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Abstract Targeted vasopeptide therapies have significantly advanced the management of pulmonary arterial hypertension (PAH). However, due to insufficient preclinical evidence regarding the involvement of the endothelin-1 (ET-1) pathway in chronic thromboembolic pulmonary hypertension (CTEPH) pathophysiology, the potential of ET-1 receptor antagonism in treating CTEPH remains uncertain. In this study, we investigated the role of the ET-1 pathway in CTEPH microvasculopathy using a multifaceted approach. Plasma ET-1 levels were measured in a cohort of 59 CTEPH patients and 41 healthy controls. Additionally, we evaluated the expression of key ET-1 pathway members in pulmonary explants from CTEPH, idiopathic PAH, and control patients. We used an in vitro system to test the hypothesis that the turbulent flow, observed near the vascular obstructions pathognomonic of CTEPH, enhances ET-1 expression. Our findings were further validated in vivo using a CTEPH piglet model that contains distinct regions representing pre- and post-thrombus lung territories. We found a twofold increase in circulating ET-1 levels in CTEPH patients compared to healthy subjects. Pulmonary explants from CTEPH patients exhibited pronounced overexpression of ET-1, endothelin receptor A (ETA), and phosphorylated myosin light chain (p-MLC) in muscularized pulmonary microvessels, suggesting heightened vascular contraction. In vitro experiments showed that turbulent flow facilitates ET-1 secretion compared to laminar flow regions. Additionally, in the CTEPH piglet model, elevated plasma ET-1 levels were observed compared to controls. Immunofluorescence and confocal microscopy analyses confirmed increased ETA and p-MLC in remodeled arteries from both pulmonary territories. However, ET-1 protein elevation was exclusively observed in the obstructed territory. These findings collectively indicate impaired vascular tone in microvessels of CTEPH patients and the CTEPH piglet model. Furthermore, our data implicates the ET-1 pathway in microvasculopathy, with turbulent flow playing a pathological role. These insights underscore the potential utility of ET-1 receptor antagonists as a promising therapeutic approach for CTEPH treatment.

Background The primary genetic risk factor for heritable pulmonary arterial hypertension is the presence of monoallelic mutations in the BMPR2 gene. The incomplete penetrance of BMPR2 mutations implies that additional triggers are necessary for pulmonary arterial hypertension occurrence. Pulmonary artery stenosis directly raises pulmonary artery pressure, and the redirection of blood flow to unobstructed arteries leads to endothelial dysfunction and vascular remodeling. We hypothesized that right pulmonary artery occlusion (RPAO) triggers pulmonary hypertension (PH) in rats with Bmpr2 mutations. Methods and Results Male and female rats with a 71 bp monoallelic deletion in exon 1 of Bmpr2 and their wild‐type siblings underwent acute and chronic RPAO. They were subjected to full high‐fidelity hemodynamic characterization. We also examined how chronic RPAO can mimic the pulmonary gene expression pattern associated with installed PH in unobstructed territories. RPAO induced precapillary PH in male and female rats, both acutely and chronically. Bmpr2 mutant and male rats manifested more severe PH compared with their counterparts. Although wild‐type rats adapted to RPAO, Bmpr2 mutant rats experienced heightened mortality. RPAO induced a decline in cardiac contractility index, particularly pronounced in male Bmpr2 rats. Chronic RPAO resulted in elevated pulmonary IL‐6 (interleukin‐6) expression and decreased Gdf2 expression (corrected P value1). In this context, male rats expressed higher pulmonary levels of endothelin‐1 and IL‐6 than females. Conclusions Our novel 2‐hit rat model presents a promising avenue to explore the adaptation of the right ventricle and pulmonary vasculature to PH, shedding light on pertinent sex‐ and gene‐related effects.

