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Background: Regular physical activity and diet can be effective in preventing cardiovascular disease. Therefore, the purpose of this study was to investigate the effect of 6 weeks of high intensity interval training (HIIT) with nano-curcumin supplementation on factors related to cardiovascular disease such as lipid profile and C-reactive protein (hs-CRP) in overweight girls. Materials and Methods: The research method was randomized-experimental with pre-post test design. 48 overweight student girls with mean age of 21.78±0.94 years and BMI equals 28.12±2.1kg/m2 were randomly divided into four groups: training (n=12), training-supplement (n=12), supplement (n=12) and control group (n=12). Supplement groups consumed a 80 mg nano-curcumin capsule daily. Training groups performed an exercise protocol of HIIT training with maximum heart rate for 6 weeks (three sessions per week). The control group did not have any regular exercise. Blood samples were obtained for measurement of lipid profile serum levels (Low Density Lipoprotein (LDL), Total Cholesterol (TC), Triglyceride (TG) and High-Density Lipoprotein (HDL)) and CRP before and after a 6-week period of exercise and supplementation. Data were analyzed by ANOVA and dependent t-test at P≤0.05. Results: In the supplement-training group, triglyceride (P=0.03) and CRP (P=0.03) significantly decreased, HDL (P=0.034) significantly increased and LDL and cholesterol did not show significant changes (P≥0.05). But there were no significant changes in lipid profile and CRP in the training and supplement groups (P≥0.05). Conclusion: HIIT training and nano-curcumin supplementation alone resulted in slight positive changes of lipid profile and CRP. But it seems that doing HIIT training together with nano-curcumin supplementation has a reinforcing effect on each other and they are more effective at preventing cardiovascular diseases.

Activation-induced cytidine deaminase (AID), highly expressed in germinal center (GC)-lymphocytes, is involved in somatic hypermutation (SHM). We examined AID expression in diffuse large B-cell lymphomas (DLBCL) of germinal center B-cell (GCB)-like and activated B-cell (ABC)-like subtypes. These two types of DLBCL are characterized by high and low expression of GC-specific genes, respectively. AID expression was detected in both GCB- and ABC-like DLBCL, thus demonstrating a dissociation between AID expression and that of other GC genes. We also tested for the presence of intraclonal heterogeneity in immunoglobulin and BCL6 genes in those same tumors and in follicle center lymphomas (FCL) that transformed to DLBCL. The level of AID expression did not correlate with the presence of intraclonal sequence heterogeneity in either IgV(H) or BCL6. Our findings suggest that lymphomas maintain some but not all of the gene expression signatures of their normal B-cell counterparts. The fact that AID expression can be elevated without intraclonal sequence heterogeneity raises the possibility that other factors are required for SHM in these tumors. We found decreased levels of AID expression in DLBCL that evolved from FCL and which had acquired new mutations in their BCL6 genes. This dissociation suggests that AID expression and SHM may occur at the time prior to the clinical detection of transformed lymphoma. [ABSTRACT FROM AUTHOR]

Background: Infections may contribute to Alzheimer's disease (AD) risk. Limited evidence suggests Toxocara spp. infection/exposure could influence AD development., Methods: We investigated Toxocara seropositivity and AD in Iranian adults using a matched case-control study. Our sample included 90 AD cases and 91 healthy older adults. Anti-Toxocara immunoglobulin G (IgG) antibodies were assessed via enzyme-linked immunosorbent assay. We computed the odds ratios (ORs) and 95% confidence intervals (CIs) through univariable and multivariable analyses, adjusting for potential confounders., Results: There were 33/90 (36.67% [95% CI 26.75 to 47.48]) anti-Toxocara IgG seropositive individuals identified among the AD cases and 21/91 (23.07% [95% CI 14.89 to 33.09]) among the healthy controls. In univariable analysis, a significant association was identified between anti-Toxocara IgG seropositivity and AD (OR 1.93 [95% CI 1.01 to 3.69], p<0.001). Moreover, the association remained significant (OR 2.18 [95% CI 1.05 to 4.49], p<0.001) in multivariable analysis after adjustment for covariates. There was no association between anti-Toxocara IgG seropositivity and the severity of AD (OR 0.75 [95% CI 0.21 to 2.61], p=0.47)., Conclusions: Our findings indicated that Toxocara exposure/infection could be a potential risk factor for development of AD. To better understand a real causality between Toxocara exposure/infection and AD and related dementias, follow-up designed and adequately powered studies are needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Liquid biopsy techniques using cell-free DNA (cfDNA) play an increasingly important role in the characterization and surveillance of solid tumors. For blood cancers, molecular response assessment techniques using circulating malignant cells or bone marrow aspirates are well established in clinical care. However, cfDNA has an emerging role in hematology as well, with the opportunity for disease assessment and quantification independent of circulating disease burden or invasive biopsies. In this review, we discuss key technologies and clinical data for the utilization of cfDNA in lymphomas, myeloma, and leukemias.

