Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of ...diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling.
Metformin and phenformin decreased the expression of pro‐apoptotic proteins by inhibiting STAT3 phosphorylation at Ser‐727 and suppressed invasion and migration by inhibiting TGFBR2‐mediated signaling
The concept of the metaverse was first coined in the science fiction novel Snow Crash published 30 years ago, serving as the pregenesis concept of the next groundbreaking development in communication ...and technology fields for several decades. Today, the concept of the metaverse is complicated and often discussed as a multidimensional notion, generally referring to multiple interconnected virtual worlds where large numbers of users can simultaneously interact in embodied form. In this article, we propose the bifold triadic relationships model to help advertising scholars understand how advertising may work in the metaverse and to guide future research endeavors. Although the metaverse as a concept has yet to fully form, we hope that this primer presents a clearer layout of how advertising can be studied at the unit level of triadic relationships among consumer, media, and engagement behaviors in the metaverse space. Using what we know thus far about immersive virtual environments and how they relate to advertising practice and scholarship, the present article serves as an impetus for new directions in advertising theory and research in the metaverse in the years to come.
Background The technique of endoscopic submucosal dissection (ESD) was introduced to be able to obtain en bloc specimens of large early GI neoplasms. The drawback of ESD is its technical difficulty, ...which, consequently, is associated with a higher rate of complication and which requires advanced endoscopic techniques and a long procedure time. Objective To assess the therapeutic outcome of ESD by expert endoscopists who have at least 3 years' experience of EMR in Korea. Design A retrospective, multicenter study. Patients From January 2006 to June 2007, 1000 early gastric cancers in 952 patients (502 men, 450 women; mean age 62.1 years, range 43-90 years) were treated by using ESD at 6 Korean ESD study group (KESG)–related university hospitals in Korea. Intervention We performed ESD procedures with typical sequences (marking, incision, and submucosal dissection). Main Outcome Measurements The rate of en bloc resection, incidence of complication, and length of procedure. Predetermined factors (various endoscopic and final pathologic features) for these outcomes. Results The rates of en bloc resection, complete en bloc resection, vertical incomplete resection, and piecemeal resection were 95.3%, 87.7%, 1.8%, and 4.1%, respectively. The rates of delayed bleeding, significant bleeding, perforation, and surgery related to complication were 15.6%, 0.6%, 1.2%, and 0.2%, respectively. The mean procedure time was 47.8 ± 38.3 minutes. The rates of en bloc resection differed significantly in relation to the location of the lesions (upper portion vs middle portion vs lower portion of the stomach, 88.6% vs 95.2% vs 96.0%, respectively; P = .02), presence of a scar (no vs yes, 96.0% vs 89.5%, respectively; P = .002), and histologic type (low-grade adenoma vs high-grade adenoma vs differentiated early gastric cancer vs undifferentiated early gastric cancer, 95.8% vs 94.6% vs 96.2% vs 83.8%, respectively; P = .007). The rates of delayed bleeding differed significantly in relation to location (upper portion vs lower portion of the stomach, 28.6% vs 13.8%, respectively; P = .003), the size of the tumor (>40 mm vs <20 mm, 28.6% vs 13.7%, respectively; P = .009), recurrent lesion (29.4% vs 15.1%, respectively; P = .024), and macroscopic type (flat vs elevated, 18.8% vs 12.4%, respectively; P = .047). Factors related to the longer procedure time were location (upper portion vs lower portion of the stomach, 64.8 vs 44.1 minutes, respectively; P < .001), the size of the tumor (>40 mm vs < 20 mm, 67.1 vs 42.0 minutes, respectively; P < .001), the presence of ulcer (54.6 vs 46.8 minutes; P < .045), and the presence of a scar (69.2 vs 45.0 minutes; P < .001). Conclusions ESD is an effective and safe therapy in the management of early gastric neoplasms. Endoscopists have to accept the need for advanced endoscopic techniques for performing ESD in the case of large lesions, scar lesions, undifferentiated cancers, or for the lesions in the upper portion of the stomach. Endoscopists require more experience to decrease complications in patients who have a large or recurrent lesion in the upper portion of the stomach; these lesions also take more time to complete the ESD procedure.
Intestinal organoids have recently emerged as an in vitro model relevant to the gut system owing to their recapitulation of the native intestinal epithelium with crypt–villus architecture. However, ...it is unclear whether intestinal organoids reflect the physiology of the in vivo stress response. Here, we systemically investigated the radiation response in organoids and animal models using mesenchymal stem cell‐conditioned medium (MSC‐CM), which contains secreted paracrine factors. Irradiated organoids exhibited sequential induction of viability loss and regrowth after irradiation (within 12 days), similar to the response of the native intestinal epithelium. Notably, treatment with MSC‐CM facilitated the reproliferation of intestinal stem cells (ISCs) and restoration of damaged crypt‐villus structures in both models. Furthermore, Wnt/Notch signaling pathways were commonly upregulated by MSC‐CM, but not radiation, and pharmacologically selective inhibition of Wnt or Notch signaling attenuated the enhanced recovery of irradiated organoids, with increases in ISCs, following MSC‐CM treatment. Interestingly, the expression of Wnt4, Wnt7a, and active β‐catenin was increased, but not notch family members, in MSC‐CM‐treated organoid after irradiation. Treatment of recombinant mouse Wnt4 and Wnt7a after irradiation improved to some extent intestinal epithelial regeneration both in vitro and in vivo. Overall, these results suggested that intestinal organoids recapitulated the physiological stress response of the intestinal epithelium in vivo. Thus, our findings provided important insights into the physiology of intestinal organoids and may contribute to the development of strategies to enhance the functional maturation of engineered organoids.
