Patient‐derived organoids are being considered as models that can help guide personalized therapy through in vitro anticancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole‐exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an ‘organoid score’ based on the variable anticancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard‐of‐care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression‐free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA‐approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anticancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients.
Whole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated ∼16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In ∼30% of the post-irradiated cells, complex genomic rearrangements, such as chromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.
<div class="section abstract"><div class="htmlview paragraph">Electric vehicles (EV’s) present new challenges to achieving the required noise, vibration & harshness performance (NVH) compared with conventional vehicles. Specifically, high-frequency noise and unexpected noise phenomenon, previously masked by the internal combustion engine can cause annoyance in an EV. Electric motor (E-motor) whine noise caused by electromagnetic excitation during E-motor operation is caused by torque ripple and radial excitation. Under high speed and high load operating conditions, the overall sound level may be low, however high frequency whine noise can impair the vehicle level NVH performance. An example of a previously masked unexpected noise phenomenon is a droning noise that can be caused by manufacturing quality variation of the spline coupling between the rotor shaft of the E-motor and the input shaft of the reducer. It is dominated by multiple higher orders of the E-motor rotation frequency.</div><div class="htmlview paragraph">In this study, the high speed and high load condition whine noise problem was reproduced through electromagnetic and structural analysis. The countermeasures (E-motor geometry refinements to reduce the excitations and mechanical system transfer path modifications to reduce the vibration response) were defined and the effects investigated. Mechanical system modification to improve NVH performance without increasing the mass is challenging. However, E-motor air-gap geometry optimization, such as slot opening modulation and rotor notch modifications achieved significant noise reduction without critical trade-off of other performance.</div><div class="htmlview paragraph">This paper also describes the basic improvement plan proposed through the simulation of the droning noise behavior. The main two manufacturing errors (pitch error in the spline coupling and the alignment error between the rotor and the gearbox shafts) that are responsible for the unexpected droning noise were identified. Using simulation it was shown that the droning noise can be reduced through improved quality control and tolerance design optimization of factors such as axis self-alignment and spline gear tooth quality.</div></div>
As the conventional histopathologic examination of thymic carcinoma (TC) is nonspecific, immunohistochemical studies along with correlative radiographic investigations are needed for its correct diagnosis. TC commonly occurs in the late 5th to early 6th decades of life but is extremely rare in childhood. It may be incidentally detected from chest radiographs taken as routine or for other reasons. However, most patients present with symptoms such as chest pain, cough, shortness of breath, dysphagia and hoarseness, which are directly attributable to the mediastinal mass. Although TC frequently invades the neighboring organs, pleura and pericardium and metastasizes to the lymph nodes, liver and lung at the time of the first diagnosis, initial or late metastasis to the bone has been seldom reported in adults. Indeed, the English literature revealed no earlier report on initial bony metastasis in a child to date. We report a case of TC in a 12-year-old boy who initially presented with scapular osteolysis masquerading as a primary bone tumor to emphasize the usefulness of combined imaging for staging and histologic studies, particularly for such an unexpected case.
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