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miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer. SIGNIFICANCE: These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5151/F1.large.jpg.

The development of next-generation sequencing (NGS) has enabled the discovery of cancer-specific driver gene alternations, making precision medicine possible. However, accurate genetic testing requires a sufficient amount of tumor cells in the specimen. The evaluation of tumor content ratio (TCR) from hematoxylin and eosin (H&E)-stained images has been found to vary between pathologists, making it an important challenge to obtain an accurate TCR. In this study, three pathologists exhaustively labeled all cells in 41 regions from 41 lung cancer cases as either tumor, non-tumor or indistinguishable, thus establishing a "gold standard" TCR. We then compared the accuracy of the TCR estimated by 13 pathologists based on visual assessment and the TCR calculated by an AI model that we have developed. It is a compact and fast model that follows a fully convolutional neural network architecture and produces cell detection maps which can be efficiently post-processed to obtain tumor and non-tumor cell counts from which TCR is calculated. Its raw cell detection accuracy is 92% while its classification accuracy is 84%. The results show that the error between the gold standard TCR and the AI calculation was significantly smaller than that between the gold standard TCR and the pathologist's visual assessment ( p < 0.05 ). Additionally, the robustness of AI models across institutions is a key issue and we demonstrate that the variation in AI was smaller than that in the average of pathologists when evaluated by institution. These findings suggest that the accuracy of tumor cellularity assessments in clinical workflows is significantly improved by the introduction of robust AI models, leading to more efficient genetic testing and ultimately to better patient outcomes. [ABSTRACT FROM AUTHOR]

Background The difference in growth and nutritional status, both important indices of population quality, between Chinese and Japanese children and adolescents is unknown. Aim This study aimed to compare growth and nutritional status between Chinese and Japanese children and adolescents. Subjects and methods The height-for-age and BMI-for-age distribution of 9,226 children and adolescents aged 7–18 years from China and Japan were described with the Lambda Mu and Sigma method. Wasting, overweight and obesity were evaluated based on BMI-for-age cut-offs of the 2007 WHO Child Growth Reference. Results For boys, the overall average height, weight and BMI of Chinese participants were 3.0 cm, 4.8 kg and 1.2 kg/m2 greater compared with Japanese participants, respectively; for girls, these were 4.6 cm, 3.9 kg and 0.6 kg/m2, respectively. Compared with Japanese children, the 3rd, 50th and 97th percentiles of height-for-age, 1Z-score, and 2Z-score of BMI-for-age of Chinese children were greater, whereas the minus 2Z-scores of Chinese children were less. The prevalence of wasting, overweight and obesity among Chinese participants was greater. Conclusions Compared with Japanese children, Chinese children tended to be taller. The worrying burden of overweight, obesity and wasting was recognised among Chinese children.

The incidence of oral cancer has recently been increasing worldwide, particularly among young individuals and women. The primary risk factors for head and neck cancers, including oral and pharyngeal cancers, are smoking, alcohol consumption, poor oral hygiene, and repeated exposure to mechanical stimuli. However, approximately one-third of the patients with oral and pharyngeal cancers are neither smokers nor drinkers, which points to the existence of other mechanisms. Recently, human microbes have been linked to various diseases, including cancer. Oral pathogens, especially periodontal pathobionts, are reported to play a role in the development of colon and other types of cancer. In this study, we employed a series of bioinformatics analyses to pinpoint Fusobacterium nucleatum as the predominant oral bacterial species in oral and pharyngeal cancer tissue samples. We successfully isolated Fn. polymorphum from the saliva of patients with oral cancer and demonstrated that Fn. polymorphum indeed promoted oral squamous cell carcinoma development by activating YAP in a mouse tongue cancer model. Our research offers scientific evidence for the role of the oral microbiome in oral cancer progression and provides insights that would help in devising preventative strategies against oral cancer, potentially by altering oral bacterial profiles. [ABSTRACT FROM AUTHOR]

