Surgery plays a central role in the diagnosis, staging, and management of pleural mesothelioma. Achieving an accurate diagnosis through surgical intervention and identifying the specific histologic ...subtype is crucial for determining the appropriate course of treatment. The histologic subtype guides decisions regarding the use of chemotherapy, immunotherapy, or multimodality treatment. The goal of surgery as part of multimodality treatment is to accomplish macroscopic complete resection with the eradication of grossly visible and palpable disease. Over the past two decades, many medical centers worldwide have shifted from performing extra-pleural pneumonectomy (EPP) to pleurectomy decortication (PD). This transition is motivated by the lower rates of short-term mortality and morbidity associated with PD and similar or even better long-term survival outcomes, compared to EPP. This review aims to outline the role of surgery in diagnosing, staging, and treating patients with pleural mesothelioma.
KRAS is a frequent oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC). It was previously thought to be an “undruggable” target due to the lack of deep binding pockets for ...specific small-molecule inhibitors. A better understanding of the mechanisms that drive KRAS transformation, improved KRAS-targeted drugs, and immunological approaches that aim at yielding immune responses against KRAS neoantigens have sparked a race for approved therapies. Few treatments are available for KRAS mutant NSCLC patients, and several approaches are being tested in clinicals trials to fill this void. Here, we review promising therapeutics tested for KRAS mutant NSCLC.
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KRAS, an oncogenic driver in lung cancer, is known as an “undruggable” targetDifferent strategies are under investigation to indirectly and directly target KRASClinical trials of small-molecule inhibitors report promising interim results
In this review, Salgia et al. discusses KRAS, a prominent oncogenic driver in lung cancer that is notoriously difficult to target. Studies have shown preclinical rationale in leveraging neoantigens and inhibiting KRAS signaling pathways in KRAS-mutant cancers. Recent advancements in clinical trials have demonstrated encouraging results with small-molecule inhibitors.
Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance ...of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.
Mitochondria form dynamic networks which adapt to the environmental requirements of the cell. We investigated the aging process of these networks in human skin cells in vivo by multiphoton ...microscopy. A study on the age-dependency of the mitochondrial network in young and old volunteers revealed that keratinocytes in old skin establish a significantly more fragmented network with smaller and more compact mitochondrial clusters than keratinocytes in young skin. Furthermore, we investigated the mitochondrial network during differentiation processes of keratinocytes within the epidermis of volunteers. We observe a fragmentation similar to the age-dependent study in almost all parameters. These parallels raise questions about the dynamics of biophysical network structures during aging processes.
Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of ...the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.
Advances in the treatment of malignant pleural mesothelioma (MPM) have been disappointing, despite the apparent need for new therapeutic options for this rare and devastating cancer. Drug resistance ...is common and surgical intervention has brought benefits only to a subset of patients. MPM is a heterogenous disease with a surprisingly low mutation rate and recent sequencing efforts have confirmed alterations in a limited number of tumor suppressors that do not provide apparent insights into the molecular mechanisms that drive this malignancy. There is increasing evidence that epigenetic regulation leads to immune evasion and transformation in MPM. Further, the low efficacy of immune checkpoint inhibitors is consistent with a suppression of genes involved in the anti-tumor immune response. We review three promising emerging therapeutic targets (STAT3, KDM4A, heparanase) and highlight their potential effects on the immune response.
The effects of tree shelters on the survival, height and diameter growth of three coniferous tree species - Scots pine (
Pinus sylvestris
L.), Norway spruce (
Picea abies
(L.) H. Karst.) and Silver ...fir (
Abies alba
Mill.) were observed. The study was conducted in two experimental plantations, established in the spring of 2016 in the Training and Experimental Forest Range Jundola (Central South Bulgaria). Three experimental variants with tree shelters - Tubex Ventex Classic, Layflat Shelterguard, Layflat Treeguard and a control one (without tree shelters) were used. Twenty to twenty-five seedlings in three replications of each variant and tree species were planted. The experimental plantation 1 included Scots pine and Norway spruce and was established on a south east-facing terrain at an altitude of 1400 m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist. The experimental plantation 2 is of Silver fir and was located on an east-facing terrain at an altitude of 1400 m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist to moist.
In the autumn of the fifth year after the establishment, inventories and measurements of heights, height increment and groundline diameter of the seedlings were made. The survival in both experimental plantations was higher in the variants with tree shelter. The height growth of all tree species was better in tree shelter variants, with the highest average height in the variant with Tubex Ventex Classic. The biggest height increment was established in the variant with Layflat Shelterguard for Norway spruce and Silver fir and in variant without tree shelters for Scots pine. The ground line diameter was highest in control variant for Scots pine and Norway spruce and in the variant with Layflat Treegard for the Silver fir.
Coronavirus disease 2019 (COVID‐19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. ...Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID‐19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS‐CoV‐2 infection. Using multiple cell‐based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS‐CoV‐2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein‐mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS‐CoV‐2 variant infectivity, supporting a role for AXL in SARS‐CoV‐2 infection and supporting further investigation of drug‐mediated AXL inhibition as a COVID‐19 treatment. This study supports further evaluation of AXL‐targeting kinase inhibitors as potential antiviral agents and treatments for COVID‐19. Additional mechanistic studies are needed to determine underlying differences in virus response.
Receptor tyrosine kinases have come to fruition as therapeutic targets in a variety of malignancies. In this group of targets, the c-Met receptor tyrosine kinase plays an important role in increased ...cell growth, reduced apoptosis, altered cytoskeletal function, increased metastasis, and other biologic changes. The ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor. Met is overexpressed and mutated in a variety of malignancies, among which germline mutations are of particular interest. Most mutations of Met have been found in the juxtamembrane, the tyrosine kinase, and the semaphorin domain. Met gain-of-function mutations lead to deregulated or prolonged tyrosine kinase activity, which is instrumental to its transforming activity. This review summarizes the biologic functions regulated by Met and its structural requirements as well as related developments in targeted therapy. Treatment approaches, including antagonism of HGF binding to Met, targeting of RNA and the Met protein, and inhibition of the tyrosine kinase domain of Met, are highlighted. Targeting of the HGF/Met pathway, alone or in combination with standard therapies, is likely to improve current therapies in Met-dependent malignancies.
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