RB1 dual role in proliferation and apoptosis: Cell fate control and implications for cancer therapy

Inactivation of the retinoblastoma (RB1) tumor suppressor is one of the most frequent and early recognized molecular hallmarks of cancer. RB1, although mainly studied for its role in the regulation of cell cycle, emerged as a key regulator of many biological processes. Among these, RB1 has been implicated in the regulation of apoptosis, the alteration of which underlies both cancer development and resistance to therapy. RB1 role in apoptosis, however, is still controversial because, depending on the context, the apoptotic cues, and its own status, RB1 can act either by inhibiting or promoting apoptosis. Moreover, the mechanisms whereby RB1 controls both proliferation and apoptosis in a coordinated manner are only now beginning to be unraveled. Here, by reviewing the main studies assessing the effect of RB1 status and modulation on these processes, we provide an overview of the possible underlying molecular mechanisms whereby RB1, and its family members, dictate cell fate in various contexts. We also describe the current antitumoral strategies aimed at the use of RB1 as predictive, prognostic and therapeutic target in cancer. A thorough understanding of RB1 function in controlling cell fate determination is crucial for a successful translation of RB1 status assessment in the clinical setting.     

Non genomic loss of function of tumor suppressors in CML: BCR-ABL promotes IκBα mediated p53 nuclear exclusion

Tumor suppressor function can be modulated by subtle variation of expression levels, proper cellular compartmentalization and post-translational modifications, such as phosphorylation, acetylation and sumoylation. The non-genomic loss of function of tumor suppressors offers a challenging therapeutic opportunity. The reactivation of a tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. The identification of mechanisms that affect tumor suppressor functions is therefore essential. In this work, we show that BCR-ABL promotes the accumulation of the NFKBIA gene product, IκBα, in the cytosol through physical interaction and stabilization of the protein. Furthermore, BCR-ABL/IκBα complex acts as a scaffold protein favoring p53 nuclear exclusion. We therefore identify a novel BCR-ABL/IκBα/p53 network, whereby BCR-ABL functionally inactivates a key tumor suppressor.     

Subependymal nodules and giant cell tumours in tuberous sclerosis complex patients: prevalence on MRI in relation to gene mutation

Purpose

The purpose of this study was to estimate the association among the presence of subependymal nodules (SENs), subependymal giant cell tumours (SGCTs) and gene mutation in tuberous sclerosis complex (TSC) patients.

Methods

Clinical records and images of 81 TSC patients were retrospectively reviewed by two neuroradiologists in consensus. All patients were assessed for gene mutations and were categorized as TSC1 or TSC2 mutation carriers, or no-mutations-identified (NMI) patients. They underwent a brain magnetic resonance imaging (MRI) using 0.1 mmol/kg of gadobutrol. Any enhancing SEN?≥?1 cm and placed near the foramen of Monro was considered SGCT. Two MRI follow-up exams for each patient with SGCT were evaluated to assess tumour growth using Wilcoxon and chi-squared tests.

Results

Of 81 patients, 44 (54 %) were TSC2 mutation carriers, 20 (25 %) TSC1 and 17 (21 %) NMI. Nine (11 %) had a unilateral and three (4 %) a bilateral SGCT. Fifty of 81 patients (62 %) showed at least one SEN. None of the 31 patients without SEN showed SGCTs, whilst 12 (24 %) of the 50 patients with at least one SEN showed SGCTs (p?=?0.003). The association between the presence of SGCT or SEN and gene mutation was not significant (p?=?0.251 and p?=?0.187, respectively). At follow-up, the median SGCT diameter increased from 14 to 15 mm (p?=?0.017), whilst the median SGCT volume increased from 589 to 791 mm³ (p?=?0.006).

Conclusions

TSC patients with SENs are more likely to present with SGCT than those without SENs, in particular for TSC2 mutation carriers. The SGCT growth rate may be missed if based on the diameter instead of on the volume.     

The applause sign in cortical and cortical-subcortical dementia

The “applause sign” is a motor perseveration described in focal and neurodegenerative disorders and characterized by fronto-subcortical dysfunction. Most previous formal investigations focused on Parkinson’s disease or progressive supranuclear palsy. We assessed the prevalence of the applause sign in patients affected by Alzheimer’s disease (AD), Lewy body dementia (LBD), corticobasal syndrome (CBS), and posterior cortical atrophy (PCA), with the aim to verify its contribution to the differential diagnosis. We enrolled 20 patients with AD, 20 with LBD, 16 with CBS, and ten with PCA, and 30 healthy controls. The three clap test (TCT) was used to elicit the applause sign, and was scored by raters blinded to the diagnosis. Correlation with motor (extrapyramidal) and cognitive measures was also performed. A maximum 40 % prevalence of a positive applause sign was found in the two parkinsonian syndromes, which could be discriminated from the two cortical groups with a positive predictive value of 82 % and a negative predictive value of 55 %. According to our findings, a diagnosis of LBD or CBS, rather than of AD or PCA, is highly probable in the presence of an abnormal TCP, but cannot be ruled out based on a negative result. No relevant correlates emerged that could clarify the origin and nature of the applause sign.     