Abstract The alloying process plays a pivotal role in the development of advanced multifunctional plasmonic materials within the realm of modern nanotechnology. However, accurate in silico predictions are only available for metal clusters of just a few nanometers, while the support of modelling is required to navigate the broad landscape of components, structures and stoichiometry of plasmonic nanoalloys regardless of their size. Here we report on the accurate calculation and conceptual understanding of the optical properties of metastable alloys of both plasmonic (Au) and magnetic (Co) elements obtained through a tailored laser synthesis procedure. The model is based on the density functional theory calculation of the dielectric function with the Hubbard-corrected local density approximation, the correction for intrinsic size effects and use of classical electrodynamics. This approach is built to manage critical aspects in modelling of real samples, as spin polarization effects due to magnetic elements, short-range order variability, and size heterogeneity. The method provides accurate results also for other magnetic-plasmonic (Au-Fe) and typical plasmonic (Au-Ag) nanoalloys, thus being available for the investigation of several other nanomaterials waiting for assessment and exploitation in fundamental sectors such as quantum optics, magneto-optics, magneto-plasmonics, metamaterials, chiral catalysis and plasmon-enhanced catalysis.

Busulfan is widely used to treat malignant diseases, particularly for therapeutic intensification prior to an autologous stem cell graft. Numerous side effects consecutive to busulfan are described, but few descriptions of pulmonary hypertension exist, while bronchiolitis obliterans remains a rare complication. We report the clinical observations of four patients from the French Pulmonary Hypertension Registry who experienced subacute pulmonary hypertension after receiving busulfan as preparation regimen before an autologous stem cell graft for malignancies (Hodgkin’s disease, Ewing’s sarcoma and primary large B cell lymphoma of the brain). Patients experienced severe pulmonary arterial hypertension 2 to 4.5 months after busulfan administration. Pulmonary hypertension improved after treatment with approved drugs for pulmonary arterial hypertension and/or corticosteroids. During the follow‐up period, two patients developed chronic respiratory insufficiency due to interstitial lung disease, leading to double lung transplantation. The pathological assessment of explanted lungs revealed interstitial lung fibrosis with advanced bronchiolar lesions and severe pulmonary vascular damage. Three of the four patients were still alive after 36 to 80 months and the fourth died unexpectedly and suddenly after 5 months. In conclusion, PAH is a rare but severe complication associated with busulfan chemotherapy in adults. Histological examinations provide evidence for diffuse pulmonary vascular damage combined with interstitial lung injury in most cases.

UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

Various high and medium entropy oxides with rock salt structures were prepared and studied as anodes for lithium batteries. All the systems had complex reaction mechanisms involving conversion reactions. Their capacity and reduction potential depend on the number of components and microstructure of the initial materials. However, the dependence is difficult to rationalize based on simple stability logic. This paper discusses the implication of our findings in the wider context of the science of high entropy materials.

The use of immune checkpoint inhibitors (ICIs) has drastically transformed the therapeutic landscape in lung cancer. Special focus has been put on immune-related toxicity; however, infections can also seem during ICI treatment. Although rare, tuberculosis (TB) has been increasingly identified after ICIs, and it seems that the programmed cell death protein 1 and programmed death-ligand 1 pathway is directly involved in its pathophysiology. Here, we describe the case of a patient with advanced NSCLC who developed abdominal TB after 32 months of pembrolizumab and who remains in tumor remission 10 months after discontinuation of this drug. Routine screening for latent TB before ICI treatment is advised, with closer collaboration between infectious disease specialists and oncologists.

Abstract Alternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.

Abstract Background The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions. Methods and results MiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patients and in lungs from rats with monocrotaline-induced pulmonary hypertension (MCT-PH). MiR-138-5p is predicted to regulate the expression of the potassium channel KCNK3, whose loss is associated with the development and progression of PAH. We hypothesized that, in vivo, miR-138-5p inhibition would restore KCNK3 lung expression and subsequently alleviate PAH. Nebulization-based delivery of anti-miR-138-5p to rats with established MCT-PH significantly reduced the right ventricular systolic pressure and significantly improved the pulmonary arterial acceleration time (PAAT). These haemodynamic improvements were related to decrease pulmonary vascular remodelling, lung inflammation and pulmonary vascular cell proliferation in situ. In vivo inhibition of miR-138-5p restored KCNK3 mRNA expression and SLC45A3 protein expression in the lungs. Conclusions We confirmed that in vivo inhibition of miR-138-5p reduces the development of PH in experimental MCT-PH. The possible curative mechanisms involve at least the normalization of lung KCNK3 as well as SLC45A3 expression.