Introduction: The current standard of care for patients with inoperable stage III non-small cell lung cancer includes chemoradiotherapy (CRT) followed by 1 year of checkpoint inhibitor (CPI) therapy. Nevertheless, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of patients with unresectable locally advanced non-small cell lung cancer treated on a phase 2 trial of short-course consolidation immunotherapy after CRT, with the goal of testing whether ctDNA may be able to identify patients who do not require a full year of treatment., Methods: Plasma samples for ctDNA analysis were collected from patients on the Big Ten Cancer Research Consortium LUN 16-081 trial after completion of CRT, before day 1 of cycle 2 (C2D1) of CPI (i.e., 1 mo after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using cancer personalized profiling by deep sequencing. Levels of ctDNA at each time point were correlated with clinical outcomes., Results: Detection of ctDNA predicted significantly inferior progression-free survival after completion of CRT (24-mo 29% versus 65%, p = 0.0048), before C2D1 of CPI (24-mo 0% versus 72%, p < 0.0001) and at the end of CPI (24-mo 15% versus 67%, p = 0.0011). In addition, patients with decreasing or undetectable ctDNA levels after 1 cycle of CPI had improved outcomes compared with patients with increasing ctDNA levels (24-mo progression-free survival 72% versus 0%, p < 0.0001). Progression of disease occurred within less than 12 months of starting CPI in all patients with increasing ctDNA levels at C2D1., Conclusions: Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment., Competing Interests: Disclosure Dr. Durm receives support from Bristol-Myers Squibb; grants or contracts from AstraZeneca, Merck, and Mirati; consulting fees from Cook Biotech; payments or honoraria from Curio Science, DAVA Oncology, and AstraZeneca; and participates on an advisory board for Curio Science, DAVA oncology, and AstraZeneca. Dr. Ganti receives research grants or contracts from VA Office of Research and Development, Merck, TAB Biosciences, NEKTAR Therapeutics, Mirati Therapeutics, IOVANCE Therapeutics, and Apexigen; royalties or licenses from Oxford University Press; consulting fees from AstraZeneca, Flagship Biosciences, G1 Therapeutics, Jazz Pharmaceuticals, Cardinal Health, Mirati Therapeutics, Beigene Ltd., Sanofi Genzyme, Blueprint Medicines, and Regeneron Pharmaceuticals; payments or honoraria from MedLearning Group and Plexus Communications; participates on a data safety monitoring board for YmAbs Therapeutics; holds leadership or fiduciary roles at Academic and Community Cancer Research United and A Breath of Hope for Lung Cancer; and has received equipment or materials from Takeda Pharmaceuticals and Chimerx. Dr. Alizadeh receives research grants or contracts from the National Cancer Institute, National Heart, Lung and Blood Institute, National Institutes of Health, Celgene, Bristol-Myers Squibb, and Pfizer; consulting fees from ADCT, Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, and Roche; has patents planned, issued, or pending with FortySeven Inc., Foresight Diagnostics, CiberMed Inc., and Roche; participates on a data safety monitoring board for Lymphoma Research Foundation; holds leadership or fiduciary roles at the American Society of Hematology, American Society of Clinical Oncology, American Society of Clinical Investigation, and Leukemia & Lymphoma Society; and has equity ownership interests in CiberMed Inc., Foresight Diagnostics, FortySeven Inc., and CARGO Therapeutics. Dr. Hanna receives grants or contracts from Merck, Genentech, Bristol-Myers Squibb, and Natera. Dr. Diehn receives grants or contracts from AstraZeneca and Varian Medical Systems; royalties or licenses from Roche and Foresight Diagnostics; consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Illumina, Gritstone Bio, and Regeneron; payments or honoraria from Bristol-Myers Squibb, Japan, and Novartis; support for attending meetings or travel from Foresight Diagnostics and Regeneron; has patents planned, issued, or pending with Stanford University; holds leadership or fiduciary roles at Foresight Diagnostics; and holds stock or stock options in CiberMed Inc., Foresight Diagnostics, and Gritstone Bio. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Small cell lung cancer (SCLC) is characterized by rapid progression after platinum resistance. Circulating tumor (ctDNA) dynamics early in treatment may help determine platinum sensitivity., Materials and Methods: Serial plasma samples were collected from patients receiving platinum-based chemotherapy for SCLC on the first 3 days of cycle one and on the first days of subsequent cycles with paired samples collected both before and again after infusions. Tumor-informed plasma analysis was carried out using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). The mean variant allele frequency (VAF) of all pretreatment mutations was tracked in subsequent blood draws and correlated with radiologic response., Results: ctDNA kinetics were assessed in 122 samples from 21 patients. Pretreatment VAF did not differ significantly between patients who did and did not respond to chemotherapy (mean 22.5% v 4.6%, P = .17). A slight increase in ctDNA on cycle 1, day 1 immediately post-treatment was seen in six of the seven patients with available draws (fold change from baseline: 1.01-1.44), half of whom achieved a response. All patients who responded had a >2-fold decrease in mean VAF on cycle 2 day 1 (C2D1). Progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with a >2-fold decrease in mean VAF after one treatment cycle (6.8 v 2.6 months, log-rank P = .0004 and 21.7 v 6.4 months, log rank P = .04, respectively)., Conclusion: A >2-fold decrease in ctDNA concentration was observed by C2D1 in all patients who were sensitive to platinum-based therapy and was associated with longer PFS and OS.

