The value of a head turn in neurolocalization

BACKGROUND: A head turn is a clinically relevant abnormality identified on neurological examination and historically has been an isolated or concomitant sign of ipsilateral forebrain dysfunction. Experimental studies in quadrupedal mammals suggest that changes in head posture may be identified as originating in other parts of the central nervous system (CNS).OBJECTIVES: To identify whether other locations within the CNS could give rise to a head turn and whether the head turn identified is isolated or concomitant with other deviations in head and body posture.ANIMALS: Forty-nine client-owned dogs with a presentation of a head turn, from 6 veterinary referral centers.METHODS: Multicenter observational prospective study including dogs with photographic evidence of a head turn, full neurological examination, and advanced imaging.RESULTS: Of the population, 15/49 had head turn only, 9/49 had head turn and head tilt only, 12/49 had head turn and body turn only, and 13/49 had head turn, head tilt, and body turn. Nearly all dogs with forebrain disease (23/24), and, all with brainstem and cerebellar disease, had an ipsilateral head turn and body turn (if present). In the cerebellar group, all head tilts were contralateral to the lesion location. In the cervical spinal cord group, all head turns, body turns and head tilts were contralateral to the lesion location.CONCLUSION: A head turn, although most likely associated with, is not exclusively seen with forebrain disease. Certain combinations of head turn, head tilt and body turn suggest a neurolocalization other than the forebrain, with appropriate classification needed.</p

Development of a mouse model for spontaneous oral squamous cell carcinoma in Fanconi anemia

Head and neck squamous cell carcinoma; Mouse model; Oral mucosaCarcinoma de células escamosas de cabeza y cuello; Modelo de ratón; Mucosa oralCarcinoma de cèl·lules escamoses de cap i coll; Model de ratolí; Mucosa oralFanconi anemia (FA) patients frequently develop oral squamous cell carcinoma (OSCC). This cancer in FA patients is diagnosed within the first 3–4 decades of life, very often preceded by lesions that suffer a malignant transformation. In addition, they respond poorly to current treatments due to toxicity or multiple recurrences. Translational research on new chemopreventive agents and therapeutic strategies has been unsuccessful partly due to scarcity of disease models or failure to fully reproduce the disease. Here we report that Fanca gene knockout mice (Fanca-/-) frequently display pre-malignant lesions in the oral cavity. Moreover, when these animals were crossed with animals having conditional deletion of Trp53 gene in oral mucosa (K14cre;Trp53F2-10/F2-10), they spontaneously developed OSCC with high penetrance and a median latency of less than ten months. Tumors were well differentiated and expressed markers of squamous differentiation, such as keratins K5 and K10. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and Fanca-/-;K14cre;Trp53F2-10/F2-10 mice constitute the first animal model of spontaneous OSCC in FA.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects CB16/12/00228/CIBERONC, PI18/00263 and P121/00208 and co-funded by FEDER and the European Union; and grants from the Spanish Fundacion Anemia de Fanconi and Fanconi Anemia Research Fund USA. J.P. was supported by a FEDER co-funded grant (ref PEJ2018-002040-A) from the Ministerio de Ciencia, Innovación y Universidades. J.O. was supported by a FEDER co-funded grant (ref PEJ-2019-TL_BMD-12905) from the Comunidad de Madrid. The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication

Early Diagnosis of Oral Cancer and Lesions in Fanconi Anemia Patients: A Prospective and Longitudinal Study Using Saliva and Plasma

