G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1.

The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer.

TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.

Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function.

Pleuropulmonary and diaphragmatic ultrasound in intensive care medicine.

The usefulness of ultrasound for chest exploration was described in 1968. It was not until the 1990s, when its use became widespread in Intensive Care Units as a diagnostic, monitoring and procedural guide tool. The fact that it is a non-invasive tool, accessible at the bedside, with a sensitivity and specificity close to computerized tomography (CT) and with a short learning curve, have made it a mandatory technique in the management of critically ill patients.

Presence of Activated (Phosphorylated) STAT3 in Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases.

Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs.

Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer.

Despite the great clinical success of immunotherapy in lung cancer patients, only a small percentage of them (<40%) will benefit from this therapy alone or combined with other strategies. Cancer cell-intrinsic and cell-extrinsic mechanisms have been associated with a lack of response to immunotherapy. The present study is focused on cancer cell-intrinsic genetic, epigenetic, transcriptomic and metabolic alterations that reshape the tumor microenvironment (TME) and determine response or refractoriness to immune checkpoint inhibitors (ICIs).

PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.

Unlabelled: Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy.

YES1 Is a Druggable Oncogenic Target in SCLC.

Introduction: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis.

Methods: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples.

Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells.

Background: One of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by the tumor cells. We have generated a CAR specific for the splice variant extra domain A (EDA) of fibronectin, which is highly expressed in the tumor stroma of many types of tumors but not in healthy tissues.

Digital onboarding in finance: a novel model and related cybersecurity risks.

Over the last few years, the financial sector has undergone a digital revolution that has had a severe impact on different related areas such as, the entities, the cybersecurity of systems, regulations and, of course, customers. SOTER project takes the challenge providing a complete set of tools to enhance the cybersecurity levels by implementing, in addition to non-technological tools, an innovative onboarding process has been implemented with the goals of increasing security, improving the user experience and integrity in the sector, and facilitating the customer entry into the digital marketplace by combining a set of breakthrough technologies. The cybersecurity research plays a crucial role in the conception and implementation of the onboarding process and for this kind of processes it has to be studied as an individual area by itself, as it is necessary to analyze the possible threats that can affect them, their origin and the solution(s) that can be taken to address them.

Two cell line models to study multiorganic metastasis and immunotherapy in lung squamous cell carcinoma.

There is a paucity of adequate mouse models and cell lines available to study lung squamous cell carcinoma (LUSC). We have generated and characterized two models of phenotypically different transplantable LUSC cell lines, i.e.

Cancer Epigenetic Biomarkers in Liquid Biopsy for High Incidence Malignancies.

Early alterations in cancer include the deregulation of epigenetic events such as changes in DNA methylation and abnormal levels of non-coding (nc)RNAs. Although these changes can be identified in tumors, alternative sources of samples may offer advantages over tissue biopsies. Because tumors shed DNA, RNA, and proteins, biological fluids containing these molecules can accurately reflect alterations found in cancer cells, not only coming from the primary tumor, but also from metastasis and from the tumor microenvironment (TME).

Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy.

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients.

Challenges and Novel Opportunities of Radiation Therapy for Brain Metastases in Non-Small Cell Lung Cancer.

Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25-50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier.

SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation.

Introduction: The use of immune-checkpoint inhibitors has drastically improved the management of patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory drugs that can reinvigorate the immune cytotoxic activity, in combination with antiprogrammed cell death 1 (PD-1) antibody, are a great promise to overcome resistance. We evaluated the impact of the SRC family kinases (SFKs) on NSCLC prognosis, and the immunomodulatory effect of the SFK inhibitor dasatinib, in combination with anti-PD-1, in clinically relevant mouse models of NSCLC.

The Smc5/6 Core Complex Is a Structure-Specific DNA Binding and Compacting Machine.

The structural organization of chromosomes is a crucial feature that defines the functional state of genes and genomes. The extent of structural changes experienced by genomes of eukaryotic cells can be dramatic and spans several orders of magnitude. At the core of these changes lies a unique group of ATPases-the SMC proteins-that act as major effectors of chromosome behavior in cells.

DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC).

The development of predictive biomarkers of response to targeted therapies is an unmet clinical need for many antitumoral agents. Recent genome-wide loss-of-function screens, such as RNA interference (RNAi) and CRISPR-Cas9 libraries, are an unprecedented resource to identify novel drug targets, reposition drugs and associate predictive biomarkers in the context of precision oncology. In this work, we have developed and validated a large-scale bioinformatics tool named DrugSniper, which exploits loss-of-function experiments to model the sensitivity of 6237 inhibitors and predict their corresponding biomarkers of sensitivity in 30 tumor types.

Substrate-decoupled, bulk-acoustic wave gyroscopes: Design and evaluation of next-generation environmentally robust devices.

This paper reports on a new type of high-frequency mode-matched gyroscope with significantly reduced dependencies on environmental stimuli such as temperature, vibration, and shock. A novel stress-isolation system is used to effectively decouple an axis-symmetric bulk-acoustic wave (BAW) vibratory gyro from its substrate, minimizing the effect that external sources of error have on the offset and scale factor of the device. Substrate-decoupled (SD) BAW gyros with a resonance frequency of 4.

Centrosome-Dependent Bypass of the DNA Damage Checkpoint by the Polo Kinase Cdc5.

Cell-cycle checkpoints are essential feedback mechanisms that promote genome integrity. However, in the face of unrepairable DNA lesions, bypass mechanisms can suppress checkpoint activity and allow cells to resume proliferation. The molecular mechanisms underlying this biological response are currently not understood.

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage.

The drive to proliferate and the need to maintain genome integrity are two of the most powerful forces acting on biological systems. When these forces enter in conflict, such as in the case of cells experiencing DNA damage, feedback mechanisms are activated to ensure that cellular proliferation is stopped and no further damage is introduced while cells repair their chromosomal lesions. In this circumstance, the DNA damage response dominates over the biological drive to proliferate, and may even result in programmed cell death if the damage cannot be repaired efficiently.

Multiscale in situ analysis of the role of dyskerin in lung cancer cells.

Dyskerin is one of the three subunits of the telomerase ribonucleoprotein (RNP) complex. Very little is known about the role of dyskerin in the biology of the telomeres in cancer cells. In this study, we use a quantitative, multiscale 3D image-based in situ method and several molecular techniques to show that dyskerin is overexpressed in lung cancer cell lines.

Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFβ1-targeting peptides P17 and P144.

Colorectal cancer (CRC) frequently metastasizes to the liver, a phenomenon that involves the participation of transforming-growth-factor-β(1) (TGFβ(1)). Blockade of the protumorigenic effects elicited by TGFβ(1) in advanced CRC could attenuate liver metastasis. We aimed in the present study to assess the antimetastatic effect of TGFβ(1)-blocking peptides P17 and P144, and to study mechanisms responsible for this activity in a mouse model.

Electrostatically tunable piezoelectric-on-silicon micromechanical resonator for real-time clock.

This paper reports on the design, fabrication, and characterization of a small form factor, piezoelectrically transduced, tunable micromechanical resonator for real-time clock (RTC) applications (32.768 kHz). The device was designed to resonate in an out-of-plane flexural mode to simultaneously achieve low-frequency operation and reduced motional resistance in a small die area.