CDK6 is activated by the atypical cyclin I to promote E2F-mediated gene expression and cancer cell proliferation.

Cyclin-dependent kinases (CDKs), together with their cyclin partners, are the master cell cycle regulators. Remarkably, the cyclin family was extended to include atypical cyclins, characterized by distinctive structural features, but their partner CDKs remain elusive. Here, we conducted a yeast two-hybrid screen to identify new atypical cyclin-CDK complexes. We identified 10 new complexes, including a complex between CDK6 and cyclin I (CCNI), which was found to be active against retinoblastoma protein. CCNI upregulation increased the proliferation of breast cancer cells in vitro and in vivo, with a magnitude similar to that seen upon cyclin D upregulation, an effect that was abrogated by CDK6 silencing or palbociclib treatment. In line with these findings, CCNI downregulation led to a decrease in cell number and a reduction in the percentage of cells reaching S phase. Finally, CCNI upregulation correlated with the high expression of E2F target genes in large panels of cancer cell lines and tissue samples from breast cancer patients. In conclusion, we unveil CCNI as a new player in the pathways that activate CDK6, enriching the wiring of cell cycle control.

Characterization of hand forces exerted during non-powered hospital bed pushing and pulling tasks.

Accurate assessment of biomechanical risk associated with pushing/pulling tasks represents a challenging issue, especially in the health system where personnel are often required to maneuver beds and carts. Most studies in this field have been carried out in the laboratory, while few data have been collected under actual working conditions. This study aims to characterize the forces exerted during non-powered hospital bed maneuvering. Twenty participants were required to move a bed (equipped with a customized handlebar to measure exerted forces) along an actual hospital path including straight, turn and maneuver phases. The results show that higher forces are associated with the initial phase (peak and mean values 222 and 68 N) while the straight, turn and maneuvering phases required similar (lower) efforts. The combined effect of left, right and transversal forces suggests that the trunk of the operator might experience axial rotation, thus calling for further investigations of this aspect.

TP53, a gene for colorectal cancer predisposition in the absence of Li-Fraumeni-associated phenotypes.

OBJECTIVE: Germline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC. DESIGN: We analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications. RESULTS: P or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (p<0.0001) (OR=5.7, 95% CI 2.8 to 10.9), none of whom fulfilled the clinical criteria established for TP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants). CONCLUSION: TP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.

Role of POLE and POLD1 in familial cancer.

PURPOSE: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. METHODS: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. RESULTS: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. CONCLUSIONS: Polymerase proofreading-associated syndrome constitutes 0.1-0.4% of familial cancer cases, reaching 0.3-0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.

Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review.

Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared with familial/early-onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.-110G>C, and FOCAD large deletions.

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1- and MSH3-associated polyposes.

Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5-2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.

NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas.

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.

Men and women with Down syndrome exhibit different kinematic (but not spatio-temporal) gait patterns.

BACKGROUND: Gait phenotypes are well documented in people with Down syndrome (pwDS), but sex-related differences are still unexplored. This study investigated the existence of possible differences in spatio-temporal and kinematic parameters of gait between men and women with DS using quantitative three-dimensional gait analysis. METHODS: Gait patterns of 117 pwDS (53 F, 64 M) who underwent a computerised gait analysis from 2002 to 2017 were retrospectively analysed to obtain spatio-temporal gait parameters and kinematics in the sagittal plane at hip, knee and ankle joints, as well as foot progression. RESULTS: Overall, when considered as a single group, the gait patterns found for pwDS confirmed the findings of previous studies. However, when analysed by sex, our data revealed that women with DS exhibit a larger hip flexion at late stance (42% to 54% of the gait cycle) and reduced knee flexion at the beginning of the swing phase (61% to 69% of the gait cycle). In contrast, men are characterised by larger foot extra-rotation angles through most of the stance phase (from 0% to 55% of the gait cycle) and at the end of the swing phase (92% to 99% of the gait cycle). No differences between men and women with DS were found concerning ankle dorsi- plantar-flexion or in all spatio-temporal parameters normalised by individuals' anthropometry, excluding cadence (higher in women). CONCLUSIONS: The findings of the present study highlight the need to investigate gait dysfunctions in pwDS by taking their sex into consideration. Such an approach may be useful not only in gaining a better understanding of the pathophysiology of gait disturbances associated with DS but also in supporting a better orientation of rehabilitative treatments.

Multi-task Dictionary Learning based on Convolutional Neural Networks for Longitudinal Clinical Score Predictions in Alzheimer's Disease.