An unusual form of the association binding kinetics of N-[3H]methylscopolamine to the split muscarinic M2trunk/M2tail receptor

The muscarinic M(2) receptor was split at the third cytoplasmic loop into two fragments: the one containing the first five transmembrane regions and the N-terminal part of the third cytoplasmic loop was named M(2trunk), while the other, which contained the last two transmembrane regions and the C-terminal part of the third cytoplasmic loop, was named M(2tail). As seen in many other G protein-coupled receptors, when these two fragments were transfected together in COS-7 cells they rescued the pharmacological profile and the functional activity of the wild-type M(2) receptor. Conversely, N-[(3)H]methylscopolamine ([(3)H]NMS) association binding experiments showed a substantial difference between the wild-type M(2) and the split M(2trunk)/M(2tail) receptors. The progression of the association binding kinetic of the M(2trunk)/M(2tail) receptor was strictly dependent upon the amount of the fragment DNA transfected. When the amount of transfected DNA was 4 microg/plate and the B(max) of [(3)H]NMS at equilibrium was around 200 fmol/mg protein the form of the association was that of classical saturation, but when the amount of transfected DNA was lower the [(3)H]NMS association reached a maximum binding point and then declined to a lower equilibrium binding level. The form of the association was temperature-dependent: as the temperature was lowered, the maximum binding point tended to be higher. We suggest that this peculiar form of the [(3)H]NMS association binding to the muscarinic M(2trunk)/M(2tail) receptor is attributable to a less stable interaction between the trunk and the tail fragments of the split receptor.     

Role of C-reactive protein in cerebrovascular disease: a critical review

C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.     

An Eight-Year Survey on Aflatoxin B1 Indicates High Feed Safety in Animal Feed and Forages in Northern Italy

Aflatoxins (AFs) remain the main concern for the agricultural and dairy industries due to their effects on the performances and quality of livestock production. Aflatoxins are always unavoidable and should be monitored. The objective of this paper is to bring to light a significant volume of data on AF contamination in several animal feed ingredients in Northern Italy. The Regional Breeders Association of Lombardy has been conducting a survey program to monitor mycotoxin contamination in animal feeds, and in this paper, we present data relating to AFB1 contamination. In most cases (95%), the concentrations were low enough to ensure compliance with the European Union’s (EU’s) maximum admitted levels for animal feed ingredients. However, the data show a high variability in AF contamination between different matrices and, within the same matrix, a high variability year over year. High levels of AFs were detected in maize and cotton, especially in the central part of the second decade of this century, i.e., 2015–2018, which has shown a higher risk of AF contamination in feed materials in Northern Italy. Variability due to climate change and the international commodity market affect future prospects to predict the presence of AFs. Supplier monitoring and control and reduced buying of contaminated raw materials, as well as performing analyses of each batch, help reduce AF spread.     

Customized Titanium Mesh for Guided Bone Regeneration with Autologous Bone and Xenograft

The augmentation of the alveolar crest after the loss of one or several teeth can be carried out using different bone augmentation techniques. These techniques include bone distraction, ridge expansion, bone block grafts, etc. Guided bone regeneration is an alternative to increase the volume of the hard tissues for the subsequent placement of the implants in the optimal three-dimensional position. The objective of this paper is to show a case report of the use of customized titanium mesh for posterior vertical bone regeneration. Case report and Results: A 59-year-old woman comes to rehabilitate edentulous spaces with implants. After taking the anamnesis and the intra and extraoral exploration, a vertical and horizontal bone defect is observed in the third quadrant. After the radiological study with CBCT, a bone height of 6.04 mm to the inferior alveolar nerve and a width of the bone crest of 3.95 mm was observed. It was decided to carry out a regeneration with a preformed titanium mesh (Avinent^®, Santpedor, Spain) and four microscrews (Avinent^®, Santpedor, Spain). The flap was closed without tension. Regular check-ups were performed without complications. At 7 months, the mesh was removed and two osteoingrated implants (Avinent^®, Santpedor, Spain) were placed with a torque greater than 45 N/cm and an ISQ of 82 and 57 N/cm, respectively. The bone gain obtained was 1.84 and 1.92 mm in width and 4.2 and 3.78 mm in height for positions 3.5 and 3.6. The newly formed bone, obtained by trephine, was well-structured and histologically indistinguishable from the previous bone. Conclusion: The use of a customized pre-formed titanium mesh together with the mixture of autologous bone and xenograft is a feasible and predictable technique for vertical bone regeneration.