Transcriptomic Analysis Reveals Early Alterations Associated with Intrinsic Resistance to Targeted Therapy in Lung Adenocarcinoma Cell Lines.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer.

Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma.

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.

The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment.

The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane-membrane, ligand-receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells. The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect. The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor-host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver-as a critical organ that produces the leading inflammatory markers described to date-will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.

Effects of media multitasking frequency on a novel volitional multitasking paradigm.

The effect of media multitasking (e.g., listening to podcasts while studying) on cognitive processes has seen mixed results thus far. To date, the tasks used in the literature to study this phenomenon have been classical paradigms primarily used to examine processes such as working memory. While perfectly valid on their own, these paradigms do not approximate a real-world volitional multitasking environment. To remedy this, as well as attempt to further validate previously found effects in the literature, we designed a novel experimental framework that mimics a desktop computer environment where a "popup" associated with a secondary task would occasionally appear. Participants could choose to attend to the popup, or to ignore it. Attending to the popup would prompt a word stem completion task, while ignoring it would continue the primary math problem verification task. We predicted that individuals who are more impulsive, more frequent media multitaskers, and individuals who prefer to multitask (quantified with the Barratt Impulsiveness Scale, a modified version of the Media Use Questionnaire, and the Multitasking Preference Inventory) would be more distracted by popups, choose to switch tasks more often and more quickly, and be slower to return to the primary task compared to those who media multitask to a lesser degree. We found that as individuals media multitask to a greater extent, they are slower to return to the previous (primary) task set and are slower to complete the primary task overall whether a popup was present or not, among other task performance measures. We found a similar pattern of effects within individuals who prefer to multitask. Our findings suggest that overall, more frequent media multitaskers show a marginal decrease in task performance, as do preferential multitaskers. Attentional impulsivity was not found to influence any task performance measures, but was positively related to a preference for multitasking. While our findings may lack generalizability due to the modifications to the Media Use Questionnaire, and this initial study is statically underpowered, this paradigm is a crucial first step in establishing a more ecologically valid method to study real-world multitasking.

Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment.

The tumor microenvironment (TME) is a complex and constantly changing cellular system composed of heterogeneous populations of tumor cells and non-transformed stromal cells, such as stem cells, fibroblasts, endothelial cells, pericytes, adipocytes, and innate and adaptive immune cells. Tumor, stromal, and immune cells consume available nutrients to sustain their proliferation and effector functions and, as a result of their metabolism, produce a wide array of by-products that gradually alter the composition of the milieu. The resulting depletion of essential nutrients and enrichment of by-products work together with other features of the hostile TME to inhibit the antitumor functions of immune cells and skew their phenotype to promote tumor progression. This review briefly describes the participation of the innate and adaptive immune cells in recognizing and eliminating tumor cells and how the gradual metabolic changes in the TME alter their antitumor functions. In addition, we discuss the overexpression of the immune checkpoints and their ligands as a result of nutrient deprivation and by-products accumulation, as well as the amplification of the metabolic alterations induced by the immune checkpoints, which creates an immunosuppressive feedback loop in the TME. Finally, the combination of metabolic and immune checkpoint inhibitors as a potential strategy to treat cancer and enhance the outcome of patients is highlighted.

Air density dependence of the soft X-ray PTW 34013 ionization chamber.

PURPOSE: We studied the dependence on air density of the response of the PTW 34013 ionization chamber, recently upgraded for dosimetry control of low energy X-ray beams. METHODS: Measurements were performed by changing the pressure conditions inside a pressure chamber. The behavior of the measurements against the air density inside this chamber was analyzed. X-ray beams generated with 50, 70, 100, 150 and 200 kVp and the two electrometer polarities were considered. RESULTS: For all beams studied, measurements corrected with the conventional temperature and pressure factor showed a residual dependence on the air density that was described with a linear function of the air density. For the 50 and 70 kVp beams, corrected measurements remained ∼1% smaller than the value found at standard pressure/temperature conditions, for both electrometer polarities and for the air density range typical in clinical conditions. For air densities smaller than the standard one, measurements found for 100, 150 and 200 kVp beams were below or above the value found at standard pressure and temperature when the negative or positive electrometer polarities were used, respectively. The differences with the measurements at standard conditions were less than 1% for the 100 kVp beam and below 4% for the other two beams. CONCLUSIONS: The PTW 34013 ionization chamber showed a dependence on the air density that is not properly described with the usual temperature and pressure correction factor. This residual dependence is negligible for low energy beams, for which this chamber is recommended, but is more substantial for beams with energy above 80 kVp.

Uso de las herramientos de la web 2. 0 en la investigación / Using web 2. 0 tools in Research

La aparición del Internet y luego la Web 2.0 han producido una gran transformación en la forma de ver y hacer investigación. La accesibilidad para conseguir documentos y la rapidez para conseguirlos, editarlos y comunicarnos con los demás son ahora características facilitadoras de la investigación. Son muchas las herramientas que constantemente están apareciendo en la Internet y que sirven para hacerla más sencilla y lo más increíble, muchas de ellas sin costo alguno.(AU)

The appearance of the Internet and then the Web 2.0 has produced a great transformation in the way of seeing and carrying out research. The accessibility to get documents and the speed to obtain, edit them and to communicate with others are now enabling characteristics of research. There are many tools that are constantly appearing on the Internet and that serve to make it simpler and more amazing, many of them free of charge.(AU)

La Web 2. 0 al servicio de la Medicina. El CIE-10 y el CIE-0 en WIKIS / Web 2. 0 applications in Medicine. CIE-10 and CIE-0 in Wikis

La aparición de la Web 2.0 ha traído múltiples herramientas muy útiles para la labor diaria del médico, herramientas que nos permiten publicar nuestras experiencias y relacionarnos más directamente con nuestros pacientes y con otros colegas. Muchos de estos instrumentos ya están siendo utilizados por instituciones de salud con mucho provecho. Una de estas herramientas son los WIKIS, una especie de páginas web que nos permiten editar y publicar en grupo desde un simple comunicado hasta productos complejos como un libro. Utilizando las wikis los 70 alumnos del curso de informática médica han logado publicar los códigos internacionales de las enfermedades y los códigos topográficos y morfológicos de las enfermedades oncológicas. (AU)

The emergence of Web 2.0 has brought many useful tools for the physician's daily work, tools that allow us to publish our experiences and engage more directly with our patients and colleagues. Many of these instruments are already being used by health institutions with much profit.One of these tools are wikis, a kind of websites that allow you to edit and post to group from a simple statement to complex products such as a book. Using wikis the 70 students in the course of medical informatics have achieved to publish international codes of diseases and topographical and morphological codes of oncological diseases.(AU)