Background and Objective: The oral first-pass metabolism is a crucial factor that plays a key role in a drug's pharmacokinetic profile. Prediction of the oral first-pass metabolism based on chemical structural parameters can be useful in the drug-design process. Developing an orally administered drug with an acceptable pharmacokinetic profile is necessary to reduce the cost and time associated with evaluating the extent of the first-pass metabolism of a candidate compound in preclinical studies. The aim of this study is to estimate the first-pass metabolism of an orally administered drug., Methods: A set of compounds with reported first-pass metabolism data were collected. Moreover, human intestinal absorption percentage and oral bioavailability data were extracted from the literature to propose a classification system that split the drugs up based on their first-pass metabolism extents. Various structural parameters were calculated for each compound. The relations of the structural and physicochemical values of each compound to the class the compound belongs to were obtained using logistic regression., Results: Initial analysis showed that compounds with logD 7.4  > 1 or a rugosity factor of > 1.5 are more likely to have high first-pass metabolism. Four different models that can predict the oral first-pass metabolism with acceptable error were introduced. The overall accuracies of the models were in the range of 72% (for models with simple descriptors) to 78% (for models with complex descriptors). Although the models with simple descriptors have lower accuracies compared to complex models, they are more interpretable and easier for researchers to utilize., Conclusion: A novel classification of drugs based on the extent of the oral first-pass metabolism was introduced, and mechanistic models were developed to assign candidate compounds to the appropriate proposed classes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Abstract: Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background this study was conducted to assess the effects of vitamin D on differentiation of bone marrow- derived mesenchymal stem cells (BM-MSCs) into insulin producing cells (IPCs). Method BM-MSCs were isolated from femur and tibia of rats and incubated in low (LG) or high glucose (HG) (5mM or 25mM), or high glucose DMEM media supplemented with vitamin D (0.2nM) (HGD) for 14 days. Cells viability was analysis by MTT assay. Differentiation of SCs was confirmed using measuring genes expression level of pdx 1 and insulin, and insulin secretion, glucose stimulated insulin secretion, and insulin content by ELISA method. Results Cell viability was significantly higher in HGD than LG (p < 0.05) in day 3, also, in HG and HGD than LG (p < 0.001), and HGD vs. HG (p < 0.001) in day 7. Pdx1 and insulin level was markedly higher in HGD than LG (p < 0.05 and p < 0.01). pdx1 expression was markedly higher in HGD (p < 0.05) than LG, also insulin expression the HG (p < 0.05), and HGD (p < 0.01) groups compared to the LG group. Insulin release at 5mM glucose was notably higher in the HGD group compared to LG (p < 0.05), and at 25mM glucose, both HG and HGD showed significant increases vs. LG (p < 0.05 and p < 0.01, respectively). Insulin content was significantly higher in both 5mM and 25mM glucose for HG and HGD vs. LG (p < 0.01 and p < 0.001, respectively). In conclusion, treatment BM-MSCs with vitamin D could increase their differentiation into IPCs and it can be considered as a potential supplementary agent in enhancing differentiation SCs into insulin generating cells., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Nowadays, a significant part of the investigations carried out in the medical field belong to cancer treatment. Generally, conventional cancer treatments, including chemotherapy, radiotherapy, and surgery, which have been used for a long time, are not sufficient, especially in malignant cancers. Because genetic mutations cause cancers, researchers are trying to treat these diseases using genetic engineering tools. One of them is clustered regularly interspaced short palindromic repeats (CRISPR), a powerful tool in genetic engineering in the last decade. CRISPR, which forms the CRISPR-Cas structure with its endonuclease protein, Cas, is known as a part of the immune system (adaptive immunity) in bacteria and archaea. Among the types of Cas proteins, Cas9 endonuclease has been used in many scientific studies due to its high accuracy and efficiency. This review reviews the CRISPR system, focusing on the history, classification, delivery methods, applications, new generations, and challenges of CRISPR-Cas9 technology., (© 2024 Wiley Periodicals LLC.)

Purpose: This study aimed to evaluate the antibacterial and cytotoxic effects of reinforced zinc oxide-eugenol (rZOE) incorporated with different concentrations of silver nanoparticles (AgNPs)., Methods: The pastes of rZOE alone or mixed with AgNPs at concentrations of 1%, 2%, and 5% of weight were prepared. In vitro antimicrobial activity of prepared materials against Streptococcus (S.) mutans and Lactobacillus (L.) acidophilus were evaluated after 2, 4, and 6 h of contact times using direct contact test (DCT) and also following 24 h incubation by well-diffusion test (WDT). The cytotoxicity of the tested materials on human dental pulp stem cells was also determined by MTT assay., Results: The DCT demonstrated that the time-dependent reductions of the colony numbers of both bacteria by three different concentrations of AgNPs incorporated into rZOE were equal but steeper than the rZOE alone (P < 0.05). The increases in growth inhibition zones of S. mutans and L. acidophilus were associated with the increasing concentration of AgNPs mixed with rZOE in the WDT; however, statistical analysis did not show any significant differences (P = 0.092). The MTT assay revealed a significantly lower percentage of cell viability after 1 day of culture only with the rZOE + AgNP5% in comparison to the rZOE alone (P = 0.011) and the control medium (P = 0.001)., Conclusion: Since the antimicrobial activities of three different concentrations of AgNPs incorporated into rZOE were equal and AgNPs had lower toxicity at lower concentrations, using AgNPs at 1% concentration is suggested to be mixed with rZOE., (© 2024. The Author(s), under exclusive licence to European Academy of Paediatric Dentistry.)

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms., (© 2024. The Author(s).)