Fanconi anemia; Cancer gene; SalivaAnèmia de Fanconi; Gen del càncer; SalivaAnemia de Fanconi; Gen del cáncer; SalivaFanconi anemia (FA) patients display an exacerbated risk of oral squamous cell carcinoma (OSCC) and oral potentially malignant lesions (OPMLs) at early ages. As patients have defects in their DNA repair mechanisms, standard-of-care treatments for OSCC such as radiotherapy and chemotherapy, give rise to severe toxicities. New methods for early diagnosis are urgently needed to allow for treatment in early disease stages and achieve better clinical outcomes. We conducted a prospective, longitudinal study wherein liquid biopsies from sixteen patients with no clinical diagnoses of OPML and/or OSCC were analyzed for the presence of mutations in cancer genes. The DNA from saliva and plasma were sequentially collected and deep-sequenced, and the clinical evaluation followed over a median time of approximately 2 years. In 9/16 FA patients, we detected mutations in cancer genes (mainly TP53) with minor allele frequencies (MAF) of down to 0.07%. Importantly, all patients that had mutations and clinical follow-up data after mutation detection (n = 6) developed oral precursor lesions or OSCC. The lead-time between mutation detection and tumor diagnosis ranged from 23 to 630 days. Strikingly, FA patients without mutations displayed a significantly lower risk of developing precursor lesions or OSCCs. Therefore, our diagnostic approach could help to stratify FA patients into risk groups, which would allow for closer surveillance for OSCCs or precursor lesions.This study was funded by Instituto de Salud Carlos III (ISCIII) through the projects CB16/12/00228/CIBERONC, PI18/00263 and P121/00208; co-funded by FEDER and the European Union; and funded by a grant from the Spanish Fundacion Anemia de Fanconi. J.P. was supported by a FEDER co-funded grant (ref. PEJ2018-002040-A) from the Ministerio de Ciencia e Innovación. J.O. was supported by a FEDER co-funded grant (ref. PEJ-2019-TL_BMD-12905) from the Comunidad de Madrid. The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication

The population-based Barcelona-Asymptomatic Intracranial Atherosclerosis Study (ASIA) : rationale and design

Large-artery intracranial atherosclerosis may be the most frequent cause of ischemic stroke worldwide. Traditional approaches have attempted to target the disease when it is already symptomatic. However, early detection of intracranial atherosclerosis may allow therapeutic intervention while the disease is still asymptomatic. The prevalence and natural history of asymptomatic intracranial atherosclerosis in Caucasians remain unclear. The aims of the Barcelona- AS ymptomatic I ntracranial A therosclerosis (ASIA) study are (1) to determine the prevalence of ASIA in a moderate-high vascular risk population, (2) to study its prognostic impact on the risk of suffering future major ischemic events, and (3) to identify predictors of the development, progression and clinical expression of this condition. Cross-over and cohort, population-based study. A randomly selected representative sample of 1,503 subjects with a mild-moderate-high vascular risk (as defined by a REGICOR score ≥ 5%) and with neither a history of cerebrovascular nor ischemic heart disease will be studied. At baseline, all individuals will undergo extracranial and transcranial Color-Coded Duplex (TCCD) ultrasound examinations to detect presence and severity of extra and intracranial atherosclerosis. Intracranial stenoses will be assessed by magnetic resonance angiography (MRA). Clinical and demographic variables will be recorded and blood samples will be drawn to investigate clinical, biological and genetic factors associated with the presence of ASIA. A long-term clinical and sonographic follow-up will be conducted thereafter to identify predictors of disease progression and of incident vascular events. The Barcelona-ASIA is a population-based study aiming to evaluate the prevalence and clinical importance of asymptomatic intracranial large-artery atherosclerosis in Caucasians. The ASIA project may provide a unique scientific resource to better understand the dynamics of intracranial atherosclerosis from its early stages and to identify new potential therapeutic targets for this condition

Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer

Cancer; Predictive markersCàncer; Marcadors predictiusCáncer; Marcadores predictivosLiquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types