Abstract Objectives To decipher the correlations between PET and DCE kinetic parameters in non-small-cell lung cancer (NSCLC), by using voxel-wise analysis of dynamic simultaneous [18F]FDG PET-MRI. Material and methods Fourteen treatment-naïve patients with biopsy-proven NSCLC prospectively underwent a 1-h dynamic [18F]FDG thoracic PET-MRI scan including DCE. The PET and DCE data were normalized to their corresponding T1-weighted MR morphological space, and tumors were masked semi-automatically. Voxel-wise parametric maps of PET and DCE kinetic parameters were computed by fitting the dynamic PET and DCE tumor data to the Sokoloff and Extended Tofts models respectively, by using in-house developed procedures. Curve-fitting errors were assessed by computing the relative root mean square error (rRMSE) of the estimated PET and DCE signals at the voxel level. For each tumor, Spearman correlation coefficients (r s) between all the pairs of PET and DCE kinetic parameters were estimated on a voxel-wise basis, along with their respective bootstrapped 95% confidence intervals (n = 1000 iterations). Results Curve-fitting metrics provided fit errors under 20% for almost 90% of the PET voxels (median rRMSE = 10.3, interquartile ranges IQR = 8.1; 14.3), whereas 73.3% of the DCE voxels showed fit errors under 45% (median rRMSE = 31.8%, IQR = 22.4; 46.6). The PET-PET, DCE-DCE, and PET-DCE voxel-wise correlations varied according to individual tumor behaviors. Beyond this wide variability, the PET-PET and DCE-DCE correlations were mainly high (absolute r s values > 0.7), whereas the PET-DCE correlations were mainly low to moderate (absolute r s values < 0.7). Half the tumors showed a hypometabolism with low perfused/vascularized profile, a hallmark of hypoxia, and tumor aggressiveness. Conclusion A dynamic “one-stop shop” procedure applied to NSCLC is technically feasible in clinical practice. PET and DCE kinetic parameters assessed simultaneously are not highly correlated in NSCLC, and these correlations showed a wide variability among tumors and patients. These results tend to suggest that PET and DCE kinetic parameters might provide complementary information. In the future, this might make PET-MRI a unique tool to characterize the individual tumor biological behavior in NSCLC.

The diagnosis of a mediastinal mass may be challenging for clinicians, since lesions arising within the mediastinum include a variety of disease entities, frequently requiring a multidisciplinary approach. Age and sex represent important information, which need to be integrated with imaging and laboratory findings. In addition, the location of the mediastinal lesion is fundamental; indeed, we propose to illustrate mediastinal diseases based on the compartment of origin. We consider that this structured approach may serve as hint to the diagnostic modalities and management of mediastinal diseases. In this review, we present primary mediastinal tumours in the evolving context of new diagnostic and therapeutic tools, with recently described entities, based on our own experience with >900 cases encountered in the past 10 years.

Pulmonary capillary haemangiomatosis (PCH) is a rare and incompletely understood histopathological finding characterised by abnormal capillary proliferation within the alveolar interstitium, which has long been noted to share many overlapping features with pulmonary veno-occlusive disease (PVOD). But are PCH and PVOD distinct entities that occur in isolation, or are they closely intertwined manifestations along a spectrum of the same disease? The classic clinical features of both PCH and PVOD include signs and symptoms related to pulmonary hypertension, hypoxaemia, markedly impaired diffusion capacity of the lung and abnormal chest imaging with ground glass opacities, septal lines and lymphadenopathy. In recent years, increasing evidence suggests that the clinical presentation, histopathological features, genetic substrate and pathobiological mechanisms of PCH and PVOD are overlapping and usually indistinguishable. The discovery of biallelic mutations in the eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) gene in heritable PCH and PVOD greatly advanced our understanding of the overlapping nature of these conditions. Furthermore, recognition of PCH and PVOD-like changes in other pulmonary vascular diseases and in conditions that cause chronic pulmonary venous hyper-perfusion or hypertension suggests that PCH/PVOD may develop as a reactive process to various insults or injuries to the pulmonary vasculature, rather than being primary angiogenic disorders.

