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Zinc oxide nanoparticles (ZnONPs), characterized by their nanoscale dimensions and unique properties, have emerged as promising materials in various applications. From electronics to biomedicine, their versatility and biocompatibility makes them valuable assets to address multifaceted challenges. This study aimed to comparatively analyze chemically synthesized ZnONPs (CS-ZnONPs) and Illicium verum-mediated ZnONPs (IV-ZnONPs) in terms of characteristics and biological activities. Characterization of both types of synthesized ZnONPs were done by using various techniques namely XRD, UV-vis spectroscopy, FTIR, TEM, and EDX. TEM and XRD results revealed the variability in size and shape of IV-ZnONPs (∼13.75 nm; triangular) and CS-ZnONPs (∼38.9 nm; flower-shaped). FTIR spectra showed the presence of different phytochemicals present in I. verum extract involved in the capping of IV-ZnONPs. Both types of ZnONPs were found to be biocompatible in nature. Furthermore, variations in their biological properties were observed using different in vitro assays, such as FRAP (242.3 ± 18.9 and 101.5 ± 9.5 μM TEAC), CUPRAC (249.8 ± 8.9 and 149.5 ± 8.2 μM TEAC), ABTS (I36.2 ± 0.5 and 28.2 ± 0.8 μM TEAC), and ORAC cell-free assays (19.9 ± 0.6 and 11.9 ± 0.9 μM TEAC) for anti-oxidant investigations of IV-ZnONPs and CS-ZnONPs, respectively. Percentage Inhibition of Vespelysine-like AGEs and pentosidine-like AGEs for anti-aging analysis were reported. In addition to these, the anti-cancerous potential of both types of ZnONPs was also studied based on MTT assay, ROS/NOS production, mitochondria membrane potential, activity of caspase 3/7 measurements, and expression of caspase-3 gene in mammalian HepG2 cell lines. Our findings revealed that both types of ZnONPs were found to be more active through electron-transfer anti-oxidant mechanism. Likewise, the findings of anti-aging analyses revealed significant difference of inhibitory potential between CS-ZnONPs and IV-ZnONPs. As far as anti-cancerous potential is concerned, both IV-ZnONPs and CS-ZnONPs were found to have promising potential against HepG2 cells. However, CS-ZnONPs were observed to have a slight edge over IV-ZnONPs. Nonetheless, the overall results indicated that ZnONPs synthesized through the green route exhibit outstanding biological potential, positioning them as promising candidates for future biomedical applications, particularly in the realm of cancer therapeutics. [ABSTRACT FROM AUTHOR]

Topical corticosteroids (TCSs) are classified into four potencies: mild, moderate, potent and very potent. Confusion arises from the wide range of products available, none of which have the potency level printed on the tubes or packaging. An online survey of patients and carers of people with eczema showed that only 17% of 984 respondents knew how many potencies there are. In a second survey, 315 respondents provided 1520 assignments of the potency of commonly used TCSs: 55.5% were correct, 21% were underestimates and 23.5% overestimates. Some errors were extreme: 12 (8%) of those using a very potent TCS considered it mild while 9 (27%) using a mild TCS considered it potent or very potent. Other themes expressed in free-text comments included inadequate and conflicting advice about using TCSs and lack of warnings about long-term adverse effects, particularly topical steroid withdrawal. Ninety-five per cent of respondents wanted TCSs to be clearly labelled with potency. [ABSTRACT FROM AUTHOR]

Background We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test. Methods We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided. Results The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (P difference =.001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model. Conclusion Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung. [ABSTRACT FROM AUTHOR]

