells, pancreatic beta cells, hepatoblast and multipotent hematopoietic cells, as well as induced reprogramming of embryonic fibroblasts into neurons. By addressing the challenges of single-cell data, our study offers insights into maximizing the efficiency of cellular trajectory analysis through strategic allocation of sequencing resources.
Topics: Single-Cell Analysis; Sequence Analysis, RNA; Humans; Animals; High-Throughput Nucleotide Sequencing
PubMed: 38940162
DOI: 10.1093/bioinformatics/btae258 -
Journal of Medical Economics Jun 2024AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm)...
AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems.Material and MethodsThis retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation.ResultsPeople with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9).ConclusionCF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.
PubMed: 38939921
DOI: 10.1080/13696998.2024.2373000 -
Journal of Extracellular Biology Feb 2024Most living organisms secrete tiny lipid bilayer particles encapsulating various biomolecular entities, including nucleic acids and proteins. These secreted...
Most living organisms secrete tiny lipid bilayer particles encapsulating various biomolecular entities, including nucleic acids and proteins. These secreted extracellular vesicles (EVs) are shown to aid in communication between cells and their environment. EVs are mainly involved in the signalling and manipulation of physiological processes. Plant EVs display similar functional activity as seen in mammalian EVs. Medicinal plants have many bioactive constituents with potential applications in cancer treatment. Particularly, Basil (), has wide therapeutic properties including anti-inflammatory, anti-cancer, and anti-infection, among others. In this study, we focused on using EVs purified from Apoplast Washing Fluid (AWF) of Basil plant leaves as a biological therapeutic agent against cancer. Characterization of Basil EVs revealed a size range of 100-250 nm, which were later assessed for their cell uptake and apoptosis inducing abilities in pancreatic cancer cells. Basil plant EVs (BasEVs) showed a significant cytotoxic effect on pancreatic cancer cell line MIA PaCa-2 at a concentration of 80 and 160 μg/mL in cell viability, as well as clonogenic assays. Similarly, RT-PCR and western blot analysis has shown up regulation in apoptotic gene and protein expression of Bax, respectively, in BasEV treatment groups compared to untreated controls of MIA PaCa-2. Overall, our results suggest that EVs from basil plants have potent anti-cancer effects in pancreatic cancer cells and can serve as a drug delivery system, demanding an investigation into the therapeutic potential of other medicinal plant EVs.
PubMed: 38939903
DOI: 10.1002/jex2.142 -
Acta Medica Philippina 2024The benefits of rapid on-site evaluation (ROSE) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of solid masses have not been convincingly shown in...
Evaluation of Fine Needle Biopsy (FNB) for Endoscopic Ultrasound (EUS)-guided Tissue Acquisition of Pancreatic Masses to Negate the Need for Rapid On-site Evaluation: A Randomized Control Trial.
BACKGROUND AND OBJECTIVES
The benefits of rapid on-site evaluation (ROSE) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of solid masses have not been convincingly shown in large, randomized trials. New equipment using EUS-guided fine needle biopsy (FNB) allows for more material to be acquired that may obviate the need for ROSE. This study aimed to evaluate if EUS-FNB without ROSE was non-inferior to EUS-FNA with ROSE in solid pancreatic masses (SPMs).
METHODS
Patients with SPMs requiring tissue sampling were randomly assigned to undergo either EUS-FNA with ROSE or EUS-FNB without ROSE. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy and secondary endpoints were specimen quality, complication rates, and procedure time.
RESULTS
Seventy-eight patients were randomized and analyzed (39 EUS-FNA with ROSE and 39 EUS-FNB without ROSE). Non-significantly different diagnostic accuracies were noted in both groups (97% with ROSE and 100% without ROSE, P < 0.371). The bloodiness of histologic samples and complication rates were not significantly different between groups. A significantly shorter mean sampling procedural time was noted for EUS-FNB over EUS-FNA with ROSE (30.4 ± 10.4 vs 35.8 ± 9.8 minutes, P < .02).
CONCLUSIONS
EUS-FNB demonstrated equal diagnostic accuracy with shorter procedure times in evaluating SPMs compared to EUS-FNA with ROSE. These new-generation FNB needles may obviate the need for ROSE.
PubMed: 38939857
DOI: 10.47895/amp.vi0.6817 -
Molecular Therapy. Oncology Jun 2024Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles...
Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy.
PubMed: 38939825
DOI: 10.1016/j.omton.2024.200789 -
Oncology Letters Aug 2024Lung metastasis is the second most common type of metastasis in colorectal cancer. Specific treatments for lung metastasis have not been developed since the underlying...
Lung metastasis is the second most common type of metastasis in colorectal cancer. Specific treatments for lung metastasis have not been developed since the underlying mechanisms are poorly understood. The present study aimed to elucidate the molecular basis of lung metastasis in colorectal cancer. In a mouse model, cell lines that were highly metastatic to the lungs were established by injecting colorectal cancer cells through the tail vein and removing them from the lungs. Differential gene expression comparing the transfected cells with their parental cells was investigated using DNA microarrays. The results were functionally interpreted using gene enrichment analysis and validated using reverse transcription-quantitative PCR (RT-qPCR). The isoforms of the identified genes were examined by melting curve analysis. The present study established colorectal cancer cell lines that were highly metastatic to the lungs. DNA microarray experiments revealed that genes (N-cadherin, VE-cadherin, , Akt and VCAM1) involved in motility, proliferation and adhesion were upregulated, and genes ( and ) with tumor-suppressive functions were downregulated in metastatic cells. () expression was upregulated in multiple metastatic cell lines using RT-qPCR. Two isoforms were overexpressed in metastatic cells. and models were established and genes associated with lung metastasis were identified to overcome the heterogeneity of the disease. Overall, aberrant expression is unreported in lung metastasis in colorectal cancer. In the present study, two isoforms with differential tissue distribution were upregulated in metastatic cells, suggesting that they promote lung metastasis in colorectal cancer.