There is a strong relationship between the dysregulation of epidermal growth factor receptor (EGFR) and the development of epithelial-derived cancers. Therefore, EGFR has usually been considered the desired target for gene therapy. Here, we propose an approach for targeting EGFR-expressing cells by phage particles capable of displaying EGF and GFP as tumor-targeting and reporting elements, respectively. For this purpose, the superfolder GFP-EGF (sfGFP-EGF) coding sequence was inserted at the N-terminus of the pIII gene in the pIT 2 phagemid. The capability of the constructed phage to recognize EGFR-overexpressing cells was monitored by fluorescence microscopy, fluorescence-activated cell sorting (FACS), and cell-based ELISA experiments. FACS analysis showed a significant shift in the mean fluorescence intensity (MFI) of the cells treated with phage displaying sfGFP-EGF compared to phage displaying only sfGFP. The binding of phage displaying sfGFP-EGF to A-431 cells, monitored by fluorescence microscopy, indicated the formation of the sfGFP-EGF-EGFR complex on the surface of the treated cells. Cell-based ELISA experiments showed that phages displaying either EGF or sfGFP-EGF can specifically bind EGFR-expressing cells. The vector constructed in the current study has the potential to be engineered for gene delivery purposes as well as cell-based imaging for tumor detection., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation., Competing Interests: Declaration of interests J.M.K., J.G.S.-M., B.J.S., M.D., L.E.W., and A.A.A. have submitted a provisional patent application (filed by Stanford University on 06/12/2023 with application number 63/507,692) on the development and applications of PDLOs. A.A.A. reports ownership interest in CiberMed, FortySeven Inc., and Foresight Diagnostics; patent filings related to cancer biomarkers; research funding from Bristol Myers Squibb and Celgene; and paid consultancy from Genentech, Karyopharm, Roche, Chugai, Gilead, and Celgene. L.E.W. reports research funding (unrelated to this study) from F. Hoffman La Roche., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment., Methods: We explored various MRI features including semi-automated 3D tumor volume measurements at different disease milestones and their association with survival in 93 CNSL patients undergoing curative-intent treatment., Results: At diagnosis, patients with more than 3 lymphoma lesions, periventricular involvement, and high 3D tumor volumes showed significantly unfavorable PFS and OS. At first interim MRI during treatment, the IPCG criteria failed to discriminate outcomes in responding patients. Therefore, we randomized these patients into training and validation cohorts to investigate whether 3D tumor volumetry could improve outcome prediction. We identified a 3D tumor volume reduction of ≥97% as the optimal threshold for risk stratification (=3D early response, 3D&#95;ER). Applied to the validation cohort, patients achieving 3D&#95;ER had significantly superior outcomes. In multivariate analyses, 3D&#95;ER was independently prognostic of PFS and OS. Finally, we leveraged prognostic information from 3D MRI features and circulating biomarkers to build a composite metric that further improved outcome prediction in CNSL., Conclusions: We developed semi-automated 3D tumor volume measurements as strong and independent early predictors of clinical outcomes in CNSL patients. These radiologic features could help improve risk stratification and help guide future treatment approaches., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: In situ vaccination (ISV) triggers an immune response to tumor-associated antigens at 1 tumor site, which can then tackle the disease throughout the body. Here, we report clinical and biological results of a phase 1/2 ISV trial in patients with low-grade lymphoma, combining an intratumoral toll-like receptor 9 (TLR9) agonist with local low-dose radiation and ibrutinib (an inhibitor of B- and T-cell kinases). Adverse events were predominately low grade. The overall response rate was 50%, including 1 complete response. All patients experienced tumor reduction at distant sites. Single-cell analyses of serial fine needle aspirates from injected and uninjected tumors revealed correlates of clinical response, such as lower CD47 and higher major histocompatibility complex class II expression on tumor cells, enhanced T-cell and natural killer cell effector function, and reduced immune suppression from transforming growth factor β and inhibitory T regulatory 1 cells. Although changes at the local injected site were more pronounced, changes at distant uninjected sites were more often associated with clinical responses. Functional immune response assays and tracking of T-cell receptor sequences provided evidence of treatment-induced tumor-specific T-cell responses. Induction of immune effectors and reversal of negative regulators were both important in producing clinically meaningful tumor responses. The trial was registered at www.clinicaltrials.gov as #NCT02927964., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels 1-4 . Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq 5 , we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHLs) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and T-cell receptor sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma and follicular lymphoma (FL), compared with that in nonmalignant tonsillar tissue. We identified 3 distinct transcriptional states of Tregs: resting, activated, and unconventional LAG3+FOXP3- Tregs. Activated Tregs were enriched in B-NHL tumors, coexpressed several checkpoint receptors, and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices, which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In 2 independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating B-NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in the peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve antitumor immunity., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In diffuse large B-cell lymphoma (DLBCL), a positive interim positron emission tomography (PET) scan predicts treatment failure, but the proportion of high-risk patients thus identified is small. To improve prediction, we combined the interim PET result with the presence or absence of an associated IgM gammopathy. Of 108 DLBCL patients participating in a prospective trial, nine (8%) were interim PET positive and 19 (18%) had an IgM gammopathy. The monoclonal protein was not associated with distinguishing genetic features, and its light chain restriction was not always concordant with the light chain restriction of the lymphoma. The information provided by interim PET and IgM gammopathy was combined to dichotomize the population into sizeable high-risk (1-2 adverse factors) and low-risk groups (no adverse factor) with widely different outcomes (population size, 25% vs. 75%; 3-year risk of progression, 51% vs. 10%; 3-year overall survival, 64% vs. 95%). Multivariable analyses including established risk factors revealed the interim PET result and the IgM gammopathy status to be the only factors significantly associated with outcome. Information about interim PET response and IgM gammopathy may be useful in studies testing risk-adapted treatment strategies., (© 2023. The Author(s).)