Introduction: Analyzing liquid biopsies for tumor-specific aberrations can facilitate detection of measurable residual disease (MRD) during treatment and at follow-up. In this study, we assessed the clinical potential of using whole-genome sequencing (WGS) of lymphomas at diagnosis to identify patient-specific structural (SVs) and single nucleotide variants (SNVs) to enable longitudinal, multi-targeted droplet digital PCR analysis (ddPCR) of cell-free DNA (cfDNA). Methods: In 9 patients with B-cell lymphoma (diffuse large B-cell lymphoma and follicular lymphoma), comprehensive genomic profiling at diagnosis was performed by 30X WGS of paired tumor and normal specimens. Patient-specific multiplex ddPCR (m-ddPCR) assays were designed for simultaneous detection of multiple SNVs, indels and/or SVs, with a detection sensitivity of 0.0025% for SV assays and 0.02% for SNVs/indel assays. M-ddPCR was applied to analyze cfDNA isolated from serially collected plasma at clinically critical timepoints during primary and/or relapse treatment and at follow-up. Results: A total of 164 SNVs/indels were identified by WGS including 30 variants known to be functionally relevant in lymphoma pathogenesis. The most frequently mutated genes included KMT2D, PIM1, SOCS1 and BCL2. WGS analysis further identified recurrent SVs including t(14;18)(q32;q21) (IGH::BCL2), and t(6;14)(p25;q32) (IGH::IRF4). Plasma analysis at diagnosis showed positive circulating tumor DNA (ctDNA) levels in 88% of patients and the ctDNA burden correlated with baseline clinical parameters (LDH and sedimentation rate, p-value <0.01). While clearance of ctDNA levels after primary treatment cycle 1 was observed in 3/6 patients, all patients analyzed at final evaluation of primary treatment showed negative ctDNA, hence correlating with PET-CT imaging. One patient with positive ctDNA at interim also displayed detectable ctDNA (average variant allele frequency (VAF) 6.9%) in the follow-up plasma sample collected 2 years after final evaluation of primary treatment and 25 weeks before clinical manifestation of relapse. Conclusion: In summary, we demonstrate that multi-targeted cfDNA analysis, using a combination of SNVs/indels and SVs candidates identified by WGS analysis, provides a sensitive tool for MRD monitoring and can detect lymphoma relapse earlier than clinical manifestation. [ABSTRACT FROM AUTHOR]

The EarlyCDT‐Lung test is a blood‐based autoantibody assay intended to identify high‐risk individuals for low‐dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT‐Lung test in ever‐smokers. We conducted a nested case‐control study within two prospective cohorts to evaluate the risk‐discriminatory performance of the EarlyCDT‐Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT‐Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT‐Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34‐2.30) for a moderate risk EarlyCDT‐Lung test result and 1.09 (95% CI: 0.48‐2.47) for a high‐risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6‐14) and overall specificity was 92% (95% CI: 87‐96) when considering a high‐risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2‐32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT‐Lung test in identifying the high‐risk subjects in ever‐smokers for lung cancer screening in the EPIC and NSHDS cohorts. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer in the stomach and oesophagus is deadly when discovered at a late stage. There are no good biomarkers for its detection or for making a prognostic prediction. In this study, we evaluate the analysis of cell-free DNA as a prognostic cancer biomarker. Cell-free DNA is DNA released from any tissue to a body fluid. When there is a tumour in the body, some of the cell-free DNA will come from that tumour, and it can be detected in a blood sample. We show that the detection of cell-free DNA from the cancer correlates to a worse prognosis than when no tumour DNA is detected. We also show that the method of analysis is important. Either a tissue biopsy must be included as a validation of the genetic variants detected or analysis of the blood cells or another blood sample after tumour resection needs to be analysed to improve detection. In this longitudinal study, cell-free tumour DNA (a liquid biopsy) from plasma was explored as a prognostic biomarker for gastro-oesophageal cancer. Both tumour-informed and tumour-agnostic approaches for plasma variant filtering were evaluated in 47 participants. This was possible through sequencing of DNA from tissue biopsies from all participants and cell-free DNA from plasma sampled before and after surgery (n = 42), as well as DNA from white blood cells (n = 21) using a custom gene panel with and without unique molecular identifiers (UMIs). A subset of the plasma samples (n = 12) was also assayed with targeted droplet digital PCR (ddPCR). In 17/31 (55%) diagnostic plasma samples, tissue-verified cancer-associated variants could be detected by the gene panel. In the tumour-agnostic approach, 26 participants (59%) had cancer-associated variants, and UMIs were necessary to filter the true variants from the technical artefacts. Additionally, clonal haematopoietic variants could be excluded using the matched white blood cells or follow-up plasma samples. ddPCR detected its targets in 10/12 (83%) and provided an ultra-sensitive method for follow-up. Detectable cancer-associated variants in plasma correlated to a shorter overall survival and shorter time to progression, with a significant correlation for the tumour-informed approaches. In summary, liquid biopsy gene panel sequencing using a tumour-agnostic approach can be applied to all patients regardless of the presence of a tissue biopsy, although this requires UMIs and the exclusion of clonal haematopoietic variants. However, if sequencing data from tumour biopsies are available, a tumour-informed approach improves the value of cell-free tumour DNA as a negative prognostic biomarker in gastro-oesophageal cancer patients. [ABSTRACT FROM AUTHOR]