PubMed: 38939626
DOI: 10.3892/ol.2024.14514 -
Journal of Extracellular Biology Mar 2024Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis due to its highly metastatic profile. Intercellular communication between cancer...
Dysregulation of intercellular communication in vitro and in vivo via extracellular vesicles secreted by pancreatic duct adenocarcinoma cells and generated under the influence of the AG9 elastin peptide-conditioned microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis due to its highly metastatic profile. Intercellular communication between cancer and stromal cells via extracellular vesicles (EVs) is crucial for the premetastatic microenvironment preparation leading to tumour metastasis. This study shows that under the influence of bioactive peptides derived from the extracellular matrix microenvironment, illustrated here by the AG-9 elastin-derived peptide (EDP), PDAC cells secrete more tumour-derived EVs. Compared to PDAC-derived EVs, tumour-derived EVs resulting from AG-9 treatment (PDAC AG-9-derived EVs) significantly stimulated cell proliferation. At constant amount, tumour-derived EVs were similarly taken up by PDAC and HMEC-1 cells. Tumour-derived EVs stimulated cell proliferation, migration, proteinase secretion, and angiogenesis. Bioluminescence imaging allowed tumour-derived EV/FLuc+ tracking in vivo in a PDAC mouse model. The biodistribution of PDAC AG-9-derived EVs was different to PDAC-derived EVs. Our results demonstrate that the microenvironment, through EDP release, may not only influence the genesis of EVs but may also affect tumour progression (tumour growth and angiogenesis), and metastatic homing by modifying the in vivo biodistribution of tumour-derived EVs. They are potential candidates for targeted drug delivery and modulation of tumour progression, and they constitute a new generation of therapeutic tools, merging oncology and genic therapy.
PubMed: 38939412
DOI: 10.1002/jex2.145 -
ACG Case Reports Journal Jul 2024Endoscopic retrograde cholangiopancreatography-guided transpapillary gallbladder drainage has emerged as an effective alternative for management of acute cholecystitis...
Endoscopic retrograde cholangiopancreatography-guided transpapillary gallbladder drainage has emerged as an effective alternative for management of acute cholecystitis in nonoperable candidates. Delayed acute pancreatitis has not been previously described as an adverse event with this procedure. In this article, we describe 3 patients who developed acute pancreatitis between 2 and 6 weeks after stent insertion with no alternative inciting cause. Delayed acute pancreatitis may represent a rare and previously uncharacterized adverse event related to transpapillary gallbladder drainage.
PubMed: 38939354
DOI: 10.14309/crj.0000000000001417 -
Frontiers in Oncology 2024Malignant pleural effusion (MPE) is prevalent among cancer patients, indicating pleural metastasis and predicting poor prognosis. However, accurately identifying MPE in...
BACKGROUND
Malignant pleural effusion (MPE) is prevalent among cancer patients, indicating pleural metastasis and predicting poor prognosis. However, accurately identifying MPE in clinical settings is challenging. The aim of this study was to establish an innovative nomogram-derived model based on clinical indicators and serum metal ion levels to identify MPE.
METHODS
From July 2020 to May 2022, 428 patients diagnosed with pleural effusion (PE) were consecutively recruited. Comprehensive demographic details, clinical symptoms, imaging data, pathological information, and laboratory results, including serum metal ion levels, were systematically collected. The nomogram was created by incorporating the most significant predictors identified through LASSO and multivariate logistic regression analysis. The predictors were assigned weighted points based on their respective regression coefficients, allowing for the calculation of a total score that corresponds to the probability of MPE. Internal validation using bootstrapping techniques assessed the nomogram's performance, including calibration, discrimination, and clinical applicability.
RESULTS
Seven key variables were identified using LASSO regression and multiple regression analysis, including dyspnea, fever, X-ray/CT compatible with malignancy, pleural carcinoembryonic antigen(pCEA), serum neuron-specific enolase(sNSE), serum carcinoembryonic antigen(sCEA), and pleural lactate dehydrogenase(pLDH). Internal validation underscored the superior performance of our model (AUC=0.940). Decision curve analysis (DCA) analysis demonstrated substantial net benefit across a probability threshold range > 1%. Additionally, serum calcium and copper levels were significantly higher, while serum zinc levels were significantly lower in MPE patients compared to benign pleural effusion (BPE) patients.
CONCLUSION
This study effectively developed a user-friendly and reliable MPE identification model incorporating seven markers, aiding in the classification of PE subtypes in clinical settings. Furthermore, our study highlights the clinical value of serum metal ions in distinguishing malignant pleural effusion from BPE. This significant advancement provides essential tools for physicians to accurately diagnose and treat patients with MPE.
PubMed: 38939338
DOI: 10.3389/fonc.2024.1431318 -
Cureus May 2024Neoplasms are among the common causes of small bowel obstruction (SBO). Metastatic disease is the most common cause of neoplastic SBO and is most commonly the result of...
Neoplasms are among the common causes of small bowel obstruction (SBO). Metastatic disease is the most common cause of neoplastic SBO and is most commonly the result of colon, ovarian, pancreatic, and gastric neoplasms. Metastatic SBO secondary to metastatic urothelial carcinoma is exceedingly rare, with only a few cases described in the literature. It is important for physicians to be aware of urothelial carcinoma as a potential etiology of SBO.
PubMed: 38939301
DOI: 10.7759/cureus.61228