Material engineering is a fundamental issue in the applications of materials in the medical field. One of the aspects of material engineering is incorporating recognition sites on the surface of biomaterials, which plays an essential role in increasing the efficiency of tissue engineering scaffolds in various aspects. The application of peptides and antibodies to establish the recognition and adhesion sites has limitations, such as fragility and instability under physical and chemical processes. Therefore, synthetic ligands such as nucleic acid aptamers have received much attention for easy synthesis, minimal immunogenicity, high specificity, and stability under processing. Due to the effective role of these ligands in increasing the efficiency of engineered constructs in this study, the advantages of nucleic acid aptamers in tissue engineering will be reviewed. Aptamer-functionalized biomaterials can attract endogenous stem cells to wounded areas and organize their actions to facilitate tissue regeneration. This approach harnesses the body's inherent regeneration potential to treat many diseases. Also, increased efficacy in controlled release, slow and targeted drug delivery are important issues in drug delivery for tissue engineering approaches which can be achieved by incorporating aptamers in drug delivery systems. Aptamer-functionalized scaffolds have very applications, such as diagnosis of cancer, hematological infections, narcotics, heavy metals, toxins, controlled release from the scaffolds, and in vivo cell tracing. Aptasensors, as a result of many advantages over other traditional assay methods, can replace older methods. Furthermore, their unique targeting mechanism also targets compounds with no particular receptors. Targeting cell homing, local and targeted drug delivery, cell adhesion efficacy, cytocompatibility and bioactivity of scaffolds, aptamer-based biosensor, and aptamer-functionalized scaffolds are the topics that will be examined in this review study., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Androgenetic alopecia (AGA) is a prevalent form of hair loss, mainly caused by follicular sensitivity to androgens. Despite developing different anti-androgen treatment options, the success rate of these treatments has been limited. Using animal models, this study evaluated the therapeutic effects of umbilical cord (UC) stem cell conditioned media (CM) combined with oral anti-androgens for hair regeneration., Materials and Methods: In this experimental study, Poloxamer 407 (P407) was used as a drug carrier for subcutaneous testosterone injection. AGA models were treated with oral finasteride, oral flutamide, and CM injections. Samples were thoroughly evaluated and compared using histological, stereological, and molecular analyses., Results: Injecting CM-loaded hydrogel alone or combined with oral intake of anti-androgens improved hair regeneration. These treatments could promote hair growth by inducing hair follicles in the anagen stage and shortening the telogen and catagen phases. Furthermore, the combination treatment led to an upregulation of hair induction gene expression with a downregulation of inflammation genes., Conclusion: Through a reduction in inflammation, injection of CM-loaded hydrogel alone or combined with oral intake of anti-androgens induces the hair cell cycle with regeneration in damaged follicles. Hence, this could be a promising therapeutic method for AGA patients.

Bacterial leaf streak of small-grain cereals is an economically important disease of wheat and barley crops. The disease occurs in many countries across the globe, with particular importance in regions characterized by high precipitation or areas in which sprinkler irrigation is used. Three genetically distinct lineages of the Gram-negative bacterium Xanthomonas translucens ( X. translucens pv. undulosa , X. translucens pv. translucens , and X. translucens pv. cerealis ) are responsible for most of the bacterial leaf streak infections on wheat and barley crops. Considering the seedborne nature of the pathogens, they are included in the A2 (high-risk) list of quarantine organisms for some European countries; hence, they are under strict quarantine control and zero tolerance. Due to the taxonomic complexities within X. translucens , the exact geographic distribution of each pathovar has not yet been determined. In this mini review, we provide an updated overview of the detection and diagnosis of the bacterial leaf streak pathogens. First, a short history of the leaf streak pathogens is provided, followed by the symptomology and host range of the causal agents. Then, the utility of conventional methods and high-throughput molecular approaches in the precise detection and identification of the pathogens is explained. Finally, we highlight the role of quarantine inspections and early detection of the pathogen in combating the risk of bacterial leaf streak in the 21st century's small-grains cereals' industry., Competing Interests: The author(s) declare no conflict of interest.

