Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease spectrum and is defined by limb pain or impending limb loss because of compromised blood flow to the affected ...extremity. Current conventional therapies for CLI include amputation, bypass surgery, endovascular therapy, and pharmacological approaches. Although these conventional therapeutic strategies still remain as the mainstay of treatments for CLI, novel and promising therapeutic approaches such as proangiogenic gene/protein therapies and stem cell‐based therapies have emerged to overcome, at least partially, the limitations and disadvantages of current conventional therapeutic approaches. Such novel CLI treatment options may become even more effective when other complementary approaches such as utilizing proper bioscaffolds are used to increase the survival and engraftment of delivered genes and stem cells. Therefore, herein, we address the benefits and disadvantages of current therapeutic strategies for CLI treatment and summarize the novel and promising therapeutic approaches for CLI treatment. Our analyses also suggest that these novel CLI therapeutic strategies show considerable advantages to be used when current conventional methods have failed for CLI treatment.
Conventional therapies critical limb ischemia (CLI) treatment encompass surgical approaches, by which the blood flow to the ischemic tissue/limb is increased. Some novel promising approaches have been shown to be effective and safe, including the application of proangiogenic gene(s) and/or protein(s), drugs, and (stem) cells such as bone marrow (BM)/peripheral blood mononuclear cells, endothelial progenitor cells, mesenchymal stem cells, and adipose‐derived stem cells (whether to be used with bioscaffolds or alone).
The progression of colorectal carcinoma (CRC) to invasive and metastatic disease may involve localized occurrences of epithelial-mesenchymal transition (EMT). However, mechanisms of the EMT process ...in CRC progression are not fully understood. We previously showed that knockdown of signal transducer and activator of transcription 3 (STAT3) up-regulated E-cadherin (a key component in EMT progression) in CRC. In this study, we examined the roles of STAT3 in CRC EMT and ZEB1, an EMT inducer, in STAT3-induced down-regulation of E-cadherin. Knockdown of STAT3 significantly increased E-cadherin and decreased N-cadherin and vimentin expressions in highly invasive LoVo CRC cells. Meanwhile, overexpression of STAT3 significantly reduced E-cadherin and enhanced N-cadherin and vimentin expressions in weakly invasive SW1116 CRC cells. Activation of STAT3 significantly increased CRC cell invasiveness and resistance to apoptosis. Knockdown of STAT3 dramatically enhanced chemosensitivity of CRC cells to fluorouracil. STAT3 regulated ZEB1 expression in CRC cells, and the STAT3-induced decrease in E-cadherin and cell invasion depended on activation of ZEB1 in CRC cells. Additionally, pSTAT3Tyr-705 and ZEB1 expressions were significantly correlated with TNM (tumor, lymph node, and metastasis stages) (p < 0.01). In conclusion, STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC. ZEB1 may participate in STAT3-induced cell invasion and E-cadherin down-regulation in CRC cells. The expressions of pSTAT3Tyr-705 and ZEB1 may be positively associated with CRC metastasis. Our data may provide potential targets to prevent and/or treat CRC invasion and metastasis.
Colorectal cancer (CRC) to metastatic disease may involve the epithelial-mesenchymal transition (EMT).
STAT3 may regulate N-cadherin, vimentin, and ZEB1 expressions. STAT3-induced cell invasion and down-regulation of E-cadherin may depend on ZEB1.
STAT3 may mediate CRC EMT progression and ZEB1 expression. Activation of STAT3 and ZEB1 proteins may contribute to worse prognosis in CRC patients.
Our data may provide potential targets to prevent and/or treat CRC invasion.
Predicting the future popularity of commodities has always been a significant issue in information filtering research. Existing methods predominantly rely on the historical popularity of products, ...assuming that historically popular items will continue to be popular in the future due to preferential attachment. However, this method has limitations as it neglects the intricate structural information within the bipartite networks connecting users and items. The prediction method based on preferential attachment fails for commodities with the same degree of popularity. In this paper, we propose a popularity prediction method that aggregates user recommendation results to forecast item popularity. The method is general and applicable to any recommendation algorithm. For simplicity, we validate the method using the classic collaborative filtering algorithm. Experiments demonstrate that this method significantly outperforms the preferential attachment predictor in accurately predicting the future popularity of niche commodities.
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•Preferential attachment fails to work on commodities with the same degree.•The method aggregates recommendations for all users to predict item popularity.•Our method surpasses preferential attachment in niche items popularity prediction.•The method applies to any recommendation algorithm.
