Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the ...clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p < 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore ...significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells’ demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine’s complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Inverted OPV devices based on sol‐gel derived vanadium oxides (VOx) as an interfacial layer are demonstrated. The VOx shows excellent characteristics as a hole‐transporting and protecting layer. The ...constructed devices exhibit enhanced performance with the studied polymers and are highly durable under accelerated conditions for long time periods.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A new method for the synthesis of highly substituted naphthyridine‐based polyheteroaromatic compounds in high yields proceeds through rhodium(III)‐catalyzed multiple CH bond cleavage and CC and CN ...bond formation in a one‐pot process. Such highly substituted polyheteroaromatic compounds have attracted much attention because of their unique π‐conjugation, which make them suitable materials for organic semiconductors and luminescent materials. Furthermore, a possible mechanism, which involves multiple chelation‐assisted ortho CH activation, alkyne insertion, and reductive elimination, is proposed for this transformation.
Activated and annulated: A rhodium‐catalyzed one‐pot synthesis of highly substituted polyheteroaromatic compounds from N‐hydroxybenzamidines and alkynes is described. This reaction likely proceeds through multiple CH bond activation and annulation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hand paralysis is one of the most common complications in stroke patients, which severely impacts their daily lives. This article presents a wearable hand rehabilitation system that supports both ...mirror therapy and task-oriented therapy. A pair of gloves, i.e., a sensory glove and a motor glove, was designed and fabricated with a soft, flexible material, providing greater comfort and safety than conventional rigid rehabilitation devices. The sensory glove worn on the nonaffected hand, which contains the force and flex sensors, is used to measure the gripping force and bending angle of each finger joint for motion detection. The motor glove, driven by micromotors, provides the affected hand with assisted driving force to perform training tasks. Machine learning is employed to recognize the gestures from the sensory glove and to facilitate the rehabilitation tasks for the affected hand. The proposed system offers 16 kinds of finger gestures with an accuracy of 93.32%, allowing patients to conduct mirror therapy using fine-grained gestures for training a single finger and multiple fingers in coordination. A more sophisticated task-oriented rehabilitation with mirror therapy is also presented, which offers six types of training tasks with an average accuracy of 89.4% in real time.
Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP ...pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.
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In cancer cells, the epithelial-mesenchymal transition (EMT) confers the ability to invade basement membranes and metastasize to distant sites, establishing it as an appealing target for therapeutic ...intervention. Here, we report a novel function of the master metabolic kinase AMPK in suppressing EMT by modulating the Akt-MDM2-Foxo3 signaling axis. This mechanistic link was supported by the effects of siRNA-mediated knockdown and pharmacologic activation of AMPK on epithelial and mesenchymal markers in established breast and prostate cancer cells. Exposure of cells to OSU-53, a novel allosteric AMPK activator, as well as metformin and AICAR, was sufficient to reverse their mesenchymal phenotype. These effects were abrogated by AMPK silencing. Phenotypic changes were mediated by Foxo3a activation, insofar as silencing or overexpressing Foxo3a mimicked the effects of AMPK silencing or OSU-53 treatment on EMT, respectively. Mechanistically, Foxo3a activation led to the transactivation of the E-cadherin gene and repression of genes encoding EMT-inducing transcription factors. OSU-53 activated Foxo3a through two Akt-dependent pathways, one at the level of nuclear localization by blocking Akt- and IKKβ-mediated phosphorylation, and a second at the level of protein stabilization via cytoplasmic sequestration of MDM2, an E3 ligase responsible for Foxo3a degradation. The suppressive effects of OSU-53 on EMT had therapeutic implications illustrated by its ability to block invasive phenotypes in vitro and metastatic properties in vivo. Overall, our work illuminates a mechanism of EMT regulation in cancer cells mediated by AMPK, along with preclinical evidence supporting a tractable therapeutic strategy to reverse mesenchymal phenotypes associated with invasion and metastasis.
Stroke survivors need continuing exercise intervention to maintain functional status. This study assessed the feasibility and efficacy of an interactive telerehabilitation exergaming system to ...improve balance in individuals with chronic stroke, compared to conventional one-on-one rehabilitation.
In this prospective case-control pilot study, 30 Taiwanese individuals with chronic stroke were enrolled and randomly allocated to an experimental group and a control group. All participants received intervention 3 times per week for 4 weeks in the study hospital. The experiment group underwent telerehabilitation using a Kinect camera-based interactive telerehabilitation system in an independent room to simulate home environment. In contrast, the control group received conventional one-on-one physiotherapy in a dedicated rehabilitation area. The effectiveness of interactive telerehabilitation in improving balance in stroke survivors was evaluated by comparing outcomes between the two groups. The primary outcome was Berg Balance Scale (BBS) scores. Secondary outcomes were performance of the Timed Up and Go (TUG) test, Modified Falls Efficacy Scale, Motricity Index, and Functional Ambulation Category.