Clinical features, diagnosis, and survival analysis of dogs with glioma

Background: Gliomas in dogs remain poorly understood. Objectives: To characterize the clinicopathologic findings, diagnostic imaging features and survival of a large sample of dogs with glioma using the Comparative Brain Tumor Consortium diagnostic classification. Animals: Ninety-one dogs with histopathological diagnosis of glioma. Methods: Multicentric retrospective case series. Signalment, clinicopathologic findings, diagnostic imaging characteristics, treatment, and outcome were used. Tumors were reclassified according to the new canine glioma diagnostic scheme. Results: No associations were found between clinicopathologic findings or survival and tumor type or grade. However, definitive treatments provided significantly (P = .03) improved median survival time (84 days; 95% confidence interval [CI], 45-190) compared to palliative treatment (26 days; 95% CI, 11-54). On magnetic resonance imaging (MRI), oligodendrogliomas were associated with smooth margins and T1-weighted hypointensity compared to astrocytomas (odds ratio [OR], 42.5; 95% CI, 2.42-744.97; P = .04; OR, 45.5; 95% CI, 5.78-333.33; P &lt; .001, respectively) and undefined gliomas (OR, 84; 95% CI, 3.43-999.99; P = .02; OR, 32.3; 95% CI, 2.51-500.00; P = .008, respectively) and were more commonly in contact with the ventricles than astrocytomas (OR, 7.47; 95% CI, 1.03-53.95; P = .049). Tumor spread to neighboring brain structures was associated with high-grade glioma (OR, 6.02; 95% CI, 1.06-34.48; P = .04). Conclusions and Clinical Importance: Dogs with gliomas have poor outcomes, but risk factors identified in survival analysis inform prognosis and the newly identified MRI characteristics could refine diagnosis of tumor type and grade

Development of a mouse model for spontaneous oral squamous cell carcinoma in Fanconi anemia

Altres ajuts: European Regional Development Fund (FEDER); the European Union; the Spanish Fundacion Anemia de Fanconi and Fanconi Anemia Research Fund USA; Comunidad de Madrid (ref PEJ-2019-TL_BMD-12905).Fanconi anemia (FA) patients frequently develop oral squamous cell carcinoma (OSCC). This cancer in FA patients is diagnosed within the first 3-4 decades of life, very often preceded by lesions that suffer a malignant transformation. In addition, they respond poorly to current treatments due to toxicity or multiple recurrences. Translational research on new chemopreventive agents and therapeutic strategies has been unsuccessful partly due to scarcity of disease models or failure to fully reproduce the disease. Here we report that Fanca gene knockout mice (Fanca ) frequently display pre-malignant lesions in the oral cavity. Moreover, when these animals were crossed with animals having conditional deletion of Trp53 gene in oral mucosa (K14cre;Trp53), they spontaneously developed OSCC with high penetrance and a median latency of less than ten months. Tumors were well differentiated and expressed markers of squamous differentiation, such as keratins K5 and K10. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and Fanca;K14cre;Trp53 mice constitute the first animal model of spontaneous OSCC in FA

