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PLoS Computational Biology Jul 2024The classification of B cell lymphomas-mainly based on light microscopy evaluation by a pathologist-requires many years of training. Since the B cell receptor (BCR) of...
The classification of B cell lymphomas-mainly based on light microscopy evaluation by a pathologist-requires many years of training. Since the B cell receptor (BCR) of the lymphoma clonotype and the microenvironmental immune architecture are important features discriminating different lymphoma subsets, we asked whether BCR repertoire next-generation sequencing (NGS) of lymphoma-infiltrated tissues in conjunction with machine learning algorithms could have diagnostic utility in the subclassification of these cancers. We trained a random forest and a linear classifier via logistic regression based on patterns of clonal distribution, VDJ gene usage and physico-chemical properties of the top-n most frequently represented clonotypes in the BCR repertoires of 620 paradigmatic lymphoma samples-nodular lymphocyte predominant B cell lymphoma (NLPBL), diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL)-alongside with 291 control samples. With regard to DLBCL and CLL, the models demonstrated optimal performance when utilizing only the most prevalent clonotype for classification, while in NLPBL-that has a dominant background of non-malignant bystander cells-a broader array of clonotypes enhanced model accuracy. Surprisingly, the straightforward logistic regression model performed best in this seemingly complex classification problem, suggesting linear separability in our chosen dimensions. It achieved a weighted F1-score of 0.84 on a test cohort including 125 samples from all three lymphoma entities and 58 samples from healthy individuals. Together, we provide proof-of-concept that at least the 3 studied lymphoma entities can be differentiated from each other using BCR repertoire NGS on lymphoma-infiltrated tissues by a trained machine learning model.
PubMed: 38954728
DOI: 10.1371/journal.pcbi.1011570 -
PloS One 2024Transperineal laser ablation is a minimally invasive thermo-ablative treatment for prostate cancer that requires the insertion of a needle for accurate optical fiber...
Transperineal laser ablation is a minimally invasive thermo-ablative treatment for prostate cancer that requires the insertion of a needle for accurate optical fiber positioning. Needle insertion in soft tissues may cause tissue motion and deformation, resulting in tissue damage and needle positioning errors. In this study, we present a wasp-inspired self-propelled needle that uses pneumatic actuation to move forward with zero external push force, thus avoiding large tissue motion and deformation. The needle consists of six parallel 0.25-mm diameter Nitinol rods driven by a pneumatic actuation system. The pneumatic actuation system consists of Magnetic Resonance (MR) safe 3D-printed parts and off-the-shelf plastic screws. A self-propelled motion is achieved by advancing the needle segments one by one, followed by retracting them simultaneously. The advancing needle segment has to overcome a cutting and friction force, while the stationary needle segments experience a friction force in the opposite direction. The needle self-propels through the tissue when the friction force of the five stationary needle segments overcomes the sum of the friction and cutting forces of the advancing needle segment. We evaluated the prototype's performance in 10-wt% gelatin phantoms and ex vivo porcine liver tissue inside a preclinical Magnetic Resonance Imaging (MRI) scanner in terms of the slip ratio of the needle with respect to the phantom or liver tissue. Our results demonstrated that the needle was able to self-propel through the phantom and liver tissue with slip ratios of 0.912-0.955 and 0.88, respectively. The prototype is a promising step toward the development of self-propelled needles for MRI-guided transperineal laser ablation as a method to treat prostate cancer.
Topics: Needles; Animals; Equipment Design; Male; Humans; Wasps; Printing, Three-Dimensional; Laser Therapy; Swine; Prostatic Neoplasms; Magnetic Resonance Imaging
PubMed: 38954720
DOI: 10.1371/journal.pone.0306411 -
PloS One 2024Childhood leukemia (CL) is a major global concern, accounting for 33% of all new cancer cases and 31% of all cancer deaths in children aged 0-14 years. Our study aimed...
BACKGROUND
Childhood leukemia (CL) is a major global concern, accounting for 33% of all new cancer cases and 31% of all cancer deaths in children aged 0-14 years. Our study aimed to analyze the global incidence and mortality rates of CL in 2020 and its relationship with the Human Development Index (HDI).