Background Acute pericarditis is frequently encountered in clinical practice; however, pericarditis as the first presentation of Graves' disease is rare and mainly limited to case reports in the literature. We hereby report a case in which a young patient presented with pericarditis as the first manifestation of Graves' disease. Case summary A 24-year-old male was admitted to hospital with presenting complaint of left-sided chest pain, gradual in onset, 6/10 in intensity, sharp in character, increased by deep breathing and improved by leaning forward. Patient also gave a history of insomnia, unintentional weight loss despite a good appetite, heat intolerance, and anxiety. On clinical examination, the patient had features of thyrotoxicosis, i.e. tachycardia, high volume pulse, and sweaty palms with fine tremors. There was no associated pericardial rub. Neck examination shows diffuse, non-tender goitre. Electrocardiogram findings were consistent with acute pericarditis. His thyroid function tests demonstrated hyperthyroidism and anti-thyroglobulin antibodies were also significantly elevated. Echocardiogram showed preserved left ventricular systolic function and a small global pericardial effusion without any signs of tamponade. He was diagnosed with Graves' disease revealing itself as pericarditis and was started on ibuprofen, beta-blockers, and carbimazole. Patient had marked clinical and biochemical improvement on 3 monthly follow-ups. Discussion Thyro-pericarditis is a rare entity, and limited literature is available regarding this combination. The exact aetiology of Graves associated pericarditis is unknown. There is a possibility of interaction of autoantibodies with receptors on pericardium. Diagnosis is based on a detailed history, clinical examination, supplemented by relevant investigations (elevated free T4 and thyroid receptor antibodies, suppressed thyroid stimulating hormone (TSH) and Imaging via ultrasound). Mainstay of treatment includes non-steroidal anti-inflammatory drugs, beta-blockers, and anti-thyroidal medications. [ABSTRACT FROM AUTHOR]

A recent article in the I BJD i [1] drew attention to the worrying gap between patients' and health professionals' opinions about the safety of topical corticosteroids (TCs). In some SmPCs, potency is described in relation to other TCs, rather than stating the potency of the TC itself. [Extracted from the article]

Classification of pediatric T‐cell acute lymphoblastic leukemia (T‐ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T‐ALL patients were characterized by genome‐wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2‐1, and novel genes in T‐ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL‐TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies. In this study, an integrated methylomic, transcriptomic, and genomic analysis was performed to investigate the biology behind prognostically relevant DNA methylation (CIMP) subgroups in pediatric T‐cell acute lymphoblastic leukemia. We identified differentially expressed genes in the CIMP subgroups including known oncogenic drivers as well as novel genes in T‐ALL biology. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. [ABSTRACT FROM AUTHOR]

Dengue fever has huge public health implications and affects over 100 million people worldwide. This review pictures the current situation of Dengue in Pakistan and presents a review of published literature. Pakistan has seen recurrent epidemics of Dengue Fever recently. Unfortunately, these epidemics are becoming more severe in their clinical manifestation. Pakistan experienced large epidemics of dengue fever during 2008, 2010 and 2011 affecting thousands of people and claiming hundreds of deaths. A comparison of data during these epidemics indicates a shift from mild to a more severe disease, which could be interpreted as an epidemiologic transition pattern in the country. Expansion of Dengue in Pakistan seems to be multifactorial, including the climate change, frequent natural disasters, vector resistance to insecticides and lack of resources. This highlights the need for rigorous vector control. Continuing education of primary care physicians is crucial for early appropriate management to reduce mortality. [ABSTRACT FROM AUTHOR]

