Surgical cure of head and neck squamous cell carcinoma (HNSCC) remains hampered by inadequately resected tumors and poor recognition of lesions with malignant potential. BLZ-100 is a ...chlorotoxin-based, tumor-targeting agent that has not yet been studied in HNSCC.
To evaluate BLZ-100 uptake in models of HNSCC and oral dysplasia.
This was an observational study (including sensitivity and specificity analysis) of BLZ-100 uptake in an orthotopic xenograft mouse model of HNSCC and a carcinogen-induced dysplasia model of hamster cheek pouches.
Various HNSCC xenografts were established in the tongues of NOD-scid IL2Rgammanull (NSG) mice. BLZ-100 was intravenously injected and fluorescence uptake was measured. To induce dysplasia, the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) was applied to the cheek pouch of Golden Syrian hamsters for 9 to16 weeks. BLZ-100 was subcutaneously injected, and fluorescence uptake was measured.
The signal-to-background ratio (SBR) of BLZ-100 was measured in tumor xenografts. To calculate the sensitivity and specificity of BLZ-100 uptake, a digital grid was placed over tissue sections and correlative histologic sections to discretely measure fluorescence intensity and presence of tumor; a receiver operating characteristic (ROC) curve was then plotted. In the hamster dysplasia model, cheeks were graded according to dysplasia severity. The SBR of BLZ-100 was compared among dysplasia grades.
In HNSCC xenografts, BLZ-100 demonstrated a mean (SD) SBR of 2.51 (0.47). The ROC curve demonstrated an area under the curve (AUC) of 0.89; an SBR of 2.50 corresponded to 92% sensitivity and 74% specificity. When this analysis was focused on the tumor and nontumor interface, the AUC increased to 0.97; an SBR of 2.50 corresponded to 95% sensitivity and 91% specificity. DMBA treatment of hamster cheek pouches generated lesions representing all grades of dysplasia. The SBR of high-grade dysplasia was significantly greater than that of mild-to-moderate dysplasia (2.31 0.71 vs 1.51 0.34, P = .006).
BLZ-100 is a sensitive and specific marker of HNSCC and can distinguish high-risk from low-risk dysplasia. BLZ-100 has the potential to serve as an intraoperative guide for tumor margin excision and identification of premalignant lesions.
T follicular helper (Tfh) cells play a very important role in mounting a humoral response. Studies conducted in mouse models have revealed with good kinetic and spatial resolution the dynamics of ...these cells in germinal centers (GC) and their cross-talk with B cells upon an immune response. However, whether a similar migratory behavior is performed by human Tfh cells is unclear, as technology to track them in situ has been lacking. In this study, we combined traditional immunohistochemistry and real-time fluorescent imaging approaches on fresh human adenoid slices to provide static and dynamic information on Tfh cells. Our data indicate that GC light zones are composed of two distinct areas in terms of Tfh cell distribution and migration. In the outer GC light zones, Tfh cells migrate actively and with a high ability to form dynamic clusters showing intense and rapid reorganization. In these outer regions, Tfh cells demonstrate multiple interactions between each other. Conversely, in central regions of GC light zones, Tfh cells are much more static, forming long-lasting conjugates. These findings reveal for the first time, to our knowledge, the dynamic behavior whereby Tfh cells migrate in human GC and highlight the heterogeneity of GC for Tfh cell motility.
Small methyl ketones are known to have high octane numbers, impressive knock resistance, and show low emissions of soot, NOx, and unburnt hydrocarbons. However, previous studies have focused on the ...analysis of smaller ketones and 3-pentanone, while the asymmetric 2-pentanone (methyl propyl ketone) has not gained much attention before. Considering ketones as possible fuels or additives, it is of particular importance to fully understand the combustion kinetics and the effect of the functional carbonyl group. Due to the higher energy density in a C5-ketone compared to the potential biofuel 2-butanone, the flame structure and the mole fraction profiles of species formed in 2-pentanone combustion are of high interest, especially to evaluate harmful species formations. In this study, a laminar premixed low-pressure (p = 40 mbar) fuel-rich (ϕ = 1.6) flat flame of 2-pentanone has been analyzed by vacuum-ultraviolet photoionization molecular-beam mass-spectrometry (VUV-PI-MBMS) enabling isomer separation. Quantitative mole fraction profiles of 47 species were obtained and compared to a model consisting of an existing base mechanism and a newly developed high-temperature sub-mechanism for 2-pentanone. High-temperature reactions for 2-pentanone were adapted in analogy to 2-butanone and n-pentane, and the thermochemistry for 2-pentanone and the respective fuel radicals was derived by ab initio calculations. Good agreement was found between experiment and simulation for the first decomposition products, supporting the initial branching reactions of the 2-pentanone sub-mechanism. Also, species indicating low-temperature chemistry in the preheating zone of the flame have been observed. The present measurements of a 2-pentanone flame provide useful validation targets for further kinetic model development.
COVID-19 causes high morbidity and mortality in adult lung transplant (LTX) recipients. Data on COVID-19 in children after LTX is limited. We report the clinical presentation and outcome of ...SARS-CoV-2 infection in 19 pediatric LTX recipients.