MATERIAL AND METHODS
In this ecologic study, we analyzed the 2020 cancer incidence and mortality data for children aged 0-14 years from the GLOBOCAN Project. We calculated the Age-Standardized Incidence Rate (ASIR) and Age-Standardized Mortality Rate (ASMR) of CL per 100,000 individuals. Pearson's correlation coefficient was used to examine the association between childhood leukemia ASIR, ASMR, and the HDI, with a statistical significance threshold of P<0.05.
RESULTS
In 2020, there were a total of 67,008 new cases of CL worldwide, with males accounting for 57.85%. The global ASIR for CL was 3.4 per 100,000 (3.9 in males, 3 in females). Additionally, there were 25,080 CL-related deaths, with males comprising 58.86%. The overall ASMR for CL was 1.3 (1.4 in males, 1.1 in females). We found a significant positive correlation (r = 0.405, P≤0.001) between the global ASIR and ASMR for CL. There was a strong positive correlation (r = 0.770, P = 0.001) between the HDI and childhood leukemia ASIR, but no significant association (r = 0.077, P = 0.337) was observed with ASMR.
CONCLUSION
Our study reveals that CL remains a significant health burden worldwide. We identified a positive correlation between the ASIR of CL and the HDI, indicating a potential role of socioeconomic factors in CL incidence.
Topics: Humans; Child; Infant; Male; Child, Preschool; Female; Incidence; Adolescent; Leukemia; Infant, Newborn; Global Health
PubMed: 38954710
DOI: 10.1371/journal.pone.0304354 -
PloS One 2024To investigate the mechanism of endothelial cell specific molecule 1 (ESM1) promoting cervical cancer cell proliferation and EMT characteristics through zinc finger...
OBJECTIVE
To investigate the mechanism of endothelial cell specific molecule 1 (ESM1) promoting cervical cancer cell proliferation and EMT characteristics through zinc finger E-box binding homeobox 1 (ZEB1)/EMT pathway.
METHODS
The correlation between ESM1 expression and prognosis of cervical cancer patients was analyzed by bioinformatics. SiHa, HeLa cell lines and corresponding control cell lines with stable ESM1 expression were obtained. Cell proliferation ability was detected by CCK-8 assay. The invasion and migration ability of Hela and SiHa cells were detected by Transwell assay and scratch closure assay. Expressions of EMT-related markers E-cadherin and Vimentin were detected by real-time PCR. The ability of silenced ESM1 to tumor formation in vivo was detected by tumor formation in nude mice. The effects of aloe-emodin on inhibit ESM1 expression and its inhibitory effect on cervical cancer cells in vitro and in vivo were analyzed by the same method.
RESULTS
ESM1 was highly expressed in cervical cancer, and the high expression of ESM1 was associated with poor prognosis of cervical cancer patients. CCK-8 results showed that the proliferation, invasion and migration of Hela and SiHa cells were significantly reduced after siRNA interfered with ESM1 expression. Overexpression of ESM1 promoted the proliferation and migration of cervical cancer cells. Mechanism studies have shown that the oncogenic effect of ESM1 is realized through the ZEB1/PI3K/AKT pathway. High throughput drug screening found that aloe-emodin can target ESM1. Inhibitory effect of aloe emodin on ESM1/ZEB1/EMT signaling pathway and cervical cancer cells.
CONCLUSION
The silencing of ESM1 expression may inhibit the proliferation, invasion, metastasis and epithelial-mesenchymal transformation of cervical cancer cells by inhibiting ZEB1/PI3K/AKT. Aloe-emodin is a potential treatment for cervical cancer, which can play an anti-tumor role by inhibiting ESM1/ZEB1.
Topics: Humans; Epithelial-Mesenchymal Transition; Uterine Cervical Neoplasms; Zinc Finger E-box-Binding Homeobox 1; Female; Animals; Cell Proliferation; Mice; Cell Movement; HeLa Cells; Proteoglycans; Neoplasm Proteins; Mice, Nude; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Signal Transduction; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Neoplasm Invasiveness; Prognosis; Mice, Inbred BALB C
PubMed: 38954708
DOI: 10.1371/journal.pone.0304597 -
PloS One 2024Developing T1-weighted magnetic resonance imaging (MRI) contrast agents with enhanced biocompatibility and targeting capabilities is crucial owing to concerns over...
