MicroRNAs (miRNAs) are increasingly implicated in the regulation of metastasis. Despite their potential as targets for anti-metastatic therapy, miRNAs have only been silenced in normal tissues of ...rodents and nonhuman primates. Therefore, the development of effective approaches for sequence-specific inhibition of miRNAs in tumors remains a scientific and clinical challenge. Here we show that systemic treatment of tumor-bearing mice with miR-10b antagomirs-a class of chemically modified anti-miRNA oligonucleotide-suppresses breast cancer metastasis. Both in vitro and in vivo, silencing of miR-10b with antagomirs significantly decreases miR-10b levels and increases the levels of a functionally important miR-10b target, Hoxd10. Administration of miR-10b antagomirs to mice bearing highly metastatic cells does not reduce primary mammary tumor growth but markedly suppresses formation of lung metastases in a sequence-specific manner. The miR-10b antagomir, which is well tolerated by normal animals, appears to be a promising candidate for the development of new anti-metastasis agents.
MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the ...E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of beta-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.
Preclinical cell models are the mainstay in the early stages of drug development. We sought to explore the preclinical data that differentiated successful from failed therapeutic agents in lung ...cancer.
One hundred thirty-four failed lung cancer drugs and twenty seven successful lung cancer drugs were identified. Preclinical data were evaluated. The independent variable for cell model experiments was the half maximal inhibitory concentration (IC50), and for murine model experiments was tumor growth inhibition (TGI). A logistic regression was performed on quartiles (Q) of IC50s and TGIs.
We compared odds of approval among drugs defined by IC50 and TGI quartile. Compared to drugs with preclinical cell experiments in highest IC50 quartile (Q4, IC50 345.01-100,000 nM), those in Q3 differed little, but those in the lower two quartiles had better odds of being approved. However, there was no significant monotonic trend identified (P-trend 0.4). For preclinical murine models, TGI values ranged from -0.3119 to 1.0000, with a tendency for approved drugs to demonstrate poorer inhibition than failed drugs. Analyses comparing success of drugs according to TGI quartile produced interval estimates too wide to be statistically meaningful, although all point estimates accord with drugs in Q2-Q4 (TGI 0.5576-0.7600, 0.7601-0.9364, 0.9365-1.0000) having lower odds of success than those in Q1 (-0.3119-0.5575).
There does not appear to be a significant linear trend between preclinical success and drug approval, and therefore published preclinical data does not predict success of therapeutics in lung cancer. Newer models with predictive power would be beneficial to drug development efforts.
Human papillomaviruses (HPVs) consist of two capsid proteins: major capsid protein L1 and minor capsid protein L2. The L2 protein has been shown to be involved in intracellular trafficking events ...that lead to the deposition of the viral DNA into the nucleus. In this study, we investigate the role of HPV16 L2 residues 43-DQILQ-47 during intracellular trafficking in human keratinocytes. We demonstrate that the highly conserved amino acids aspartic acid, isoleucine, and leucine are involved with the intracellular trafficking of the virus. Amino acid substitution of the isoleucine and leucine residues with alanine residues results in a significant decrease in infectivity of the pseudovirions without any changes to the binding or internalization of the virus. The pseudovirions containing these substitutions exhibit an altered trafficking pattern and do not deposit the viral pseudogenome into the nucleus. Instead, these mutated pseudovirions display a lack of interaction with syntaxin 18, an ER SNARE protein, are unable to progress past the endoplasmic reticulum (ER) and are redirected to the lysosomes. The results of this study help to elucidate the role and potential involvement of the 43-DQILQ-47 sequence during intracellular trafficking, specifically during trafficking beyond the ER.
High-risk types of human papillomaviruses (HPVs), such as HPV16, are highly associated with cervical, anogenital, and oropharyngeal cancers. The minor capsid protein L2 is essential for the intracellular trafficking of the viral DNA to the nucleus. This study investigates the role of amino acid residues 43-DQILQ-47 of the HPV16 L2 protein in the intracellular trafficking of the virus. Understanding how the virus traffics through the cell is a key factor in the development of additional preventative antiviral therapies. This study illustrates, through modification of the 43-DQILQ-47 sequence in pseudovirions, the importance of the 43-DQILQ-47 sequence in the trafficking of the virus beyond the endoplasmic reticulum.