Computer-aided diagnosis (CAD) systems for medical images are seen as effective tools to improve the efficiency of diagnosis and prognosis of Alzheimers disease (AD). The current state-of-the-art models for many images analyzing tasks are based on Convolutional Neural Networks (CNN). However, the lack of training data is a common challenge in applying CNN to the diagnosis of AD and its prodromal stages. Another challenge for CAD applications is the controversy between the requiring of longitudinal cortical structural information for higher diagnosis/prognosis accuracy and the computing ability for processing varied imaging features. To address these two challenges, we propose a novel computer-aided AD diagnosis system CNN-Multitask Stochastic Coordinate Coding (MSCC) which integrates CNN with transfer learning strategy, a novel MSCC algorithm and our effective AD-related biomarkers-multivariate morphometry statistics (MMS). We applied the novel CNN-MSCC system on the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset to predict future cognitive clinical measures with baseline Hippocampal/Ventricle MMS features and cortical thickness. The experimental results showed that CNN-MSCC achieved superior results. The proposed system may aid in expediting the diagnosis of AD progress, facilitating earlier clinical intervention, and resulting in improved clinical outcomes.

'Timed up and go' and brain atrophy: a preliminary MRI study to assess functional mobility performance in multiple sclerosis.

Motor and cognitive disabilities are related to brain atrophy in multiple sclerosis (MS). 'Timed up and go' (TUG) has been recently tested in MS as functional mobility test, as it is able to evaluate ambulation/coordination-related tasks, as well as cognitive function related to mobility. The objective of this study is to evaluate the relationship between brain volumes and TUG performances. Inclusion criteria were a diagnosis of MS and the ability to walk at least 20 m. TUG was performed using a wearable inertial sensor. Times and velocities of TUG sub-phases were calculated by processing trunk acceleration data. Patients underwent to a brain MRI, and volumes of whole brain, white matter (WM), grey matter (GM), and cortical GM (C) were estimated with SIENAX. Sixty patients were enrolled. Mean age was 41.5 ± 11.6 years and mean EDSS 2.3 ± 1.2. Total TUG duration was correlated to lower WM (ρ = 0.358, p = 0.005) and GM (ρ = 0.309, p = 0.017) volumes. A stronger association with lower GM volume was observed for intermediate (ρ = 0.427, p = 0.001) and final turning (ρ = 0.390, p = 0.002). TUG is a useful tool in a clinical setting as it can not only evaluate patients' disability in terms of impaired functional mobility, but also estimate pathological features, such as grey atrophy.

msBiodat analysis tool, big data analysis for high-throughput experiments.

BACKGROUND: Mass spectrometry (MS) are a group of a high-throughput techniques used to increase knowledge about biomolecules. They produce a large amount of data which is presented as a list of hundreds or thousands of proteins. Filtering those data efficiently is the first step for extracting biologically relevant information. The filtering may increase interest by merging previous data with the data obtained from public databases, resulting in an accurate list of proteins which meet the predetermined conditions. RESULTS: In this article we present msBiodat Analysis Tool, a web-based application thought to approach proteomics to the big data analysis. With this tool, researchers can easily select the most relevant information from their MS experiments using an easy-to-use web interface. An interesting feature of msBiodat analysis tool is the possibility of selecting proteins by its annotation on Gene Ontology using its Gene Id, ensembl or UniProt codes. CONCLUSION: The msBiodat analysis tool is a web-based application that allows researchers with any programming experience to deal with efficient database querying advantages. Its versatility and user-friendly interface makes easy to perform fast and accurate data screening by using complex queries. Once the analysis is finished, the result is delivered by e-mail. msBiodat analysis tool is freely available at http://msbiodata.irb.hr.

[A case report of eccrine porocarcinoma]. / Porocarcinoma eccrino: caso clinic.

Eccrine porocarcinoma (EPC) is a rare malignant skin appendage tumour deriving from the intraepithelial ductal parts of the sweat glands. First described by Pinkus e Mehregan nel 1963 as an epidermotropic eccrine carcinoma, it is rarely reported in medical literature and represents 0.005-0.01% of all skin tumors. We report a case of a 88-year-old Caucasian female presented to our Clinic with an asymptomatic, red-brown , irregularly shaped firm nodule on the left thigh aroused 15 years earlier. The lesion has been excised and histopathological examination showed an "eccrine porocarcinoma aroused on eccrine poroma". Review of the literature on this rare condition and possible therapeutic strategies are also discussed.

Walking improvements with nabiximols in patients with multiple sclerosis.

Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial-temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled-9 male and 11 female-with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial-temporal parameters of gait revealed an increased speed (+15 %, p < 0.001), cadence (+6 %, p < 0.001) and stride length (+10 %, p < 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (p < 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion-extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Bullous pemphigoid induced by m-TOR inhibitors in renal transplant recipients.