Thymus- and activation-regulated chemokine (TARC, also known as CCL17) is used as a biomarker for atopic dermatitis. The methods currently used for its measurement are complex, time-consuming, and require large machinery, warranting the need for a method that is simple, has a quick turnaround time, and requires less complex machinery. We evaluated the analytical performance of a novel latex turbidimetric immunoassay method, "Nanopia TARC", on 174 residual serum samples from patients with skin or allergic diseases. This evaluation included the assessment of the limit of blank/detection/quantification (LOB/D/Q), precision, accuracy, linearity, interference, and commutability between Nanopia TARC and "HISCL TARC", based on the chemiluminescent enzyme immunoassay (CLEIA) method. The LOB/D/Q values were 13, 57, and 141 pg/mL, respectively. The coefficient of variation of the repeatability was 0.9–3.8%, and that of the intermediate precision was 2.1–5.4%. The total error of the accuracy was 1.9–13.4%. The linearity was 141 and 19,804 pg/mL for TARC. The correlation coefficient between Nanopia TARC and HISCL TARC determined using the Passing–Bablok regression analysis was 0.999. Furthermore, the concordance of diagnostic criteria with AD was 92%. Nanopia TARC was confirmed to have the same analytical performance for TARC measurement as the existing CLEIA method. [ABSTRACT FROM AUTHOR]

Ribosome biogenesis in the nucleolus is an important process that consumes 80% of a cell's intracellular energy supply. Disruption of this process results in nucleolar stress, triggering the activation of molecular systems that respond to this stress to maintain homeostasis. Although nucleolar stress was originally thought to be caused solely by abnormalities of ribosomal RNA (rRNA) and ribosomal proteins (RPs), an accumulating body of more current evidence suggests that many other factors, including the DNA damage response and oncogenic stress, are also involved in nucleolar stress response signaling. Cells reacting to nucleolar stress undergo cell cycle arrest or programmed death, mainly driven by activation of the tumor suppressor p53. This observation has nominated nucleolar stress as a promising target for cancer therapy. However, paradoxically, some RP mutations have also been implicated in cancer initiation and progression, necessitating caution. In this article, we summarize recent findings on the molecular mechanisms of nucleolar stress and the human ribosomal diseases and cancers that arise in its wake. [ABSTRACT FROM AUTHOR]

Centromere‐associated protein E (CENP‐E) is a kinesin motor protein essential for mitosis and a new target for anticancer agents with less side effects. To rationally design anticancer drug candidates based on structure, it is important to determine the three‐dimensional structure of the CENP‐E motor domain bound to its inhibitor. Here, we report the first crystal structure of the CENP‐E motor domain in complex with a non‐hydrolysable ATP analogue, adenylyl‐imidodiphosphate (AMPPNP). Furthermore, the structure is compared with the ADP‐bound form of the CENP‐E motor domain as well as the AMPPNP‐bound forms of other kinesins. This study indicates that helix α4 of CENP‐E participates in the slow binding of CENP‐E to microtubules. These results will contribute to the development of anticancer drugs targeting CENP‐E. [ABSTRACT FROM AUTHOR]

Phase-I analysis of historical data from a statistical process is a strategic problem in Statistical Process Monitoring and control. Before the establishment of process stability, it is challenging to model historical data. Consequently, a distribution-free approach is a natural choice in Phase-I monitoring. Existing distribution-free Phase-I control charts are suitable for detecting instability in location and scale parameters only and are often insensitive in complex processes involving skewness or shape parameters. A new Phase-I control chart is proposed to identify more general shifts, including location, scale and skewness. The proposed Phase-I scheme is efficient in such a situation. The proposed Phase-I scheme uses subsamples, and the plotting statistic is based on the omnibus multi-sample linear rank statistic corresponding to the location, scale and skewness shifts. The new scheme can identify subsamples that are not in control, and it can also indicate one or more process parameters where a deviation has occurred. The encouraging performance of the proposed scheme is established with a large-scale numerical study based on Monte-Carlo in detecting shifts of various nature in a comprehensive class of situations. An illustration based on monitoring the waiting time data from a customer service centre is given. Some concluding remarks and some future research problems are also offered. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to evaluate the effects of four premolar extractions and orthodontic treatment on changes to the lips and vermilion height during a posed smile.