Developing T1-weighted magnetic resonance imaging (MRI) contrast agents with enhanced biocompatibility and targeting capabilities is crucial owing to concerns over current agents' potential toxicity and suboptimal performance. Drawing inspiration from "biomimetic camouflage," we isolated cell membranes (CMs) from human glioblastoma (T98G) cell lines via the extrusion method to facilitate homotypic glioma targeting. At an 8:1 mass ratio of ferric chloride hexahydrate to gallic acid (GA), the resulting iron (Fe)-GA nanoparticles (NPs) proved effective as a T1-weighted MRI contrast agent. T98G CM-coated Fe-GA NPs demonstrated improved homotypic glioma targeting, validated through Prussian blue staining and in vitro MRI. This biomimetic camouflage strategy holds promise for the development of targeted theranostic agents in a safe and effective manner.
Topics: Gallic Acid; Humans; Magnetic Resonance Imaging; Cell Line, Tumor; Contrast Media; Iron; Biomimetic Materials; Glioblastoma; Nanoparticles; Ferric Compounds; Cell Membrane
PubMed: 38954698
DOI: 10.1371/journal.pone.0306142 -
PloS One 2024Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized...
INTRODUCTION
Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics.
METHODS
Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma.
RESULTS
CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated.
CONCLUSIONS
PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.
Topics: Humans; Pancreatic Neoplasms; Male; Female; Adenocarcinoma; Middle Aged; Aged; Tumor Microenvironment; B7-H1 Antigen; HLA-G Antigens; Programmed Cell Death 1 Ligand 2 Protein; Prognosis; CD8-Positive T-Lymphocytes; Adult; T-Lymphocytes, Regulatory; Aged, 80 and over; Macrophages
PubMed: 38954689
DOI: 10.1371/journal.pone.0305648 -
PloS One 2024Uterine leiomyomas (often referred to as fibroids or myomas) are common benign, hormone-dependent tumors that grow in the uterus and occur in approximately 25% of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Uterine leiomyomas (often referred to as fibroids or myomas) are common benign, hormone-dependent tumors that grow in the uterus and occur in approximately 25% of reproductive age women, depending on selected population. Treatment recommendation is typically based on fibroid size, location, the patient's age, reproductive plans, and obstetrical history. Despite the range of treatment options available for uterine fibroids and their symptoms, including hysterectomy, myomectomy, endometrial ablation, endometrial uterine artery embolization, and magnetic resonance-guided focused-ultrasound surgery, myomectomy remains the gold standard treatment for patients who desire fertility-preserving surgery for their uterine fibroids. Myomectomy, while a prevalent surgical option for the removal of fibroids, carries known risks such as fibroid recurrence, symptom recurrence, and the subsequent need for reintervention. Despite ongoing research and advances in medical treatments for fibroids, there currently are no universally recommended therapeutic interventions proven to effectively delay the recurrence of fibroids or the return of symptoms following this procedure. This situation underscores a significant area of unmet medical need and highlights the importance of continued investigation into preventive strategies and long-term management options for patients undergoing fibroid removal with uterine preservation. We designed a study to assess the efficacy of the new FDA-approved GnRH antagonist, Myfembree in delaying the return of fibroids and their associated symptoms.
METHODS
A randomized, prospective, open-label clinical trial. The participants (n = 136) will be randomly distributed into two groups. The Control Group (Standard of care) will receive treatment with standard of care (SoC) after surgical myomectomy and the treatment group will receive Relugolix combination therapy (Myfembree®) after surgical myomectomy. The study protocol was approved by the University of Chicago's Institutional Review Board (IRB#22-0282), ensuring that all participants would provide written informed consent before their inclusion.
DISCUSSION
In this project, we propose the use of daily dosed Relugolix combination therapy (Relugolix with estradiol and norethindrone acetate), which is approved for uterine fibroids treatment, has the potential to delay the recurrence of fibroid symptoms, prolong the improved quality of life and delay need for re-intervention after uterine sparing surgery.