BACKGROUND: Bullous pemphigoid (BP) is an acquired autoimmune disease, with typical histology and immune pathological findings, which might be associated with drug therapy. The list of responsible drugs increases every year, but a current literature revision do not include the mammalian target of rapamycin (mTOR) inhibitors. By converse, bullous pemghigoid cases have been described in renal transplant recipients and associated with the allogenic graft itself, causing a cross reaction against the skin, or unbalancing the immune response, through a chronic cell-mediated suppression, non-specifically favouring the autoantibody production. OBJECT AND RESULTS: Two cases of BP occurred, respectively, 10 days to 2 months after the addition to their current regimen of everolimus in a 35-year-old woman and sirolimus in a 65-year-old man. The graft functionality was within normal range. General corticosteroids therapy resistance, immediate improvement after drug discontinuation (dechallenge) and relapse after re-exposure (rechallenge) were striking criteria supporting a causative role of the drugs, grouped in the mTOR inhibitors class. CONCLUSIONS: The diagnosis of drug-induced events is crucial for early management, and particularly bullous eruptions affect patients' health and quality of life. Additional research is necessary to confirm the m-TOR inhibitors association, which exploit the possible mechanisms and eventually point out preventive measures.

Granulomatous reactions after injections of multiple aesthetic micro-implants in temporal combinations: a complication of filler addiction.

BACKGROUND: Granulomatous reaction is a well-known complication following soft filler procedures. However, the diagnosis of filler-induced granulomas may be challenging because of the occasional reluctance of patients to report the previously performed aesthetic procedure. OBJECTIVE: To describe a new clinical situation in which some patients, in the quest for physical perfection, become addicted to multiple sequential cosmetic injections, increasing the risk of adverse reactions. METHODS: We describe three women who developed diffuse facial nodular tumefaction after multiple procedures of filler injections into their face that occurred at different times in the previous years. RESULTS: Histopathology showed a granulomatous reaction including different combined substances that were identified with different types of micro-implants in the same biopsy. CONCLUSIONS: Excessive demand of multiple cosmetic injections may increase the frequency of skin granulomatous reactions and can be included in the spectrum of similar addictive dysmorphophobic behaviours. Histopathology is the best mean to achieve the diagnosis.

Diffuse dermal angiomatosis: a clinical mimicker of vasculitis associated with calciphylaxis and monoclonal gammopathy.

Diffuse dermal angiomatosis is a form of cutaneous reactive angiomatosis characterized clinically by painful erythematous or violaceous lesions with ulcers that may mimic cutaneous vasculitis/vasculopathy. Histologically it shows a benign, diffuse proliferation of endothelial cells with tiny blood vessels in the papillary and reticular dermis. Herein, we report four patients with diffuse dermal angiomatosis in the setting of calciphylaxis and monoclonal gammopathy and review the cases previously published in the literature. Comorbidities and management will also be discussed.

Thalidomide-induced granuloma annulare.

Granuloma annulare (GA) is an acquired, usually self-limiting, asymptomatic granulomatous skin disease with well recognized clinical and histological features that occurs in children and adults generally before the age of 30. Five clinical types are described including the localized, generalized, subcutaneous, perforating, and patch forms. The possible role of immune dysregulation has been pointed out in the pathogenesis of GA, as it has been reported in association with several diseases and conditions like diabetes, thyroid diseases, malignancies, tuberculosis, human immunodeficiency, Epstein Barr and hepatitis C virus infection. Drug-induced GA is a rare presentation, that can appear similar or identical to idiopathic GA. We present a 75-year-old Caucasian man with a violaceous ring-like firm, papular eruption, localized on the dorsal aspect of both hands, with histological features of GA, which subsequently resolved with the discontinuation of thalidomide he had started 1 month earlier for the treatment of a multiple myeloma. The lesions appeared with renewed intensity after resuming a therapy cycle. Jones's algorithm for the diagnosis of adverse drug reactions (ADR) showed a certain association, thus the final diagnosis of thalidomide-induced GA was made.

The effects of low arched feet on foot rotation during gait in children with Down syndrome.

BACKGROUND: In children with Down syndrome (DS) hypotonia and ligament laxity are characteristic features which cause a number of orthopaedic issues, such as flat foot. The aim of this study was to determine if children with flat foot are characterised by an accentuated external foot rotation during walking. METHOD: Fifty-five children with DS and 15 typically developing children recruited as control group were assessed using three-dimensional gait analysis, using an optoelectronic system, force platforms and video recording. Parameters related to foot rotation were identified and calculated and the participants' foot morphology was assessed using the arch index. RESULTS: Data obtained in this study showed that while DS children without flat foot displayed the foot position on the transverse plane globally close to controls during the whole gait cycle, the DS children with flat foot were characterised by higher extra-rotation of the foot in comparison with those without flat foot and controls. CONCLUSIONS: Our results suggest that the presence of flatfoot lead the children with DS to extra-rotate their feet more than the children without flat foot. From a clinical point of view, these results could enhance the rehabilitative programmes in DS.