Multiple effects of CDK4/6 inhibition in cancer: From cell cycle arrest to immunomodulation

Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation. CDK4/6 are cyclin-dependent kinases activated in response to proliferative signaling, which induce RB hyper-phosphorylation and hence activation of E2F transcription factors, thus promoting cell cycle progression through the S phase. Pharmacologic inhibition of CDK4/6 by palbociclib, ribociclib, or abemaciclib has been showing promising activity in multiple cancers with the best results achieved in combination with other agents. Indeed, CDK4/6 inhibitors are currently approved in combination with endocrine therapy for the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. Moreover, a number of clinical trials are currently underway to test the efficacy of combining CDK4/6 inhibitors with different drugs not only in breast but also in other types of cancer. Beyond the inhibition of cell proliferation, CDK4/6 inhibitors have recently revealed new effects on cancer cells and on tumor microenvironment. In particular, it has been reported that these agents induce a senescent-like phenotype, impact on cell metabolism and exert both immunomodulatory and immunogenic effects. Here we describe recent data on the anti-tumor effects of CDK4/6 inhibitors as single agents or in combined therapies, focusing in particular on their metabolic and immunomodulatory activities

Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies

Transactive response DNA-binding protein 43 (TDP-43) mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically localized form of TDP-43 (TDP-43-ΔNLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive, and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test, and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-ΔNLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. To determine whether these symptoms were reversible, we suppressed Tg expression for 14 d in 1.5-month-old mice showing an established behavioral phenotype but modest neurodegeneration and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When Tg expression was suppressed in 6.5-month-old mice showing overt neurodegeneration, motor deficits were irreversible. These results indicate that TDP-43-ΔNLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies.Fil: Alfieri, Julio Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Pino, Natalia S.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Müller Igaz, Lionel Ivan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Native Hypovitaminosis D in CKD Patients : From Experimental Evidence to Clinical Practice

Native hypovitaminosis D (n-hVITD) is frequently found from the early stages of chronic kidney disease (CKD) and its prevalence increases with CKD progression. Even if the implications of n-hVITD in chronic kidney disease-mineral bone disorder (CKD-MBD) have been extensively characterized in the literature, there is a lot of debate nowadays about the so called "unconventional effects" of native vitamin D (25(OH)VitD) supplementation in CKD patients. In this review, highlights of the dimension of the problem of n-hVITD in CKD stages 2-5 ND patients will be presented. In addition, it will focus on the "unconventional effects" of 25(OH)VitD supplementation, the clinical impact of n-hVITD and the most significant interventional studies regarding 25(OH)VitD supplementation in CKD stages 2-5 ND

Agroecosystem Performances of Livestock Farms in a Mountain Area of Sicily

Agroecosystem performance indicators (APIs) represent instruments for studying agroecosystem performance via an input/output approach and a knowledge base, with the aim of improving the sustainability level of the farm\u27s activity (Tellarini & Caporali, 2000). This research used APIs to evaluate the influence of stocking rate on the performance (in terms of energy) of farms in a mountainous area of northern Sicily, Italy

Molecular mechanism of APC/C activation by mitotic phosphorylation.

In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our results reveal the mechanism for the regulation of mitotic APC/C by phosphorylation and provide a rationale for the development of selective inhibitors of this state

Tailoring treatment of salivary duct carcinoma (SDC) by liquid biopsy: ARv7 expression in circulating tumor cells

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Spontaneous bacterial peritonitis due to carbapenemase-producing Enterobacteriaceae: Etiology and antibiotic treatment

Carbapenem antibiotics were first introduced in the 1980s and have long been considered the most active agents for the treatment of multidrug-resistant gram-negative bacteria. Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged as organisms causing spontaneous bacterial peritonitis. Infections caused by CRE have shown a higher mortality rate than those caused by bacteria sensitive to carbapenem antibiotics. Current antibiotic guidelines for the treatment of spontaneous bacterial peritonitis are insufficient, and rapid de-escalation of empiric antibiotic treatment is not widely recognized. This review summarizes the molecular characteristics, epidemiology and possible treatment of spontaneous bacterial peritonitis caused by CRE

Molecular basis of APC/C regulation by the spindle assembly checkpoint.

In the dividing eukaryotic cell, the spindle assembly checkpoint (SAC) ensures that each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex (APC/C), the E3 ubiquitin ligase responsible for initiating chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), which inhibits the APC/C and delays chromosome segregation. By cryo-electron microscopy, here we determine the near-atomic resolution structure of a human APC/C–MCC complex (APC/C(MCC)). Degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit responsible for substrate interactions. BubR1 also obstructs binding of the initiating E2 enzyme UbcH10 to repress APC/C ubiquitination activity. Conformational variability of the complex enables UbcH10 association, and structural analysis shows how the Cdc20 subunit intrinsic to the MCC (Cdc20(MCC)) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced

Serological survey for mycoplasma hyopneumoniae in free-living wild boars from Campos Gerais region, Paraná, Brasil.

The south region of Brazil was responsible for 80.3% of total pork meat export in the country in 2015 (2), with the state of Paraná accountable for 21% of the total pork meat production in that year. Pig farming represented 5.7% of the agricultural gross income of the state in 2016, and the Campos Gerais region accounted for 13.2% of that amount (2). Wild boars are the result of crossbreeding between boars (Sus scrofa scrofa) and domestic pigs (Sus scrofa domesticus). The total population of free-living wild boars in Brazil is unknown (11), but sightings are common in the crop fields and near livestock farms of different regions of Paraná state, including in Campos Gerais (9). The health status of pig herds is important in terms of maintenance and growth of pork production and exports and there are evidences that domestic pigs and wild boars share vulnerabilities in certain viral and bacterial pathogen infections (12). Mycoplasma hyopneumoniae (Mhyo) is a bacterial pathogen that causes porcine enzootic pneumonia, an economically important disease that affects both domestic pigs and wild boars. Mhyo was first isolated in 1965, simultaneously in the United Kingdom (UK) and in the United States of America (USA) (3; 7). Economic losses related to this pathogen and mycoplasmal pneumonia in pig herds are associated with decreased feed efficiency, reduced average of the daily weight gain, and increased medication costs. Thus, knowing the health status of free-living wild boars in the regards of this pathogen is important for the biosecurity of the pork production. The aim of this study was to investigate antibodies against Mhyo in serum samples of free-living wild boars in Campos Gerais region