Comparison of outcomes between experimental and control groups revealed no significant differences between groups at baseline and post-intervention for all outcome measures. However, BBS scores improved significantly in both groups (control group: p = 0.01, effect size = 0.49; experimental group: p = 0.01, effect size = 0.70). Completion times of TUG tests also improved significantly in the experimental group (p = 0.005, effect size = 0.70).
The Kinect camera-based interactive telerehabilitation system demonstrates superior or equal efficacy compared to conventional one-on-one physiotherapy for improving balance in individuals with chronic stroke. Trial registration ClinicalTrials.gov. NCT03698357. Registered October 4, 2018, retrospectively registered.
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With the progression of molecular techniques, the detection of circulating plasma DNA (cpDNA) is clinically feasible. However, the role of the cpDNA levels in gastric cancer is not well understood. ...This study assessed the mutational profile in primary tumors and clarified the clinical utility of quantitative and qualitative cpDNA alterations in 277 patients with advanced gastric cancer. The concentrations of cpDNA were measured by TaqMan qPCR, and 68 mutations in 8 genes were studied for cpDNA mutations. The median cpDNA concentrations in patients with stages I, II, and III gastric cancer were 3979, 3390 and 4278 copies/mL, respectively, and increased to 11,380 copies/mL in patients with Stage IV gastric cancer (p < 0.001). Among the 35 patients harboring cpDNA mutations, Stage IV patients (100%) were more likely to display high cpDNA levels than were Stage I (33.3%), II (75%) and III patients (66.7%) (p = 0.037). Patients displaying high cpDNA levels were more likely to experience peritoneal recurrence and exhibited significantly lower 5‐year overall survival rates (39.2% vs. 45.8%, p = 0.039) than did patients displaying low cpDNA levels. Only for late stage (Stages III or IV) gastric cancer, patients harboring cpDNA mutations were more likely to experience vascular invasion (20% vs. 2.4%, p = 0.036) and exhibited a lower 5‐year overall survival rate than did those lacking cpDNA mutations (5.6% vs. 31.5%, p = 0.028). High cpDNA levels are associated with peritoneal recurrence and poor prognosis in patients with advanced gastric cancer; harboring cpDNA mutations is associated with poor prognosis among patients with late stage gastric cancer.
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Patients whose gastric cancer returns despite curative surgery tend to suffer poor prognosis. According to the authors of this study; however, it may be possible to catch recurrent disease before it reaches advanced stages using circulating plasma (cp) DNA, a blood‐based biomarker. In advanced gastric cancer patients, cpDNA levels were associated with tumor recurrence and initial recurrence pattern, with high cpDNA levels signaling an increased likelihood of peritoneal recurrence versus locoregional or distant recurrence. Primary tumor mutations in cpDNA were linked to reductions in 5‐year survival, suggesting that cpDNA mutational status can predict poor prognosis in late‐stage disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Calycosin, a bioactive isoflavonoid isolated from root extracts of
, has been reported to inhibit melanogenesis, the mechanism of which remains undefined. In this study, we interrogated the ...mechanistic basis by which calycosin inhibits melanin production in two model systems, i.e., B16F10 melanoma cells and zebrafish embryos. Calycosin was effective in protecting B16F10 cells from α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and tyrosinase activity. This anti-melanogenic effect was accompanied by decreased expression levels of microphthalmia-associated transcription factor (MITF), a key protein controlling melanin synthesis, and its target genes tyrosinase and tyrosinase-related protein-2 (TRP-2) in calycosin-treated cells. Mechanistically, we obtained the first evidence that calycosin-mediated MITF downregulation was attributable to its ability to block signaling pathways mediated by cAMP response element-binding protein (CREB) and p38 MAP kinase. The protein kinase A (PKA) inhibitor H-89 and p38 inhibitor SB203580 validated the premise that calycosin inhibits melanin synthesis and tyrosinase activity by regulating the PKA/CREB and p38 MAPK signaling pathways. Moreover, the in vivo anti-melanogenic efficacy of calycosin was manifested by its ability to suppress body pigmentation and tyrosinase activity in zebrafish embryos. Together, these data suggested the translational potential of calycosin to be developed as skin-lightening cosmeceuticals.
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