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
Unlike the left ventricle (LV), the left atrium (LA) has a thin-walled structure and has been regarded as a simple conduit chamber. However, the unique function of the LA to modulate LV filling has ...recently drawn much attention. Because LA structure and function are directly influenced by the LV filling pressure, LA assessment is an essential step in the diagnosis of diastolic dysfunction that can help predict new-onset atrial fibrillation, assess the risk of further embolic events, and identify high-risk patients for adverse cardiovascular events. Even in the recent era of multimodality imaging, 2-dimensional (2D) echocardiography is the most common imaging method and the central modality for evaluation of LA function. LA strain derived from 2D echocardiography can help assess LA function objectively and demonstrates the 3 distinct phasic motions of the LA cycle. Further, LA strain provides invaluable pathophysiologic information and helps to predict clinical prognosis in various cardiovascular diseases. In this review article, we focus on LA strain: basic concepts, advantages over conventional parameters, and some unresolved issues. Additionally, we present a brief history of the clinical evidence for LA strain. Through this review, we suggest echocardiography for LA strain assessment in clinical practice.
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.
•Immersive virtual environments successfully promote environmental behaviors.•Embodying perceptually rich, interactive experiences leads to paper conservation.•Individuals use 20% less paper after ...cutting down a virtual tree.•The increase in environmental behavior lasts for up to one week afterwards.•An internal environmental locus of control is the underlying mechanism.
Immersive virtual environments (IVEs) allow individuals to see, hear, and feel digital stimuli as if they were in the physical world. Two studies tested the power of embodied experiences within IVEs by comparing the effects of cutting a virtual tree against reading a print description or watching a video depiction of the tree-cutting process to encourage paper conservation. Experiment 1 found that IVEs led participants to consume 20% less paper than participants who read a print description of tree cutting. Experiment 2 demonstrated that IVEs elicited greater self-reported internal environmental locus of control and self-reported environmental behaviors than print and video messages one week following the virtual experience. Moreover, internal environmental locus of control served as a mediator, driving environmental behaviors. We discuss the implications of using embodied experiences for behavior change.
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.
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.
Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to ...prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.
The skin is impacted by every form of external radiation therapy. However, effective therapeutic options for severe, acute radiation-induced skin reactions are limited. Although platelet-rich plasma ...(PRP) is known to improve cutaneous wound healing, its effects in the context of high-dose irradiation are still poorly understood.
We investigated the regenerative functions of PRP by subjecting the dorsal skin of mice to local irradiation (40 Gy) and exposing HaCaT cells to gamma rays (5 Gy). The cutaneous benefits of PRP were gauged by wound size, histologic features, immunostains, western blot, and transepithelial water loss (TEWL). To assess the molecular effects of PRP on keratinocytes of healing radiation-induced wounds, we evaluated AKT signaling.
Heightened expression of keratin 14 (K14) was documented in irradiated HaCaT cells and skin tissue, although the healing capacity of injured HaCaT cells declined. By applying PRP, this capacity was restored via augmented AKT signaling. In our mouse model, PRP use achieved the following: (1) healing of desquamated skin, acutely injured by radiation; (2) activated AKT signaling, improving migration and proliferation of K14 cells; (3) greater expression of involucrin in keratin 10 cells and sebaceous glands; and (4) reduced TEWL, strengthening the cutaneous barrier function.
Our findings indicate that PRP enhances the functions of K14 cells via AKT signaling, accelerating the regeneration of irradiated skin. These wound-healing benefits may have merit in a clinical setting.
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.
n-In2O3 nanorods codecorated with n-Fe2O3 and p-Co3O4 nanoparticles were synthesized by the thermal evaporation of In2S3 powders in an oxidizing atmosphere followed by the solvothermal deposition of ...Fe2O3 and Co3O4 nanoparticles, and their ethanol gas sensing properties were examined. The p-Co3O4-decorated n-In2O3 nanorods exhibited stronger and faster response to ethanol gas than the n-Fe2O3-decorated n-In2O3 nanorods due to the larger modulation of the conduction channel width and interfacial potential barrier height, and stronger catalytic activity of p-Co3O4 than n-Fe2O3. Furthermore, the codecorated In2O3 nanorod sensor exhibited significantly stronger and faster response to ethanol gas than its mono-oxide nanoparticle-decorated counterparts under the condition of the same total amount of the decorating nanoparticles. The origin of the synergistic effects of codecoration on the ethanol sensing properties of the In2O3 nanorod sensor is not the formation of compounds or nanoalloys between the oxides but the formation of a large number of the p–n junctions between the two different types of decorating oxides, i.e., Fe2O3–Co3O4 p–n junctions in addition to the Co3O4–In2O3 p–n junctions.
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