The extent to which in vitro intestinal organoids system recapitulate the physiology of in vivo stress response remains unclear. Kim and colleagues reported that intestinal organoids recapitulated the in vivo physiological response to radiation exhibiting specific responses to damage and regeneration. Moreover, the authors revealed that MSC‐CM‐activated Wnt4/7a signaling pathway partially improve the intestinal epithelial regeneration both in vitro and in vivo. These findings may contribute to the development of strategies to enhance the functional maturation of engineered organoids.
Large-scale single-cell analyses have become increasingly important given the role of cellular heterogeneity in complex biological systems. However, no current techniques enable optical imaging of ...uniquely-tagged individual cells. Fluorescence-based approaches can only distinguish a small number of distinct cells or cell groups at a time because of spectral crosstalk between conventional fluorophores. Here we investigate large-scale cell tracking using intracellular laser particles as imaging probes that emit coherent laser light with a characteristic wavelength. Made of silica-coated semiconductor microcavities, these laser particles have single-mode emission over a broad range from 1170 to 1580 nm with sub-nm linewidths, enabling massive spectral multiplexing. We explore the stability and biocompatibility of these probes in vitro and their utility for wavelength-multiplexed cell tagging and imaging. We demonstrate real-time tracking of thousands of individual cells in a 3D tumour model over several days showing different behavioural phenotypes.
Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and ...specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin‐mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss‐ and gain‐of‐function experiments revealed that it regulates CRC malignancy through TGF‐β expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF‐β signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.
HAS2 is preferentially overexpressed in malignant‐type CRC cancer cells compared with that in mildtype CRC. By studying cells with loss‐ and gain‐of‐function of HAS2, we demonstrated that HAS2 is a critical regulator for the malignant behavior of CRC such as therapeutic resistance or metastatic ability. Importantly, HAS2 promoted CRC malignancy through HA ligand‐independent TGF‐β regulation.
Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations ...associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.
We report a dual functional sensing mechanism for ultrasensitive chemoresistive sensors based on SnO2–ZnO core–shell nanowires (C–S NWs) for detection of trace amounts of reducing gases. C–S NWs were ...synthesized by a two-step process, in which core SnO2 nanowires were first prepared by vapor–liquid–solid growth and ZnO shell layers were subsequently deposited by atomic layer deposition. The radial modulation of the electron-depleted shell layer was accomplished by controlling its thickness. The sensing capabilities of C–S NWs were investigated in terms of CO, which is a typical reducing gas. At an optimized shell thickness, C–S NWs showed the best CO sensing ability, which was quite superior to that of pure SnO2 nanowires without a shell. The dual functional sensing mechanism is proposed as the sensing mechanism in these nanowires and is based on the combination of the radial modulation effect of the electron-depleted shell and the electric field smearing effect.
Abstract Background The results of recent studies have suggested that high-grade serous ovarian cancer predominantly arises within the fallopian tubes. The reduction of ovarian cancer (OC) risk in ...women with a history of bilateral salpingectomy (BS) has been reported. We performed a meta-analysis to determine the impact of BS in preventing OC in the general population. Methods We searched the PubMed, MEDLINE, and EMBASE databases and CENTRAL in the Cochrane Library for all English-language articles published up to January 2015, using the key words ‘ovarian cancer’ and ‘bilateral salpingectomy.’ Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated by standard meta-analysis techniques. Results Of the 77 studies retrieved, three were included in this meta-analysis, including one cohort study and two population-based case-control studies with 3509 patients who underwent BS and 5,655,702 controls who did not undergo salpingectomy. Over the combined study period, 29 of the 3509 BS patients developed OC compared with 44,006 of the 5,655,702 without salpingectomy. The meta-analysis results based on the fixed effects model revealed a significant decrease in the risk of OC occurrence in the patients who underwent BS relative to the controls (OR = 0.51, 95% CI 0.35–0.75, I2 = 0%). This pattern was also observed in subgroup analysis for the study type. Conclusions Our results suggest that removal of the fallopian tubes is an effective measure to reduce OC risk in the general population. Therefore, prophylactic bilateral salpingectomy should be considered for women who require hysterectomy with benign indications or sterilisation procedures.
Guided by the framework of self‐determination theory (SDT), this study examined the effects of external rewards on undermining customers’ intrinsic motivation to engage in a retail loyalty program. ...Two experiments revealed that participants who received a salient, controlling reward (i.e., a promise of reward with an explicit requirement and deadline, without options of choice) reported lower intrinsic motivation to use the loyalty program than participants who received a nonsalient, autonomy‐supportive reward (i.e., a promise of reward with a less explicit requirement and no deadline, with options of choice). However, the undermined intrinsic motivation of those who received the salient, controlling reward was enhanced when they were given verbal feedback acknowledging their potential negative feelings associated with using the loyalty program. These findings provide important practical implications for designing a more effective loyalty program.
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