Background: The scientific and clinical communities now recognize that sperm DNA integrity is crucial for successful fertilization, good embryo development, and offspring quality of life. Despite the apparent unanimity, this criterion is rarely evaluated in clinical practice. We evaluated the sperm DNA fragmentation index of nearly 1200 sperm samples and its connections based on the patient's age, body mass index, the season of sperm collection, geographical location, medical history, and addictive behaviors., Methods: A cohort of 1503 patients who were referred to the Royan Institute between July 2018 and March 2020 was examined. Only 1191 patient records with demographic data, complete semen analysis, and DNA fragmentation index measurements were included in the final cohort. Documents were classified, incorporated into statistical models, and analyzed., Results: The results confirmed previous findings that the sperm DNA fragmentation index was significantly higher in aging men. The sperm DNA fragmentation index and high DNA stainability levels were significantly higher in spring and summer samples than in those of other seasons. No correlation was found between semen DNA fragmentation index and patient body mass index, although the study cohort was significantly overweight. Contrary to what might be expected, we observed that the sperm DNA fragmentation index was higher in rural than in urban patients. Intriguingly, epileptic patients exhibited significantly higher sperm DNA fragmentation index levels., Discussion and Conclusion: Age is the factor that is most strongly associated with sperm DNA fragmentation index levels. Our analysis of 1191 samples indicates that between the ages of 19 and 59, the sperm DNA fragmentation index increases by an average of 2% each year. Intriguingly, from an epidemiological perspective, the warm season (spring/summer) is associated with a higher sperm DNA fragmentation index in the study population, possibly due to the deleterious effect of temperature on sperm quality. Some neurological diseases, such as epilepsy, are associated with decreased sperm DNA integrity. This observation could be related to the iatrogenic effects of associated therapies. In the study cohort, body mass index did not appear to be correlated with the DNA fragmentation index., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: There is arguing evidence regarding the association between maternal infections during pregnancy and the risk of intellectual disability (ID) in children. This systematic review and meta-analysis are essential to determine and address inconsistent findings between maternal infections during pregnancy and the risk of ID in children., Methods: The MOOSE and PRISMA guidelines were followed to perform and report on this study. The Medline/PubMed, Web of Science, Embase, and Scopus databases were searched from inception up to March 15, 2023, to identify potentially eligible studies. Inclusion and exclusion criteria were applied, as well as the Newcastle-Ottawa Scale was used to assess the methodological quality of studies included. The included studies were divided into two types based on the participants: (1) ID-based studies, which involved children with ID as cases and healthy children as controls and evaluated maternal infection in these participants; (2) infection-based studies, which assessed the prevalence or incidence of ID in the follow-up of children with or without exposure to maternal infection. We used Random-effects models (REM) to estimate the overall pooled odds ratio (OR) and 95% confidence intervals (CIs). The between-studies heterogeneity was assessed with the χ2-based Q-test and I2 statistic. Subgroup and sensitivity analyses were applied to explore the source of heterogeneity and results consistency., Results: A total of eight studies including 1,375,662 participants (60,479 cases and 1,315,183 controls) met the eligibility criteria. The REM found that maternal infection significantly increased the risk of ID in children (OR, 1.33; 95% CI, 1.21-1.46; I2 = 64.6). Subgroup analysis showed a significant association for both infection-based (OR, 1.27; 95%CI, 1.15-1.40; I2 = 51.2) and ID-based (OR, 1.44; 95%CI, 1.19-1.74; I2 = 77.1) studies. Furthermore, subgroup analysis based on diagnostic criteria revealed a significant association when maternal infection or ID were diagnosed using ICD codes (OR, 1.33; 95% CI, 1.20-1.48; I2 = 75.8)., Conclusion: Our study suggests that maternal infection during pregnancy could be associated with an increased risk of ID in children. This finding is consistent across different types of studies and diagnostic criteria. However, due to the heterogeneity and limitations of the included studies, we recommend further longitudinal studies to confirm the causal relationship and the underlying mechanisms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rezaeinejad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Physical and visual elements that help people find their way around an environment are called visual cues (VCs). The current study aims to evaluate adults' wayfinding abilities (navigation, orientation, spatial anxiety, and distance estimation) and VC (navigational color coding) preferences in terms of color and position; additionally, investigates their differences in adults' life span phases (young adults, early middle-aged adults, and late middle-aged adults)., Background: Wayfinding in complex environments such as healthcare centers has been challenging for most people. Although VCs are being used increasingly to facilitate wayfinding, considering people's preferences regarding VCs, especially navigational color coding, are neglected., Methods: Obtained data from a survey of 375 healthcare center visitors with textual and photo questionnaires were analyzed by descriptive statics and one-way analysis of variance., Results: Young adults preferred VCs with "mixed colors and positioned in the middle of the floor," early middle-aged adults preferred "warm color VCs in the middle of the wall," and late middle-aged adults preferred "warm color VCs at the bottom of the wall." Additionally, the results demonstrated that with aging, navigation and distance estimation abilities deteriorate, and spatial anxiety increases., Conclusions: The outcomes of the present study increase our knowledge regarding the impact of adults' life span phases on their wayfinding abilities and VC preferences and offer suggestions for architects and healthcare center stakeholders to provide environments that improve adults' wayfinding.

Purpose: Teduglutide is the first and only FDA-approved drug for long-term treatment of short bowel syndrome (SBS). The current study aimed to present an approach for production of teduglutide using recombinant DNA technology., Methods: The coding gene for teduglutide was cloned into pGEX-2T vector, where coding sequence for factor Xa cleavage site was added between GST and teduglutide coding genes. The GST-teduglutide protein was overexpressed in E. coli BL21 (DE3) strain and affinity purified using glutathione sepharose affinity column., Results: On-column proteolytic activity of factor Xa followed by size exclusion chromatography resulted in the pure teduglutide. Circular dichroism (CD) spectropolarimetry showed that the produced teduglutide folds into mainly α-helical structure (>50%), as expected. In mass spectroscopy analysis, the fragments of teduglutide resulted by cyanogen bromide cleavage as well as those expected theoretically due to mass fragmentation were identified. The functionality of the produced peptide was evaluated by measuring its proliferative effect on Caco2 intestinal epithelial cells, and the results indicated that produced teduglutide induces cell proliferation by 19±0.30 and 33±7.82 % at 1.21 and 3.64 µM concentrations, respectively, compared to untreated cells., Conclusion: Teduglutide was successfully expressed and purified and its functionality and structural integrity were confirmed by in vitro experiments. We believe that the experimental-scale method presented in the current study can be useful for pilot-scale and also industrial-scale production of teduglutide., Competing Interests: The authors declare no conflict of interest., (©2023 The Authors.)

