Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients’ personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients’ samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers.
Highlights d Tumor organoid cultures from >1,000 patients reveal genomic/transcriptomic fidelity d Establishment of chemically defined minimal medias for each solid tumor type d Pan-cancer neural network predicts drug response from label-free light microscopy
Point mutations in ras genes have been found in a large number and wide variety of human tumors. These oncogenic Ras mutants are locked in an active GTP-bound state that leads to a constitutive and deregulated activation of Ras function. The dogma that ras oncogenes are dominant, whereby the mutation of a single allele in a cell will predispose the host cell to transformation regardless of the presence of the normal allele, is being challenged. We have seen that increasing amounts of Ras protooncogenes are able to inhibit the activity of the N-Ras oncogene in the activation of Elk in NIH 3T3 cells and in the formation of foci. We have been able to determine that the inhibitory effect is by competition between Ras protooncogenes and the N-Ras oncogene that occurs first at the effector level at the membranes, then at the processing level and lastly at the effector level in the cytosol. In addition, coexpression of the N-Ras protooncogene in thymic lymphomas induced by the N-Ras oncogene is associated with increased levels of p107, p130 and cyclin A and decreased levels of Rb. In the present report, we have shown that the N-Ras oncogene is not truly dominant over Ras protooncogenes and their competing activities might be depending on cellular context. Key words: oncogene inhibition; N-Ras; protooncogene; Ras processing; Ras effectors ras genes play an important role in a variety of differentiation processes and signal transduction, including the regulation of cell proliferation, vesicle movement, cell survival, T-cell activation, apoptosis and cytoskeleton. 1,2 The 3 ras genes encode 4 highly related proteins of 21 kd in size that are ubiquitously expressed: N-Ras, H-Ras, K-RasA and K-RasB. 2,3 Ras is synthesized on free ribosomes as a soluble inactive protein that requires several posttranslational modifications in order to reach the cell membranes where it exhibits its biologic activity. These modifications include prenylation, proteolysis, carboxymethylation and palmitoylation. 4 -7 Once activated by ligand-mediated extracellular stimuli, Ras induces the activation of effector molecules to propagate downstream signals in the cytoplasm and nucleus of the cell. Ras effectors preferentially bind to Ras-GTP through the effector domain loop found in amino acids 32-40. There are several different mammalian proteins that have been described as Ras effectors: Raf, phosphatidylinositol 3-kinase (PI3K), Ral GDP dissociation stimulator (RalGDS), members of the Rho family, mitogen-activating protein kinase 1 (MEKK1), Nore1, among others. 2,3,8 Specific point mutations in ras genes at codons 12, 13 and 61 have been found in a large number and wide variety of human tumors. 9 These mutations render Ras as an oncogene since it is constitutively active (in the GTP-bound form), leading to a deregulated activation of Ras function. 2,3,5,9 -11 In order to dissect the effects of the different downstream pathways of Ras, oncogenic mutants in the effector domain of Ras have been characterized. Thus, Ras/V12/E38 binds Raf and not PI3...
Emerging evidence suggests that ribosome heterogeneity may have important functional consequences in the translation of specific mRNAs within different cell types and under various conditions. Ribosome heterogeneity comes in many forms including post-translational modification of ribosome proteins (RPs), absence of specific RPs, and inclusion of different RP paralogs. The Drosophila genome encodes two RpS5 paralogs, RpS5a and RpS5b. While RpS5a is ubiquitously expressed, RpS5b exhibits enriched expression in the reproductive system. Deletion of RpS5b results in female sterility marked by developmental arrest of egg chambers at stages 7-8, disruption of vitellogenesis, and posterior follicle cell (PFC) hyperplasia. While transgenic rescue experiments suggest functional redundancy between RpS5a and RpS5b, molecular, biochemical, and ribo-seq experiments indicate that RpS5b mutants display increased rRNA transcription and RP production, accompanied by increased protein synthesis. Loss of RpS5b results in microtubule-based defects and mislocalization of Delta and Mindbomb1, leading to failure of Notch pathway activation in PFCs. Together, our results indicate that germ cell specific expression of RpS5b promotes proper egg chamber development by ensuring the homeostasis of functional ribosomes.
Background : The presence of mild traumatic brain injury (mTBI) increases post-traumatic stress disorder (PTSD) symptoms in the months following injury. However, factors that link mTBI and PTSD development are still unclear. Acute stress responses after trauma have been associated with PTSD development. mTBI may impair cognitive functions and increase anxiety immediately after trauma. Objective : This research aimed to test the possibility that mTBI increases acute stress symptoms rapidly, which in turn results in PTSD development in the subsequent months. Method : Fifty-nine patients were recruited from the emergency rooms of local hospitals. Post-mTBI, acute stress, and PTSD symptom severity were measured using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Acute Stress Disorder Scale (ASDS), and PTSD Checklist for DSM-5 (PCL-5), respectively. Results : Moderated mediation analysis indicated that ASDS, at 2 weeks post-trauma, mediated the relationship between RPQ scores at 2 weeks and PCL-5 scores at 3 months post-trauma, only for patients who met mTBI diagnostic criteria. Conclusions : These findings present preliminary evidence suggesting that acute stress disorder symptoms may be one of the mechanisms involved in the development of PTSD among trauma survivors who have experienced mTBI, which provides a theoretical basis for early intervention of PTSD prevention after mTBI.
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