Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among ...those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell-cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.
Lithography-based ceramics manufacturing (LCM) processes enable the sophisticated 3 dimensional (3D) shaping of ceramics by additive manufacturing (AM). The build-up occurs, like many other AM ...processes, layer by layer, and is initiated by light. The built-in digital mirror device (DMD) enables the specific exposure of desired pixels for every layer, giving as a consequence a first estimation of the printing resolution in the x and y axes. In this work, a commercial zirconia slurry and the CeraFab 7500, both from Lithoz GmbH (Vienna, Austria), were used to investigate the potential of reaching this resolution. The results showed that the precision of a part is strongly dependent on the applied exposure energy. Higher exposure energies resulted in oversized dimensions of a part, whereas too low energy was not able to guarantee the formation of a stable part. Furthermore, the investigation of the layer thickness showed that the applied exposure energy (mJ/cm
) was acting in a volume, and the impact is visible in x, y, and z dimensions. The lowest applied exposure energy was 83 mJ/cm
and showed the most accurate results for a layer thickness of 25 μm. With this energy, holes and gaps smaller than 500 μm could be printed; however, the measurements differed significantly from the dimensions defined in the design. Holes and gaps larger than 500 μm showed deviations smaller than 50 μm from the design and could be printed reliably. The thinnest printable gaps were between 100 and 200 μm. Concerning the wall thickness, the experiments were conducted to a height of 1 cm. Taking into account the stability and deformation of the walls as well, the best results after sintering were achieved with thicknesses of 200-300 μm.
In recent times, high-throughput screening analyses have broadly defined the RNA cellular targets of TDP-43, a nuclear factor involved in neurodegeneration. A common outcome of all these studies is ...that changing the expression levels of this protein can alter the expression of several hundred RNAs within cells. What still remains to be clarified is which changes represent direct cellular targets of TDP-43 or just secondary variations due to the general role played by this protein in RNA metabolism. Using an HTS-based splicing junction analysis we identified at least six bona fide splicing events that are consistent with being controlled by TDP-43. Validation of the data, both in neuronal and non-neuronal cell lines demonstrated that TDP-43 substantially alters the levels of isoform expression in four genes potentially important for neuropathology: MADD/IG20, STAG2, FNIP1 and BRD8. For MADD/IG20 and STAG2, these changes could also be confirmed at the protein level. These alterations were also observed in a cellular model that successfully mimics TDP-43 loss of function effects following its aggregation. Most importantly, our study demonstrates that cell cycle alterations induced by TDP-43 knockdown can be recovered by restoring the STAG2, an important component of the cohesin complex, normal splicing profile.
Toll-like receptor 2 (TLR2) expressed on myeloid cells mediates the recognition of harmful molecules belonging to invading pathogens or host damaged tissues, leading to inflammation. For this ability ...to activate immune responses, TLR2 has been considered a player in anti-cancer immunity. Therefore, TLR2 agonists have been used as adjuvants for anti-cancer immunotherapies. However, TLR2 is also expressed on neoplastic cells from different malignancies and promotes their proliferation through activation of the myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. Furthermore, its activation on regulatory immune cells may contribute to the generation of an immunosuppressive microenvironment and of the pre-metastatic niche, promoting cancer progression. Thus, TLR2 represents a double-edge sword, whose role in cancer needs to be carefully understood for the setup of effective therapies. In this review, we discuss the divergent effects induced by TLR2 activation in different immune cell populations, cancer cells, and cancer stem cells. Moreover, we analyze the stimuli that lead to its activation in the tumor microenvironment, addressing the role of danger, pathogen, and microbiota-associated molecular patterns and their modulation during cancer treatments. This information will contribute to the scientific debate on the use of TLR2 agonists or antagonists in cancer treatment and pave the way for new therapeutic avenues.
A strictly gluten-free diet (GFD) is the basis for managing celiac disease (CD). Numerous studies have reported nutritional deficiencies/imbalances ascribable to a GFD. The aim of this review is to ...describe nutritional deficiencies observed in children with celiac disease on a GFD, to discuss the clinical consequences related to these nutritional imbalances, and to identify strategies that may be adopted to treat them.
We reviewed the MEDLINE and EMBASE databases between January 1998 and January 2019.
Children are, regardless of whether they are on a gluten-free diet or not, at risk of consuming too much fat and insufficient fiber, iron, vitamin D, and calcium. These imbalances may be exacerbated when children are on a gluten-free diet. In particular, the intake of folate, magnesium, zinc, and foods with a high glycemic index in children with CD who are on a GFD is significantly altered.
Therapeutic protocols should include nutritional education to help teach subjects affected by disorders such as CD the importance of labels, the choice of foods, and the combination of macro- and micronutrients. Children with CD on a GFD should be encouraged to rotate pseudo-cereals, consume gluten-free commercial products that have been fortified or enriched, and use foods that are local and naturally gluten-free.