Between March 2020 and June 2022, SARS-CoV-2 testing was performed on all pediatric LTX patients with COVID-19 symptoms or contact with a SARS-CoV-2 infected person. Positive patients were prospectively evaluated for symptoms, treatment and outcome. Vaccination status and immune response were recorded.
Nineteen out of 51 pediatric LTX recipients had a SARS-CoV-2 infection. Mean age was 12.3 years (IQR 9-17), 68% were female, 84% had preexisting comorbidities. Mean time between LTX and SARS-CoV-2 infection was 4.8 years (IQR 2-6). No patients experienced severe COVID-19: 11% were asymptomatic, and 89% had mild symptoms, primarily rhinitis (74%), fever (47%), and cough (37%). One SARS-CoV-2 positive patient was hospitalized due to combined fungal and bacterial infection. Mean duration of symptoms was 10.5 days (IQR 3-16), whereas mean period of positivity by antigen test was 21 days (IQR 9-27, p = 0.013). Preventive antiviral therapy was initiated in 3 patients. After a mean follow-up of 2.5 months (IQR 1.1-2.4), no patient reported persistent complaints related to COVID-19. Lung function tests remained stable.
Unlike adult LTX recipients, children and adolescents are at low risk for severe COVID-19, even with risk factors beyond immunosuppression. Our findings cast doubt on the necessity of excessive isolation for these patients and should reassure clinicians and caregivers of LTX patients.
While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant ...morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway.
We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models.
CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice.
Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
Fine-needle aspiration cytology (FNAC) is recommended by international guidelines for the preoperative evaluation of suspicious thyroid nodules >1 cm. Despite robust evidence from endocrine centers ...demonstrating the key role of FNAC results for the indication of surgery, the method is not routinely used in European clinics. The database EUROCRINE
, which was introduced in 2015 with the scope of registering operations of the endocrine system, allows for a large-scale analysis of the current service reality in Europe concerning FNAC use and associated accuracy.
Operations performed to "exclude malignancy", registered from January 2015 to December 2018 in EUROCRINE
, were analyzed. Parameters of accuracy were calculated for FNAC. FNAC results were considered "test positive" in the case of Bethesda category IV, V, and VI, since these categories usually prompt surgical interventions in European centers for thyroid surgery. Bethesda category II and III were considered "test negative".
Of 8,791 operations, 5,780 had preoperative FNAC (65.7%). The overall malignancy rate was 28.3% (2,488/8,791). Malignancy rates were 68.8% for Bethesda VI, 69.9% for Bethesda V, 32.6% for Bethesda IV, 28.2% for III, 20.2% for Bethesda II, and 24.5% for Bethesda I. After exclusion of papillary microcarcinomas (PTMCs), the sensitivity of FNAC was 71.7% and specificity 43.5%, the positive predictive value was 29.1% and the negative predictive value 82.7%.
Although the indication to "exclude malignancy" was the predominant reason that prompted thyroid resection in the present cohort, FNAC was only used in about 65.7% of cases. When performed, FNAC was associated with unexpectedly low accuracy. Interestingly, in Bethesda II, 20.2% of malignant entities were present (13.3% after the exclusion of PTMCs).
The incidence of gastrointestinal infections continues to increase, and infectious colitis contributes significantly to morbidity and mortality worldwide. Carcinoembryonic antigen-related cell ...adhesion molecule 1 (CEACAM1) has been discovered to be strongly involved in the intestinal homeostasis. However, whether intestinal CEACAM1 expression has an impact on the control of infectious colitis remains elusive. Citrobacter rodentium (C. rodentium) is a gram-negative enteric pathogen that induces colonic inflammation in mice, with a critical role for CD4
+
T cell but not CD8
+
T cell immunity to primary infection. Here, we show that Ceacam1
−/−
mice are much more susceptible to C. rodentium infection than wildtype mice, which is mediated by a defect in the intestinal barrier and, surprisingly, by a dysregulated CD8
+
T cell but not CD4
+
T cell response in the colon. CEACAM1 expression is essential for the control of CD8
+
T cell immunity, as CEACAM1 deficiency during C. rodentium infection inhibits CD8
+
T cell exhaustion. We conclude that CEACAM1 is an important regulator of CD8
+
T cell function in the colon, and blocking CEACAM1 signaling to activate CD8
+
T cells may have unforeseen side effects.
Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. ...In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.
Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed.
A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio OR: 1.49, 95% confidence interval CI: 1.03–2.14), reduced to 34% in boys aged <2 years (OR: 1.34, 95% CI: 1.05–1.71) and 25% in boys aged 0–14 years (OR: 1.25, 95% CI: 1.06–1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15–2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00–1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers.
Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.
•Accelerated foetal growth was associated with childhood acute myeloid leukaemia.•The association was marked in large-for-gestational-age newborns.•The association was stronger in infant boys and minimally differentiated leukaemia.•Accelerated foetal growth age-, sex- and subtype- related differentials were showed.•These associations could shed light into the biology of AML and its subtypes.
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