Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Manejo actual de la otitis externa maligna. Una revisión sistemática.

INTRODUCTION: Malignant external otitis (OEM), or also called necrotizing external otitis, is a life-threatening infection, mainly affecting the external auditory canal, producing osteomyelitis of the temporal bone; extends to the base of the skull and surrounding tissue, causing sepsis; eventually compromising the cranial nerves and generating multisystemic. Objectives: To describe the current management of malignant external otitis. Specific objectives: 1) To determine the etiology of malignant external otitis. 2) To determine the complications of malignant external otitis. METHODS: A systematic review was performed according to the PRISMA 2020 guidelines with a search for scientific articles, with the term malignant external otitis. We recovered 40 articles corresponding to the last 5 years, obtained from databases such as Cochrane, academic Google, Medline, Mendeley, ScientDirect, IntechOpen. The risks of bias in the studies showed systematic differences due to the heterogeneity of the patients and the treatments between the groups. RESULTS: the management of malignant external otitis includes treatment with anti-pseudomonas antibiotics such as fluoroquinolones in combination with a beta-lactam and an antifungal such as amphotericin B, voriconazole, fluconazole, or echinocandin; in addition to treatment with surgical debridement of the ear canal and radical mastoidectomy, to avoid the risk of neurocranial sepsis, obtaining good results. DISCUSSION: Malignant external otitis is a pathology of rare occurrence that affects immune immunocompromised patients, whose morbidity and mortality is high, if not treated properly. Its main causal agents are: pseudomona aeruginosa, staphylococcus aureus, Candida spp, Aspergillus spp and Geotrichum. The importance of this research lies in optimizing care in the patient with OEM, making a timely clinical and imaging diagnosis, to provide an effective therapeutic alternative, based on broad-spectrum antibiotic therapy, antifungal treatment, and surgical treatment, to avoid complications.INTRODUCCIÓN: La otitis externa maligna (OEM), o también llamada otitis externa necrotizante, es una infección potencialmente mortal, que afecta principalmente al canal auditivo externo, produciendo osteomielitis del hueso temporal; se extiende hasta la base del cráneo y tejido circundante, provocando sepsis; llegando a comprometer los nervios craneales y generar afección multisistémica. Objetivos General: Describir el manejo actual de la otitis externa maligna. Objetivos específicos: 1) Determinar la etiología de la otitis externa maligna.  2) Determinar las complicaciones de la de la otitis externa maligna. MÉTODOS: se realizó una revisión sistemática según las guías PRISMA 2020 con búsqueda de artículos científicos, con el termino otitis externa maligna. Se recuperaron 40 artículos correspondientes a los últimos 5 años, obtenidos de bases de datos como Cochrane, Google académico, Medline, Mendeley, ScientDirect, IntechOpen. Los riesgos de sesgo en los estudios observaron diferencias sistemáticas por la heterogeneidad de los pacientes y los tratamientos entre los grupos.  RESULTADOS: el manejo de la otitis externa maligna incluye tratamiento con antibióticos anti pseudomona como las fluoroquinolonas en combinación con un betalactámico y un antifúngico como la anfotericina B, voriconazol, fluconazol o equinocandinas; además del tratamiento con desbridamiento quirúrgico del canal auditivo y mastoidectomía radical, para evitar el riesgo de sepsis neurocraneal, obteniéndose buenos resultados.  DISCUSIÓN: La otitis externa maligna, es una patología de rara ocurrencia que afecta a pacientes inmunocomprometidos, cuya morbimortalidad es alta, si no se trata adecuadamente. Sus principales agentes causales son: pseudomona aeruginosa, estafilococo aureus, Cándida spp, Aspergillus spp y Geotrichum. La importancia de esta investigación radica en optimizar la atención en el paciente con OEM, realizando un diagnóstico clínico e imagenológico oportuno, para brindar una alternativa terapéutica eficaz, basada en antibioticoterapia de amplio espectro, el tratamiento antifúngico, complementario al tratamiento quirúrgico, para evitar complicaciones

Reading to Learn: Understanding Reading Within Integrated Vocabulary Instruction In A1 Efl Learners

El presente estudio de investigación trató de explorar los efectos de la instrucción de vocabulario integrado en el desempeño de la comprensión lectora de los estudiantes de nivel a1 de inglés como idioma extranjero en un colegio público rural en ecuador. Los participantes fueron estudiantes entre 15 y 17 años en su primer año de bachillerato, todos ellos fueron seleccionados por un muestreo a conveniencia. Los participantes estuvieron divididos en dos grupos (tradicional e integrado) y se les solicitó participar en ocho lecciones de lectura. Después de cada clase, los estudiantes participaron en una prueba de comprensión de lectura basada en preguntas de comprensión literal. Además, las percepciones del grupo experimental se recogieron mediante un cuestionario. Adicionalmente, se utilizó una escala de conocimientos de vocabulario (vks) tres veces para medir el conocimiento previo, el aprendizaje y la retención de palabras.GuayaquilMaster In Teaching English As A Foreign Languag

K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling

SummaryK-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca2+ signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-RasV12-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this “undruggable” protein

Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes

Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.

Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras-mediated Met expression drives "K-Ras addiction" in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients

RIT1 oncoproteins escape LZTR1-mediated proteolysis.

RIT1 oncoproteins have emerged as an etiologic factor in Noonan syndrome and cancer. Despite the resemblance of RIT1 to other members of the Ras small guanosine triphosphatases (GTPases), mutations affecting RIT1 are not found in the classic hotspots but rather in a region near the switch II domain of the protein. We used an isogenic germline knock-in mouse model to study the effects of RIT1 mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, we detected a RIT1 interactor, leucine zipper-like transcription regulator 1 (LZTR1), that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Our results highlight a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1

UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth.

UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)-TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs

Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway

Rat sarcoma (Ras) GTPases regulate cell proliferation and survival through effector pathways including Raf-MAPK, and are the most frequently mutated genes in human cancer. Although it is well established that Ras activity requires binding to both GTP and the membrane, details of how Ras operates on the cell membrane to activate its effectors remain elusive. Efforts to target mutant Ras in human cancers to therapeutic benefit have also been largely unsuccessful. Here we show that Ras-GTP forms dimers to activate MAPK. We used quantitative photoactivated localization microscopy (PALM) to analyze the nanoscale spatial organization of PAmCherry1-tagged KRas 4B (hereafter referred to KRas) on the cell membrane under various signaling conditions. We found that at endogenous expression levels KRas forms dimers, and KRas(G12D), a mutant that constitutively binds GTP, activates MAPK. Overexpression of KRas leads to formation of higher order Ras nanoclusters. Conversely, at lower expression levels, KRas(G12D) is monomeric and activates MAPK only when artificially dimerized. Moreover, dimerization and signaling of KRas are both dependent on an intact CAAX (C, cysteine; A, aliphatic; X, any amino acid) motif that is also known to mediate membrane localization. These results reveal a new, dimerization-dependent signaling mechanism of Ras, and suggest Ras dimers as a potential therapeutic target in mutant Ras-driven tumors