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals, suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultradeep sequencing of prediagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, P = 0.03 and 0/20, P = 0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with the potential for discriminating subjects at risk of developing FL or monitoring residual disease., Significance: Our study provides direct evidence for recurrent genetic aberrations preceding FL diagnosis, revealing the combination of BCL2 translocation with CREBBP KAT domain mutations as characteristic committed lesions of FL CPCs. Such prediagnostic mutations are detectable years before clinical diagnosis and may help discriminate individuals at risk for lymphoma development. This article is highlighted in the In This Issue feature, p. 1275., (©2023 American Association for Cancer Research.)

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.

Machine learning (ML) is increasingly used in clinical oncology to diagnose cancers, predict patient outcomes, and inform treatment planning. Here, we review recent applications of ML across the clinical oncology workflow. We review how these techniques are applied to medical imaging and to molecular data obtained from liquid and solid tumor biopsies for cancer diagnosis, prognosis, and treatment design. We discuss key considerations in developing ML for the distinct challenges posed by imaging and molecular data. Finally, we examine ML models approved for cancer-related patient usage by regulatory agencies and discuss approaches to improve the clinical usefulness of ML., Competing Interests: Declaration of interests A.A.A. is an advisor to Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, and Roche. E.W. is a shareholder of RadNet, Inc. J.Z. is an advisor to Adela, Enable Medicine, and InterVenn Biosciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, one-third of patients experience refractory or relapsed disease. Studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) did not result in improved outcomes; however, L and O together may enhance natural killer-cell mediated antibody-dependent cellular toxicity when paired with CHOP. Here, we report on a phase 1b/2 study of 53 patients with newly diagnosed DLBCL who received 6 cycles of LO-CHOP. The end of treatment overall and complete response rates of the 50 evaluable patients were 98% and 90%, respectively. After a median follow-up of 4.5 years, the 4-year progression free and overall survival rates were 87.4% and 91.3%, respectively. Grade 3 to 4 adverse events were experienced by 70% of patients, including neutropenia (38%), thrombocytopenia (17%), fatigue (13%), and neutropenic fever (13%). Of the 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pretreatment ctDNA with cancer personalized profiling by deep sequencing, 24 (73%) were classifiable by the LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using phased variant enrichment and detection sequencing, 16/18 evaluable patients (89%) showed no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA. This trial has been registered at www.clinicaltrials.gov as NCT02529852., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL., Patients and Methods: We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL., Results: Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value., Conclusion: We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL., [Media: see text].

Multiple sclerosis (MS) is a neurological disease that leads to severe physical and cognitive disabilities. Drugs used in the treatment of MS vary from small synthetic molecules to large macromolecules such as antibodies. Sphingosine 1-phosphate receptor modulators are frequently used for the treatment of MS. These medicines prevent the egress of lymphocytes from secondary lymphoid organs leading to immune system suppression. Currently, four S1PR modulators are on the market and several potential drug candidates are in clinical trials for the treatment of MS. These compounds differ in chemical structure, adverse effects, and efficacy points of view. The current article reviews the latest studies on S1PR1 modulators and compares them with other MS drugs in terms of efficacy, tolerability, and safety. A special focus was dedicated to discussing the structure-activity relationships of these compounds and performing a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to gain better insight into the ligand-receptor interaction mode., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies.

