In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms HHS Public AccessAuthor manuscript Nat Biotechnol. Author manuscript; available in PMC 2017 November 01. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript (CRC) and metastasis that rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/ Δ;Kras G12D/+ ;Trp53Δ/ Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.Recent tumor sequencing studies have identified a large number of candidate genes that are mutated in CRCs and may contribute to carcinogenesis, tumor phenotype, and treatment responses in subsets of patients. 1,2 Traditionally, functional assessment of putative cancerassociated genes in vivo has required the development of genetically engineered mouse models (GEMMs) of CRC through extensive intercrossing or de novo generation of genetargeted mice, which is expensive and time consuming. Most GEMMs of CRC such as the Apc Min mouse 3,4 are also limited by delayed tumor onset (i.e., 2-4 months) and high tumor burden (i.e., 30-100 polyps) in the small intestine, which is a rare location for human intestinal tumors and precludes study of tumor progression beyond early adenomas or longitudinal studies using colonoscopy 5,6 . Tumorigenesis can be localized to the colon with either Apc loss driven by a colon-specific promoter, which is limited by slow tumor growth (i.e., 4-6 months) 7-9 , or somatic deletion of Apc in the distal colon of Apc fl/fl mice with rectal enema of adenoviral Cre, which is requires colonic injury and/or time-consuming surgery 10-12 .In addition to GEMMs, human and mouse cell lines are used to model CRC in vivo. Typical sites of transplantation are the mouse flank or kidney capsule, which do not recapitulate the native stroma of the colon mucosa. 6 Several groups have sought to orthotopically deliver tumor cell lines into the mouse colon, either surgically into the cecal serosa 13 (which is not the relevant tissue layer for CRC development) or into the...

This paper investigates the limited attainment of adult compared to child language acquisition in terms of learned attention to morphological cues. It replicates Ellis and Sagarra in demonstrating short-term learned attention in the acquisition of temporal reference in Latin, and it extends the investigation using eye-tracking indicators to determine the extent to which these biases are overt or covert. English native speakers learned adverbial and morphological cues to temporal reference in a small set of Latin phrases under experimental conditions. Comprehension and production data demonstrated that early experience with adverbial cues enhanced subsequent use of this cue dimension and blocked the acquisition of verbal tense morphology. Effects of early experience of verbal morphology were less pronounced. Eye-tracking measures showed that early experience of particular cue dimensions affected what participants overtly focused upon during subsequent language processing and how this overt study resulted in turn in covert attentional biases in comprehension and in productive knowledge.Naturalistic second language acquisition (L2A) tends not to reach nativelike ability. Although it may be sufficient for everyday communicative purposes, adultacquired language predominantly includes nouns, verbs, and adverbs with closedclass items, in particular grammatical morphemes and prepositions, that fail to be put to full nativelike use (

Limbless animals like snakes inhabit most terrestrial environments, generating thrust to overcome drag on the elongate body via contacts with heterogeneities. The complex body postures of some snakes and the unknown physics of most terrestrial materials frustrates understanding of strategies for effective locomotion. As a result, little is known about how limbless animals contend with unplanned obstacle contacts. We studied a desert snake, Chionactis occipitalis, which uses a stereotyped head-to-tail traveling wave to move quickly on homogeneous sand. In laboratory experiments, we challenged snakes to move across a uniform substrate and through a regular array of force-sensitive posts. The snakes were reoriented by the array in a manner reminiscent of the matter-wave diffraction of subatomic particles. Force patterns indicated the animals did not change their self-deformation pattern to avoid or grab the posts. A model using open-loop control incorporating previously described snake muscle activation patterns and body-buckling dynamics reproduced the observed patterns, suggesting a similar control strategy may be used by the animals. Our results reveal how passive dynamics can benefit limbless locomotors by allowing robust transit in heterogeneous environments with minimal sensing.

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A qualitative study of lymphoma survivors living in rural Georgia was conducted using 12 individual semistructured telephone interviews. The travel distance was the greatest barrier to care, with other issues including communication and navigating between local clinics and larger cancer centers. The participants saw technology as an important solution and detailed their research priorities. Background: We gathered rural patient perspectives on lymphoma care and unmet needs throughout the treatment course to better understand their attitudes toward treatment and their barriers to participating in clinical research studies. Patients and Methods: We conducted 12 individual semi-structured telephone interviews in the spring of 2018 with lymphoma survivors from rural counties in Georgia. Patients were identified by a residential address in counties classified as rural according to the Rural-Urban Commuting Areas codes. Participants were recruited from regional patient education conferences and from current research participants at a university research hospital in Georgia. The interviews were recorded and transcribed verbatim. Thematic analysis and MAXQDA, version 18.0.8, were used to facilitate a constant comparative coding process during theme development. Results: The greatest barrier to care was the travel distance. The participants described difficulty navigating between local clinics and larger cancer centers. The lack of communication between the local and specialized clinics complicated the process, and participants had difficulty contacting or seeking advice from the team at the larger cancer centers. Seeking treatment from specialized clinics farther away introduced additional barriers. Most participants agreed that the use of technology was important for improved communication. Participants described lymphoma etiology, subtype-specific studies, alternative therapies, and quality of life as key research priorities. Conclusion: These findings suggest that targeted research and interventions are necessary to address the specific needs of rural patients with and survivors of lymphoma. To address the disparity in health outcomes within rural populations, healthcare professionals and investigators can use these data to engage rural patients in treatment decision-making and research planning.