Despite increasing availability of therapeutic agents, Sézary syndrome (SS) remains associated with a generally poor prognosis. Typically, patients endure multi-line treatment, frequently with disappointingly short durations of clinical benefit. Time to next treatment (TTNT) measures the interval from the date of commencement of one therapy to the date of initiation of the next line of therapy, and provides a simple and reliable surrogate for duration of clinical benefit outside of clinical trials [ 1 ]. In this multi-centre collaborative study, we review the clinical outcomes of patients with SS/ mycosis fungoides (MF) with B1-2 blood involvement, and compare the treatment efficacy of the currently available systemic therapies using TTNT. In this retrospective analysis, eligible patients were identified from University Hospital Birmingham, Birmingham, Peter MacCallum Cancer Centre, Melbourne, and Hôpital Saint Louis, Paris. Strict eligibility required biopsy-proven MF/SS, with B1-2 blood involvement, newly diagnosed during 1/1/2012 to 31/12/2020. Studied treatment groups include monotherapy and combination therapies of interferon, methotrexate, ECP, HDAC inhibitors, retinoids, monoclonal antibodies, biologicals, chemotherapy, allogeneic stem cell transplant, and best supportive care. The primary endpoint was TTNT, with the aim to compare the efficacy of these systemic therapies. 178 patients were eligible. 77 (43%) were female, median age was 66 (17–94) years. At diagnosis, 35 (20%) patients had Stage IIIB, 131 (74%) Stage IVA and 12 (7%) Stage IVB MF/SS. Large cell transformation was present in 35 (20%) patients at time of diagnosis. A total of 802 treatment lines were delivered, of which 711 were systemic therapies and were included for analysis. Of the 178 patients, 168 received systemic therapy first-line: the most commonly delivered first-line systemic treatments were ECP-containing regimens in 42 (25%) patients (ECP-monotherapy, 17, ECP-based combination therapy, 25), retinoid monotherapy in 34 (19%), interferon monotherapy in 25 (14%) and methotrexate monotherapy in 25 (14%) patients. TTNT and overall survival data will be presented. As a surrogate for duration of clinical benefit, TTNT is a useful endpoint to retrospectively compare the treatment efficacy of currently available systemic therapies for SS/MF with B1-2 blood involvement. Long-term disease control with durable clinical benefit remains the ultimate goal for patients with SS/MF with blood involvement. [ABSTRACT FROM AUTHOR]

Traditionally, Sezary syndrome (SS) has been associated with few therapeutic options and poor prognosis, with 5-year disease-specific survival (DSS) less than one-third in historical cohorts. However, newer therapies and combinations are associated with impressive time-to-next-treatment (TTNT), particularly allogeneic stem-cell transplantation (AlloSCT) and combination therapies notably those including extracorporeal photopheresis. In this multicentre, international study, we explored the prognostic outcomes of 178 patients exclusively managed for SS, diagnosed between 2012 and 2020, and treated in the modern therapeutic era. In this cohort, 58 different therapies were delivered, with 13.5% of patients receiving AlloSCT. Long-term survival exceeded historical reports with 5-year DSS and OS of 56.4% and 53.4% respectively. In those receiving AlloSCT, prognosis was excellent: 5-year DSS and OS were 90.5% and 78.0% respectively. Confirming the results from the Cutaneous Lymphoma International Consortium (CLIC), LDH and LCT had significant prognostic impact. Unlike earlier studies, stage did not have prognostic impact; we speculate that greater relative benefit favours patients with extensive lymphomatous nodal disease (Stage IVA2) compared to historical reports. For patients ineligible for AlloSCT, the prognosis remains relatively poor (5-year DSS 51.4% and OS 49.6%), representing ongoing unmet needs for more effective novel agents and investigation of improved therapeutic combinations., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test., Methods: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided., Results: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model., Conclusion: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung., (© The Author(s) 2023. Published by Oxford University Press.)

TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A -related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca , an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara -/- ; tspearb -/- double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)