Abstract Background Skeletal muscles express a highly specialized proteome that allows the metabolism of energy sources to mediate myofiber contraction. This muscle-specific proteome is partially derived through the muscle-specific transcription of a subset of genes. Surprisingly, RNA sequencing technologies have also revealed a significant role for muscle-specific alternative splicing in generating protein isoforms that give specialized function to the muscle proteome. Main body In this review, we discuss the current knowledge with respect to the mechanisms that allow pre-mRNA transcripts to undergo muscle-specific alternative splicing while identifying some of the key trans-acting splicing factors essential to the process. The importance of specific splicing events to specialized muscle function is presented along with examples in which dysregulated splicing contributes to myopathies. Though there is now an appreciation that alternative splicing is a major contributor to proteome diversification, the emergence of improved “targeted” proteomic methodologies for detection of specific protein isoforms will soon allow us to better appreciate the extent to which alternative splicing modifies the activity of proteins (and their ability to interact with other proteins) in the skeletal muscle. In addition, we highlight a continued need to better explore the signaling pathways that contribute to the temporal control of trans-acting splicing factor activity to ensure specific protein isoforms are expressed in the proper cellular context. Conclusions An understanding of the signal-dependent and signal-independent events driving muscle-specific alternative splicing has the potential to provide us with novel therapeutic strategies to treat different myopathies.

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

Aberrant alternative splicing (AS) is a hallmark of cancer and a potential target for novel anti-cancer therapeutics. Breast cancer-associated AS events are known to be linked to disease progression, metastasis, and survival of breast cancer patients. To identify altered AS programs occurring in metastatic breast cancer, we perform a global analysis of AS events by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq). We demonstrate that, relative to low-metastatic, high-metastatic breast cancer cells show different AS choices in genes related to cancer progression. Supporting a global reshape of cancer-related splicing profiles in metastatic breast cancer we found an enrichment of RNA-binding motifs recognized by several splicing regulators, which have aberrant expression levels or activity during breast cancer progression, including SRSF1. Among SRSF1-regulated targets we found DCUN1D5, a gene for which skipping of exon 4 in its pre-mRNA introduces a premature termination codon (PTC), thus generating an unstable transcript degraded by nonsense-mediated mRNA decay (NMD). Significantly, distinct breast cancer subtypes show different DCUN1D5 isoform ratios with metastatic breast cancer expressing the highest level of the NMD-insensitive DCUN1D5 mRNA, thus showing high DCUN1D5 expression levels, which are ultimately associated with poor overall and relapse-free survival in breast cancer patients. Collectively, our results reveal global AS features of metastatic breast tumors, which open new possibilities for the treatment of these aggressive tumor types.

Alternative splicing (AS) is an important posttranscriptional regulatory process. Damaged or unnecessary cells need to be removed though apoptosis to maintain physiological processes. Caspase-2 pre-mRNA produces pro-apoptotic long mRNA and anti-apoptotic short mRNA isoforms through AS. How AS of Caspase-2 is regulated remains unclear. In the present study, we identified a novel regulatory protein SRSF9 for AS of Caspase-2 cassette exon 9. Knock-down (KD) of SRSF9 increased inclusion of cassette exon and on the other hand, overexpression of SRSF9 decreased inclusion of this exon. Deletion mutagenesis demonstrated that exon 9, parts of intron 9, exon 8 and exon 10 were not required for the role of SRSF9 in Caspase-2 AS. However, deletion and substitution mutation analysis revealed that AGGAG sequence located at exon 10 provided functional target for SRSF9. In addition, RNA-pulldown mediated immunoblotting analysis showed that SRSF9 interacted with this sequence. Gene ontology analysis of RNA-seq from SRSF9 KD cells demonstrates that SRSF9 could regulate AS of a subset of apoptosis related genes. Collectively, our results reveal a basis for regulation of Caspase-2 AS.

Fe2O3 and Fe2O3:Ge nanofibers (NFs) were prepared via electrospinning and thoroughly characterized via several techniques in order to investigate the effects produced by germanium incorporation in the nanostructure and crystalline phase of the oxide. The results indicate that reference Fe2O3 NFs consist of interconnected hematite grains, whereas in Fe2O3:Ge NFs, constituted by finer and elongated nanostructures developing mainly along their axis, an amorphous component coexists with the dominant α-Fe2O3 and γ-Fe2O3 phases. Ge4+ ions, mostly dispersed as dopant impurities, are accommodated in the tetrahedral sites of the maghemite lattice and probably in the defective hematite surface sites. When tested as anode active material for sodium ion batteries, Fe2O3:Ge NFs show good specific capacity (320 mAh g−1 at 50 mA g−1) and excellent rate capability (still delivering 140 mAh g−1 at 2 A g−1). This behavior derives from the synergistic combination of the nanostructured morphology, the electronic transport properties of the complex material, and the pseudo-capacitive nature of the charge storage mechanism.