The patient was a woman in her 60s. She was found to have proteinuria on a health checkup. She did not have any particular subjective symptoms, and no definitive diagnosis was made, despite serological findings indicative of immune abnormalities. A renal biopsy was performed. Light microscopy of renal tissue section revealed mesangial proliferative nephritis. Electron microscopic findings included electron-dense deposits and fibrillar/tubular structures with a diameter of 20–30 nm. These findings suggested the presence of cryoglobulin (CG), but CG was not detected in qualitative or quantitative hematologic tests. Thus, the serum samples were stored at 37°C for a long period of time and then cooled to 4°C. When the obtained precipitates were examined, CG was successfully detected. CG that precipitates only after a long period of time is referred to as slow cryoglobulin (sCG), and sCG is extremely rare. The present case is the first documented case, to our knowledge, of renal disorders caused by sCG. It should be noted that there are some cases in which it takes much time for CG to precipitate. Thus, when CG cannot be detected, it is necessary to spend much time to determine whether CG precipitates. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the fifth most common cancer of female cancer death and leading cause of lethal gynecological cancers. High‐grade serous ovarian carcinoma (HGSOC) is an aggressive malignancy that is rapidly fatal. Many cases of OC show amplification of the 8q24 chromosomal region, which contains the well‐known oncogene MYC. Although MYC amplification is more frequently observed in OCs than in other tumor types, due to the large size of the 8q24 amplicon, the functions of the vast majority of the genes it contains are still unknown. The TIGD5 gene is located at 8q24.3 and encodes a nuclear protein with a DNA‐binding motif, but its precise role is obscure. We show here that TIGD5 often co‐amplifies with MYC in OCs, and that OC patients with high TIGD5 mRNA expression have a poor prognosis. However, we also found that TIGD5 overexpression in ovarian cancer cell lines unexpectedly suppressed their growth, adhesion, and invasion in vitro, and also reduced tumor growth in xenografted nude mice in vivo. Thus, our work suggests that TIGD5 may in fact operate as a tumor suppressor in OCs rather than as an oncogene. [ABSTRACT FROM AUTHOR]

Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic antiinflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, [Rip-cre.sup.+] [Pten.sup.flox/flox] mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in [Rip.sup.+] neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex., Inflammation is an integral component of insulin resistance and type 2 diabetes (1-3), and activation of both circulating monocytes and tissue-resident macrophages is necessary for the development of peripheral insulin [...]

Wheelchair rugby is a contact sport in which falls are common and injury rates are high, yet the characteristics of the falls are still under-reported. We investigated the fall characteristics of men's wheelchair rugby players by functional classification, using all 36 official match videos from the Rio 2016 and Tokyo 2020 summer Paralympic Games. The videos were analyzed to evaluate the number of falls, playing time when the fall occurred, playing phase (offense or defense), contact with other players, foul judgement, direction of the fall, and the body part first in contact with the floor. All 182 men's wheelchair rugby players (Rio 2016, 94; Tokyo 2020, 88) were classified as low-point players or high-point players depending on their functional classification. A total of 200 falls were detected, 27 (13.5%) for low-point players and 173 (86.5%) for high-point players. Significant differences were noted between low-point players and high-point players in the direction of the fall and body part first in contact with the floor. High-point players had more falls in the forward and left-right directions, whereas low-point players were characterized by a higher percentage of falls in the left-right and backward directions. Additionally, high-point players landed on the floor with their hands with high frequency, whereas low-point players landed with their elbows and shoulders more often. Our findings suggest the significance of devising measures to prevent falls during men's wheelchair rugby games according to their functional classification. [ABSTRACT FROM AUTHOR]