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches., Competing Interests: Declaration of interests B.J.S. reports consultancy for Foresight Diagnostics. D.M.K. reports consultancy for Roche, Adaptive Biotechnologies, and Genentech and equity ownership interest in Foresight Diagnostics S.K.A. reports speaker honoraria from Takeda. M.J.F. reports consultancy and research funding from Adaptive Biotechnologies, research funding from Kite/Gilead, stock options from Allogene Therapeutics, and equity in Roche/Genentech. M.S.E. reports consultancy for Foresight Diagnostics. J.H.B. reports research funding from Kite Pharma. S.B. reports employment and stock ownership at Kite-a Gilead company. J.W. has research funding from Kite/Gilead, BMS, Novartis, Genentech/Roche, Morphosys/Incyte, AstraZeneca, and ADC Therapeutics, and consulting funding for Kite/Gilead, BMS, Novartis, Genentech/Roche, Morphosys/Incyte, AstraZeneca, ADC Therapeutics, Merck, MonteRosa, Umoja, and Ikusda. M.S.K. reports research funding from CRISPR Therapeutics and Nutcracker Therapeutics, and advisory committee membership for Myeloid Therapeutics and Daiichi Sankyo. Y.N. reports consulting for Leica Biosystems and Roche, and research funding from Kite Pharma. C.L.M. holds several patents focused on CAR T cells therapies; is a co-founder and holds equity in Lyell Immunopharma, CARGO Therapeutics, and Link Cell Therapies, which are developing CAR-based therapies; and consults for Lyell, CARGO, Link, Apricity, Nektar, Immatics, Mammoth, and Ensoma. R.G.M. is a co-founder of and holds equity in Link Cell Therapies and Syncopation Life Sciences. R.G.M. is a consultant for Lyell Immunopharma, NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, GammaDelta Therapeutics, Aptorum Group, Zai Labs, ImmunAI, Gadeta, FATE Therapeutics (DSMB), and Waypoint Bio. M.D. reports research funding from AstraZeneca, Genentech, Varian Medical Systems, and Illumina; ownership interest in CiberMed and Foresight Diagnostics; and consultancy from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Gritstone Oncology, Illumina, Novartis, and Roche. D.B.M. holds a patent with Pharmacyclics supporting ibrutinib for chronic graft-versus-host disease and receives consulting or research fees or serves as an advisor for Pharmacyclics, Kite Pharma, Adaptive Biotechnologies, Novartis, BMS, Janssen Pharmaceuticals, Roche, Genentech, Precision Bioscience, Allogene, Miltenyi Biotec, Fate Therapeutics, 2Seventy, and Adicet. A.A.A. reports consultancy for Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, and Roche; scientific advisory board membership in the Lymphoma Research Foundation; professional affiliations with the American Society of Hematology, American Society of Clinical Oncology, American Society of Clinical Investigation, and Leukemia & Lymphoma Society; research funding from the National Cancer Institute, National Heart, Lung, and Blood Institute, National Institutes of Health, Celgene, Bristol Myers Squibb, and Pfizer; patent filings, including patent issued, licensed, and with royalties paid from FortySeven, a patent pending and Licensed to Foresight, a patent pending relating to MARIA, a patent issued and licensed to CiberMed, a patent issued, a patent pending to CiberMed, a patent issued to Idio-type Vaccines, and a patent issued, licensed, and with royalties paid From Roche; and equity ownership interests in CiberMed Inc., Foresight Diagnostics, FortySeven Inc., and CARGO Therapeutics. B.J.S., D.M.K., M.S.E., M.D., and A.A.A. also report patent filings related to cancer biomarkers. The remaining authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Metal-fluoroquinolones have more antibacterial and cytotoxic effects compared to free fluoroquinolones. In this work, a bidentated Mn (II) complex with ofloxacin (MOC) was synthesized and its cytotoxicity activity, oxidative stress and DNA binding were studied. Anti- proliferative and cytotoxic tests revealed that MOC exhibits better anti proliferative and cytotoxic activities compared to OFL which was attributed to the more interaction of MOC with DNA. Therefore, the interaction of MOC with DNA was investigated by using voltammetry, UV-Vis, fluorescence, and in silico methods. The results revealed that MOC interacts with DNA via electrostatic and outside hydrogen binding via minor groove. The proposed DNA binding modes may support the greater in-vitro cytotoxicity of MOC compared to OFL alone.

Purpose: Drug repurposing is an approach successfully used for discovery of new therapeutic applications for the existing drugs. The current study was aimed to use the combination of in silico methods to identify FDA-approved drugs with possible S1P 1 agonistic activity useful in multiple sclerosis (MS). Methods: For this, a 3D-QSAR model for the known 21 S1P 1 agonists were generated based on 3D-QSAR approach and used to predict the possible S1P 1 agonistic activity of FDA-approved drugs. Then, the selected compounds were screened by docking into S1P 1 and S1P 3 receptors to select the S1P 1 potent and selective compounds. Further evaluation was carried out by molecular dynamics (MD) simulation studies where the S1P 1 binding energies of selected compounds were calculated. Results: The analyses resulted in identification of cobicistat, benzonatate and brigatinib as the selective and potent S1P 1 agonists with the binding energies of -85.93, -69.77 and -67.44 kcal. mol -1 , calculated using MM-GBSA algorithm based on 50 ns MD simulation trajectories. These values are better than that of siponimod (-59.35 kcal mol -1 ), an FDA approved S1P 1 agonist indicated for MS treatment. Furthermore, similarity network analysis revealed that cobicistat and brigatinib are the most structurally favorable compounds to interact with S1P 1 . Conclusion: The findings in this study revealed that cobicistat and brigatinib can be evaluated in experimental studies as potential S1P 1 agonist candidates useful in the treatment of MS., Competing Interests: The authors declare no conflict of interest., (©2023 The Authors.)

Tissues are composed of diverse cell types and cellular states that organize into distinct ecosystems with specialized functions. EcoTyper is a collection of machine learning tools for the large-scale delineation of cellular ecosystems and their constituent cell states from bulk, single-cell, and spatially resolved gene expression data. In this chapter, we provide a primer on EcoTyper and demonstrate its use for the discovery and recovery of cell states and ecosystems from healthy and diseased tissue specimens., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Low-grade lymphomas have a 1%-3% annual risk of transformation to a high-grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case-control series of patients matched by histology and follow-up time. We measured PET parameters including maximum standard uptake value (SUV-max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)-based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow-up time was similar. We observed a significant incremental increase in SUV-max and TLG between control, pretransformation and post-transformation groups ( P  < 0.05). By multivariable analysis, we identified a significant interaction between SUV-max and TLG such that SUV-max had highest significance for low volume cases ( P  = 0.04). We developed a scoring model incorporating SUV-max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low-grade lymphoma., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies., (© 2022 by The American Society of Hematology.)

In this review, gene delivery and its applications are discussed in tissue engineering (TE); also, new techniques such as the CRISPR-Cas9 system, synthetics biology and molecular dynamics simulation to improve the efficiency of the scaffolds have been studied. CRISPR-Cas9 is expected to make significant advances in TE in the future. The fundamentals of synthetic biology have developed powerful and flexible methods for programming cells via artificial genetic circuits. The combination of regenerative medicine and artificial biology allows the engineering of cells and organisms for use in TE, biomaterials, bioprocessing and scaffold development. The dynamics of protein adsorption at the scaffold surface at the atomic level can provide valuable guidelines for the future design of TE scaffolds /implants.