Radiomics is a rapidly evolving field that involves extracting and analysing quantitative features from medical images, such as computed tomography or magnetic resonance images. Radiomics has shown ...promise in brain tumor diagnosis and patient-prognosis prediction by providing more detailed and objective information about tumors' features than can be obtained from the visual inspection of the images alone. Radiomics data can be analyzed to determine their correlation with a tumor's genetic status and grade, as well as in the assessment of its recurrence vs. therapeutic response, among other features. In consideration of the multi-parametric and high-dimensional space of features extracted by radiomics, machine learning can further improve tumor diagnosis, treatment response, and patients' prognoses. There is a growing recognition that tumors and their microenvironments (habitats) mutually influence each other-tumor cells can alter the microenvironment to increase their growth and survival. At the same time, habitats can also influence the behavior of tumor cells. In this systematic review, we investigate the current limitations and future developments in radiomics and machine learning in analysing brain tumors and their habitats.
Given the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of
expression in RCC and their impacts on RCC outcomes.
We conducted a pooled ...multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing.
-high/low expression was defined as the ≥75th/<25th percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from the time of tissue collection or therapy start.
We included 1,724 patients in the analysis. FOLH1 expression was significantly higher in clear cell (71%) compared to non-clear cell RCC tumors (19.0 versus 3.3 TPM,
< 0.001) and varied by specimen site (45% primary kidney/55% metastasis, 13.6 versus 9.9 TPM,
< 0.001).
expression was correlated with angiogenic gene expression (Spearman = 0.76,
< 0.001) and endothelial cell abundance (Spearman = 0.76,
< 0.001). While OS was similar in patients with
-high versus -low ccRCC, patients with
-high clear cell tumors experienced a longer time on cabozantinib treatment (9.7 versus 4.6 months, respectively, HR 0.57, 95% CI 0.35-0.93,
< 0.05).
We observed differential patterns of
expression based on histology and tumor site in RCC.
was correlated with angiogenic gene expression, increased OS, and a longer duration of cabozantinib treatment.
Thrombocytopenia is a frequent complication of cancer may be due to a variety of causes including malignancy itself, acute disease processes, or cancer therapy. Systemic cancer therapy is the most ...common cause of thrombocytopenia in cancer patients observed nearly two-thirds of patients with solid tumors. Thrombocytopenia with traditional chemotherapy agents is most frequently the result of megakaryocyte cytotoxicity. Oxaliplatin is a platinum derivative commonly used in gastrointestinal malignancies and is associated with drug-induced immune thrombocytopenia.
Background
CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan‐cancer data regarding the frequency of CDK12 ...alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real‐world clinical‐grade sequencing.
Methods
This was a single‐center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described.
Results
In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12‐altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow‐up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11–5.74). Ten patients with CDK12‐altered tumors received at least one immune checkpoint inhibitor‐containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression‐free survival for patients who had metastatic disease and received a checkpoint inhibitor‐containing regimen was 1.16 years (95% CI: 0.32–2.00).
Conclusion
CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12‐altered tumors.
CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitive tumors to immune checkpoint inhibition. Pan‐cancer data regarding the frequency of CDK12 alterations is limited. CDK12 altered tumors represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition.
A long terme, un sommeil de mauvaise qualité peut entraîner de graves problemes de santé. Comme de plus en plus de gens optent pour des traitements non médicaux, notamment en recourant a la musique ...pour améliorer la qualité du sommeil, les professionals de la santé doivent savoir comment utiliser efficacement la musique. Cet examen systématique de la littérature se veut l'étude, la synthese et l'analyse de 56 études portant sur l'incidence de la musique sur la qualité du sommeil publiée entre janvier 2007 et décembre 2019. Les auteurs ont constaté que les études (a) ont été réalisées par des chercheurs provenant de disciplines et de pays variés; (b) ont été menées aupres d'un grand nombre de participants issus de populations cliniques et non cliniques; (c) faisaient appel a toute une gamme de modeles de recherche, d'interventions, d'outils de mesure et de contextes pour les choix musicaux; et (d) ont donné lieu a des résultats majoritairement positifs. De ces 56 études, 52 (92,9 %) ont démontré une incidence positive de la musique sur la qualité du sommeil, tandis que 4 (7,1 %) n'en dégageaient aucune. Sept articles (12,5 %) indiquent que la musique a un effet d'importance égale ou supérieure aux autres traitements visant a accroître la qualité du sommeil. Il faudrait que les travaux de recherche futurs prévoient des descriptions plus détaillées d'interventions musicales pour découvrir lesquelles sont les plus efficaces pour améliorer la qualité du sommeil de différentes populations.
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