TRIAL REGISTRATION
The study protocol was approved by the Institutional Review Board of the University of Chicago on 9/16/2022 and was registered at ClinicalTrials.gov with number NCT05538689 on Sep 7, 2022. All subjects will provide informed consent to participate.
Topics: Humans; Female; Uterine Myomectomy; Leiomyoma; Standard of Care; Uterine Neoplasms; Adult; Middle Aged; Randomized Controlled Trials as Topic; Quality of Life
PubMed: 38954680
DOI: 10.1371/journal.pone.0306053 -
The Journal of Clinical Investigation Jul 2024Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in immunocompromised individuals such as kidney transplant recipients (KTRs). The...
Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in immunocompromised individuals such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in immunosuppressed individuals have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in immunocompromised patients and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with non-controlled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific CD8+ T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of CD8+ T cells could be targeted by inhibiting CD38 to reverse hypo-responsiveness in individuals who fail to control chronic viral infection.
PubMed: 38954588
DOI: 10.1172/JCI179561 -
JMIR Research Protocols Jul 2024Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for...
Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.
BACKGROUND
Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown.
OBJECTIVE
The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables.
METHODS
This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data.
RESULTS
In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing.
CONCLUSIONS
A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol.
TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/51381.
Topics: Humans; Erlotinib Hydrochloride; Gefitinib; Lung Neoplasms; ErbB Receptors; Retrospective Studies; New Zealand; Mutation; Female; Male; Protein Kinase Inhibitors; Antineoplastic Agents; Cohort Studies; Middle Aged; Aged
PubMed: 38954434
DOI: 10.2196/51381 -
Journal of Medical Internet Research Jul 2024Young adults engage in behaviors that place them at risk for skin cancer. Dissemination of digital health promotion interventions via social media is a potentially... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Young adults engage in behaviors that place them at risk for skin cancer. Dissemination of digital health promotion interventions via social media is a potentially promising strategy to modify skin cancer risk behaviors by increasing UV radiation (UVR) protection and skin cancer examinations.
OBJECTIVE
This study aimed to compare 3 digital interventions designed to modify UVR exposure, sun protection, and skin cancer detection behaviors among young adults at moderate to high risk of skin cancer.
METHODS
This study was a hybrid type II effectiveness-implementation randomized controlled trial of 2 active interventions, a digital skin cancer risk reduction intervention (UV4.me [basic]) compared with an enhanced version (UV4.me2 [enhanced]), and an electronic pamphlet (e-pamphlet). Intervention effects were assessed over the course of a year among 1369 US young adults recruited primarily via Facebook and Instagram. Enhancements to encourage intervention engagement and behavior change included more comprehensive goal-setting activities, ongoing proactive messaging related to previously established mediators (eg, self-efficacy) of UVR exposure and protection, embedded incentives for module completion, and ongoing news and video updates. Primary outcome effects assessed via linear regression were UVR exposure and sun protection and protection habits. Secondary outcome effects assessed via logistic regression were skin self-exams, physician skin exams, sunscreen use, indoor tanning, and sunburn.
RESULTS
The active interventions increased sun protection (basic: P=.02; enhanced: P<.001) and habitual sun protection (basic: P=.04; enhanced P=.01) compared with the e-pamphlet. The enhanced intervention increased sun protection more than the basic one. Each active intervention increased sunscreen use at the 3-month follow-up (basic: P=.03; enhanced: P=.01) and skin self-exam at 1 year (basic: P=.04; enhanced: P=.004), compared with the e-pamphlet. Other intervention effects and differences between the Basic and Enhanced Intervention effects were nonsignificant.
CONCLUSIONS
The active interventions were effective in improving several skin cancer risk and skin cancer prevention behaviors. Compared with the basic intervention, the enhanced intervention added to the improvement in sun protection but not other behaviors. Future analyses will explore intervention engagement (eg, proportion of content reviewed).
TRIAL REGISTRATION
ClinicalTrials.gov NCT03313492; http://clinicaltrials.gov/ct2/show/NCT03313492.
Topics: Humans; Skin Neoplasms; Young Adult; Male; Female; Adult; Social Media; Health Promotion; Adolescent; Risk-Taking
PubMed: 38954433
DOI: 10.2196/55831