Early-Stage Breast Cancer Detection in Breast Milk

Breast cancer; Breast milkCáncer de mama; Leche maternaCàncer de mama; Llet maternaBreast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection. Significance: For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image.We thank the patients who participated in the study and donated samples for analysis for their generous contribution, with particular thanks to the first patient, Maite, and her daughter Àneu, who inspired us to initiate this study (oral consent to name the patient and her daughter was provided by the patient, and her legal partner provided written consent after patient's exitus). We are grateful to Javier Carmona for his valuable contributions and support in the manuscript's conceptualization, preparation, and revision. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment and the CERCA Programme from the Generalitat de Catalunya for their support of this research. The authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) for the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033). This research is financially supported by the “El paseíco de la mama” Foundation. C. Saura was the recipient of a II FERO-GHD grant from the FERO Foundation (FERO/5086), a Junior Clinical award from the Spanish Association Against Cancer Foundation (FAECC; CLJUN212026ORTI), and a SEOM-Daiichi Sankyo grant for its support on the Breast Cancer Research Projects 2021 (SEOM/FECMA2022) and received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00198) and from the Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER), cofunded by the European Union (PI21/01020). C. Ortiz was the recipient of a Junior Clinician award from the FAECC (CLJUN212026ORTI) and a SEOM-Daiichi Sankyo grant for its support on the Breast Cancer Research Projects 2021 (SEOM/FECMA2022), and received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00198). N. Bayó-Puxan received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00205), MCIN/AEI/10.13039/501100011033 (GPE2022-001029) and MCIN/AEI/10.130.39/501100011033, and the European Union “Next GenerationEU/PRTR” (ECT2020-000827). J.M. Miquel received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00205), MCIN/AEI/10.130.39/501100011033, and the European Union “Next GenerationEU/PRTR” (ECT2020-000827). J. Arribas is funded by the Breast Cancer Research Foundation (BCRF-23-008), Instituto de Salud Carlos III (project reference numbers AC15/00062, CB16/12/00449, and PI22/00001), and the European Commission under the framework of the ERA-NET TRANSCAN-2 initiative cofinanced by FEDER and Asociación Española Contra el Cáncer. A. Vivancos was the recipient of a project award from the FAECC (AVP/18/AECC/3219) and received funding from the Advanced Molecular Diagnostic (DIAMAV) program from the FERO Foundation (8361) and from ISDIN for supporting the development of liquid biopsy applications at the Cancer Genomics Lab (1848). M. Sansó was the recipient of a II FERO-GHD grant from the FERO Foundation (FERO/5086) and an investigator award from the FAECC (INVES19056SANS), and received funding from the Health Research Institute of the Balearic Islands (IdISBa), the RADIX-Janssen program (RADIX/JANSSEN21/01), and the Miguel Servet Program funded by the ISCIII (CP22/00131)

Way forward for using in vitro neurotoxicity models in testing strategy: update of FP6 integrated Project "ACUTETOX"

[Purpose]: To develop a strategy in which general cytotoxicity, together with e.g. organspecific endpoints and biokinetic features, are taken into consideration in the in vitro prediction of oral acute systemic toxicity. This presentation summarizes published results from the ACuteTox Project (Forsby et al., in press; Suñol et al., 2009).[Methods]: A set of reference compounds were tested against approximately 50 neuronal endpoints using neural cell lines, and primary neuronal and reaggregate cultures. In vitro data were compared with acute human lethal blood concentration (LC50).[Results]: The testing of a subset of 20 reference compounds revealed that GABAA receptor (GABAAR) function, acetylcholine esterase activity, cell membrane potencial (CMP), glucose uptake, total RNA expression and altered gene expression of NF-H, GFAP, MBP, HSP32 and caspase-3 were the best endpoints. Thirty-six additional chemicals were analyzed against this combined battery of tests. No single endpoint was shown to give a perfect improvement in the in vitro- in vivo correlation. The functional neuronal endpoints GABAAR and cell membrane potential measured in primary neuronal cultures and in the SH-SY5Y cell line identified a high number of chemicals as neurotoxic compounds. A combined analysis of NF-H, GFAP, MBP and HSP32 mRNA expression, glucose uptake and total RNA synthesis measured in aggregated embryonic brain cells was the most sensitive assay. Alteration of caspase-3 mRNA expression in cultured cerebellar granule cells gave a good estimate of the LC50 for a small set of referente chemicals.[Conclusions]: All outliers in the correlation analysis between basal cytotoxicity and human LC50, except atropine and acetonitrile, were identified as alerts by at least one of the endpoints in the test battery. The genomic biomarkers NF-H, GFAP, MBA, HSP32 and caspase-3 were very sensitive endpoints. They showed the possibilities to use high throughput quantitative microarray analyses for toxicological screening. The combined CMP and GABAAR assays correctly identified outliers.EU FP6-512051, FIS PI06-1212 (Spain),The Animal Welfare Agency and The Foundation for research without animal experiments (Sweden