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease that is caused by the progressive occlusion of the distal pulmonary arteries, eventually leading to right heart failure and death. Almost 40% of patients with PAH are iron deficient. Although widely studied, the mechanisms linking between PAH and iron deficiency remain unclear. Here we review the mechanisms regulating iron homeostasis and the preclinical and clinical data available on iron deficiency in PAH. Then we discuss the potential implications of iron deficiency on the development and management of PAH.

Angiophagy has been described as a non-fibrinolytic mechanism of pulmonary artery (PA) patency restoration after distal (1000 μm). In lung samples from patients with histories of pulmonary embolisms, we observed PA angiophagy stigma for embolic specimens derived from blood clots and from bone marrow emboli. This study provides an original pathological description and staging of PA angiophagy in a large animal model of CTEPH and in humans after pulmonary embolism.

Alternative splicing generates multiple protein isoforms from one primary transcript and represents one of the major drivers of proteomic diversity in human cells [...]

Sn-modification of TiO2 photocatalysts has been recently proposed as a suitable strategy to improve pollutant degradation as well as hydrogen production. In particular, visible light activity could be promoted by doping with Sn2+ species, which are, however, thermally unstable. Co-promotion with N and Sn has been shown to lead to synergistic effects in terms of visible light activity, but the underlying mechanism has, so far, been poorly understood due to the system complexity. Here, the structural, optical, and electronic properties of N,Sn-copromoted, nanostructured TiO2 from sol-gel synthesis were investigated: the Sn/Ti molar content was varied in the 0–20% range and different post-treatments (calcination and low temperature hydrothermal treatment) were adopted in order to promote the sample crystallinity. Depending on the adopted post-treatment, the optical properties present notable differences, which supports a combined role of Sn dopants and N-induced defects in visible light absorption. X-ray absorption spectroscopy at the Ti K-edge and Sn L2,3-edges shed light onto the electronic properties and structure of both Ti and Sn species, evidencing a marked difference at the Sn L2,3-edges between the samples with 20% and 5% Sn/Ti ratio, showing, in the latter case, the presence of tin in a partially reduced state.

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p

We investigated the electronic and magnetic properties of KCuF3 and KCu0.875Mg0.125F3 crystals by means of Density Functional periodic computations at the B3LYP level of theory. We considered four possible magnetic ordering of the unpaired electrons on copper ions. Both materials are correctly predicted as being 1D antiferromagnetic insulators, and the superexchange parameters in the crystallographic ab planes and along the c direction measure +10 and -600 K, respectively. Residual spin polarization is found also on fluorine atoms, in agreement with literature results. We found a complete orbital ordering at Cu sites: in the copper reference frame dxy, dyz, dxz, and dz2 orbitals contain about 2 electrons each, while the dx2-y2 orbital is only partially filled. The perturbation induced by doping of KCuF3 with Mg is very strong and localized on the first shell of F neighbours. Mg has a very small influence on the ordering of the 3d orbitals of copper and on the Cu-Cu magnetic superexchange parameters but reduces significantly the absolute energy differences between the antiferromagnetic ground state and the ferromagnetic phase, in agreement with the experiment. The absence of long range effects makes Mg a suitable dopant for the investigation of strongly correlated electronic systems by means of orbital dilution.

Pulmonary hypertension (PH) with complicating chronic lung diseases and/or hypoxia falls into group 3 of the updated classification of PH. Patients with chronic obstructive lung disease (COPD), diffuse lung disease (such as idiopathic pulmonary fibrosis (IPF)) and with sleep disordered breathing are particularly exposed to the risk of developing PH. Although PH in such a context is usually mild, a minority of patients exhibit severe haemodynamic impairment, defined by a mean pulmonary arterial pressure (mPAP) of ≥35 mmHg or mPAP values ranging between 25 mmHg and 35 mmHg with a low cardiac index (

Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.

Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.