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The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic Kras.sup.G12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes. Exosomes improve the delivery of siRNA to mutant KRAS in the pancreatic tumours and bypass immune clearance better than artificial liposomes, probably owing to enhanced macropinocytocis and presence of CD47 on exosomes, respectively. Exosomes target KRAS in the pancreas Mutant KRAS is a common driver of pancreatic cancer, and decreasing its expression with siRNA is a potential strategy to forestall pancreatic tumour growth. To improve delivery of short interfering RNA to the pancreas, Raghu Kalluri and colleagues harness exosomes and show that these endogenous vesicles can bypass immune clearance better than artificial liposomes, probably owing to expression of CD47 in their membrane. The iExosomes are uptaken preferentially by pancreatic tumour cells. The authors suggest that this uptake is facilitated by increased macropinocytosis. iExosomes are able to reduce KRAS oncogenic signalling and reduce tumour growth in mouse models of pancreatic cancer., Author(s): Sushrut Kamerkar [sup.1] , Valerie S. LeBleu [sup.1] , Hikaru Sugimoto [sup.1] , Sujuan Yang [sup.1] , Carolina F. Ruivo [sup.2] [sup.4] , Sonia A. Melo [sup.1] [sup.2] [sup.4] [...]

Objective: To analyze the characteristics of vocal fold movement and glottic closure in patients with laryngeal neurogenic injury. Methods: A total of 185 patients with vocal fold paralysis diagnosed by laryngeal electromyography as neurogenic damage to cricothyroid muscle, thyreoarytenoid muscle and posterior cricoarytenoid muscle were enrolled, they were divided into unilateral vocal fold paralysis group and bilateral vocal fold paralysis group, respectively, and superior laryngeal paralysis group, recurrent laryngeal nerve paralysis group and vagal nerve paralysis group according to nerve injury. The characteristics of vocal fold movement and glottic closure were analyzed under strobe laryngoscope. The qualitative evaluation of vocal fold movement was fixed vocal fold, reduced vocal fold movement and normal vocal fold movement, and the qualitative evaluation of glottic closure was glottic closure and glottic imperfection. The results were analyzed statistically. Results: The proportion of normal, reduced and fixed vocal fold motion in bilateral vocal fold paralysis group was significantly different from that in unilateral vocal fold paralysis group（ P <0.05）, the composition of normal and reduced vocal fold motion in bilateral vocal fold paralysis group（47.70%） was significantly greater than that in unilateral vocal fold paralysis group（12.27%）. There was no significant difference between the proportion of glottic closure and glottic imperfecta in bilateral vocal fold paralysis group and unilateral vocal fold paralysis group（ P <0.05）. The proportion of decreased vocal fold motion in superior laryngeal nerve paralysis group（50.00%） was higher than that in recurrent laryngeal nerve paralysis group（9.32%） and vagal nerve paralysis group（9.00%）. The proportion of decreased and fixed vocal fold motion in superior laryngeal nerve paralysis group, recurrent laryngeal nerve paralysis group and vagal nerve paralysis group was statistically significant（ P <0.05）.There was no significant difference in glottic closure among the three groups（ P <0.05）. Conclusion: Vocal fold movement characteristics of patients with laryngeal neurogenic injury were mainly vocal fold fixation, or normal or weakened vocal fold movement. There may be missed diagnosis of unilateral vocal fold paralysis in clinical practice. In half of the patients with superior laryngeal nerve palsy, vocal fold movement is characterized by vocal fold fixation., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.