Sensor-based technological therapy devices may be good candidates for neuromotor rehabilitation of people with Multiple Sclerosis (MS), especially for treating upper extremities function limitations. ...The sensor-based device rehabilitation is characterized by interactive therapy games with audio-visual feedback that allows training the movement of shoulders, elbows, and wrist, measuring the strength and the active range of motion of upper limb, registering data in an electronic database to quantitatively monitoring measures and therapy progress.
This study aimed to investigate the effects of sensor-based motor rehabilitation in add-on to the conventional neurorehabilitation, on increasing the upper limb functions of patients with MS.
Thirty patients were enrolled in the study and randomly assigned to the experimental group and the control group. The training consisting of twelve sessions of upper limb training was compared with twelve sessions of upper limb sensory-motor training, without robotic support. Both rehabilitation programs were performed for 40 minutes three times a week, for 4 weeks, in addition to conventional therapy. All patients were evaluated at the baseline (T0) and after 4 weeks of training (T1).
The within-subject analysis showed a statistically significant improvement in both groups, in the Modified Barthel Index and in the Rivermead Mobility Index scores and a significant improvement in Multiple Sclerosis Quality of Life-54 in the experimental. The analysis of effectiveness revealed that, compared with baseline (T0), the improvement percentage in all clinical scale scores was greater in the experimental group than the control group.
Proposed training provides an intensive and functional-oriented rehabilitation that objectively evaluates achieved progress through exercises. Therefore, it can represent a good complementary strategy for hand rehabilitation in MS patients.
Brachycephalic breeds of dogs, most of which show signs of the brachycephalic syndrome may have greater parasympathetic stimulation than other breeds, leading to higher values of heart rate ...variability and vagal tone index. The aim of this study was to establish a computerized electrocardiographic study and an assessment of the vagus sympathetic balance through heart rate variability and vagal tone index of five brachycephalic breeds compared to mesocephalic dogs. Sixty dogs were used, divided into groups made up of Boxers, English Bulldogs, French Bulldogs, Pugs, Shih-Tzu and no defined breed mesocephalic dogs. Statistical analysis was carried out using the Shapiro-Wilk test, Kruskal-Wallis and Dunn's test or ANOVA and Bonferroni (p<0.05). In the evaluation of vagal sympathetic balance among all the dogs, there was a negative correlation between heart rate and HRV 10RR (r = - 0.7678; p < 0.0001), HRV 20RR (r = - 0.8548, p < 0.0001) and VVTI (r = - 0.2770; p = 0.0321). It can therefore be concluded that the dog's breed and morphology did not alter its electrocardiographic parameters or heart rate variability. The vagal tone index, which in other studies differed in brachycephalic dogs, showed no difference when compared separately in brachycephalic breeds.
NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell ...metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IκBα downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-κB target gene expression and poor prognosis in human patients.
Exon and intron definition in pre-mRNA splicing De Conti, Laura; Baralle, Marco; Buratti, Emanuele
Wiley interdisciplinary reviews. RNA,
January/February 2013, Volume:
4, Issue:
1
Journal Article
Peer reviewed
One of the fundamental issues in RNA splicing research is represented by understanding how the spliceosome can successfully define exons and introns in a huge variety of pre‐mRNA molecules with ...nucleotide‐precision. Since its first description, researchers in this field have identified and characterized many fundamental elements and players capable of affecting the splicing process, both in a negative and positive manner. Indeed, it can be argued that today we know a great deal about the forces that make an exon, an exon and an intron, an intron. As will be discussed in this review, these decisions are a result of a complex combinatorial control resulting from many different factors/influences. Most importantly, these influences act across several levels of complexity starting from the relatively simple interaction between two consensus 5′ and 3′ splice sites to much more complex factors: such as the interplay between silencer or enhancer sequences, transcriptional processivity, genomic milieu, nucleosome positioning, and histone modifications at the chromatin level. Depending on local contexts, all these factors will act either antagonistically or synergistically to decide the exon/intron fate of any given RNA sequence. At present, however, what we still lack is a precise understanding of how all these processes add up to help the spliceosome reach a decision. Therefore, it is expected that future challenges in splicing research will be the careful characterization of all these influences to improve our ability to predict splicing choices in different organisms or in specific contexts. WIREs RNA 2013, 4:49–60. doi: 10.1002/wrna.1140
This article is categorized under:
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
RNA Processing > Splicing Mechanisms
RNA Processing > Splicing Regulation/Alternative Splicing
The 21st international congress on Progress in Vaccination against Cancer (PIVAC-22, https://www.pivac22.it/) was held from September 26 to September 28, 2022, at the Molecular Biotechnology Center ..."Guido Tarone" in Turin, Italy. The meeting covered the most recent advances in the field of cancer immunotherapy, with a focus on the tumor microenvironment, and addressed how alterations to the microenvironment's molecular and metabolic features and the microbiota impact upon the response to immunotherapy.
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