Neurotrophins and their receptors are key molecules that are known to be critical in regulating nervous system development and maintenance and have been recognized to be also involved in regulating ...tissue formation and healing in skeletal tissues. Studies have shown that neurotrophins and their receptors are widely expressed in skeletal tissues, implicated in chondrogenesis, osteoblastogenesis, and osteoclastogenesis, and are also involved in regulating tissue formation and healing events in skeletal tissue. Increased mRNA expression for neurotrophins NGF, BDNF, NT‐3, and NT‐4, and their Trk receptors has been observed in injured bone tissues, and NT‐3 and its receptor, TrkC, have been identified to have the highest induction at the injury site in a drill‐hole injury repair model in both bone and the growth plate. In addition, NT‐3 has also recently been shown to be both an osteogenic and angiogenic factor, and this neurotrophin can also enhance expression of the key osteogenic factor, BMP‐2, as well as the major angiogenic factor, VEGF, to promote bone formation, vascularization, and healing of the injury site. Further studies, however, are needed to investigate if different neurotrophins have differential roles in skeletal repair, and if NT‐3 can be a potential target of intervention for promoting bone fracture healing.
Increasing evidence now suggests that neurotrophins also have important roles in bone. Among the neurotrophins and receptors, the NT‐3/TrkC signaling (induced far more prominently compared to other NTs and other Trk receptors) may potentially play a prominent role in the bone healing.
The serine/threonine phosphatase PP4 has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. We previously showed that PP4 is required ...for mouse B cell development, germinal center (GC) formation and immunoglobulin (Ig) class switch recombination (CSR). Here, we investigate the mechanisms underlying this requirement and demonstrate that murine PP4-deficient B lymphocytes have a defect in cell proliferation. Strikingly, the DNA damage response pathway that involves ATM/p53 and is linked to cell cycle arrest and impaired cell survival is strongly induced in these mutant B cells. In response to LPS + IL-4, stimuli that trigger IgG1 production, these PP4-deficient B cells show inefficient phosphorylation of ATR, leading to reduced retention of γH2AX-NBS1 complexes at sites of DNA damage, and compromised switching to IgG1. However, beyond the cell proliferation phase, conditional deletion of PP4 under the control of AID/cre completely restores normal IgG1 production in mutant B cell cultures. In vivo, co-deletion of PP4 and p53 by AID/cre partially rescues switching to IgG1 in B cells of mice immunized with TNP-KLH. Our findings establish that PP4 is indispensable for preventing DNA replication stress that could interfere with CSR, thereby promoting antibody switching during the humoral immune response.
Although there is evidence to support the beneficial effects of statins on major cardiovascular events, few studies address the protective effect of statins on limb outcome.
To investigate whether ...the use of statin is associated with a risk reduction in lower-extremity amputation in type 2 diabetes mellitus (DM) patients with peripheral arterial disease (PAD).
Observational cohort study.
A nationwide DM database in Taiwan from 2000 to 2011.
A total of 69,332 patients aged ≥20 years with DM and PAD were identified.
Patients were divided into three groups: 11,409 patients were statin users, 4430 patients used nonstatin lipid-lowering agents, and 53,493 patients were nonusers.
The primary outcome was lower-extremity amputation. Secondary outcomes were in-hospital cardiovascular death and all-cause mortality.
Compared with nonusers, statin users were associated with lower risks of lower-extremity amputation adjusted hazard ration (aHR), 0.75; 95% confidence interval (CI), 0.62 to 0.90, in-hospital cardiovascular death (aHR, 0.78; 95% CI, 0.69 to 0.87), and all-cause mortality (aHR, 0.73; 95% CI, 0.69 to 0.77). In the propensity score matching analysis, the effect of statin on the risk of lower-extremity amputation was consistent. Only statin users were associated with the risk reduction of lower-extremities amputation (HR, 0.77; 95% CI, 0.61 to 0.97) and cardiovascular death (HR, 0.78; 95% CI, 0.68 to 0.89) when taking competing risk of death into consideration.
Compared with statin nonusers who were never treated with lipid-lowering drugs, this study found that statin users had a lower risk of lower-extremity amputation and cardiovascular death in patients with DM and PAD.
The prognostic value of chronic obstructive pulmonary disease (COPD) as a comorbidity in heart failure has been well documented. However, the role of pulmonary function indices in patients with heart ...failure and preserved ejection fraction (HFpEF) remains to be elucidated. Subjects with HFpEF received pulmonary function tests and echocardiogram. Total lung capacity (TLC), residual volume (RV), forced expiratory flow rate between 25% and 75% of vital capacity (FEF25-75), forced expiratory volume in the 1.sup.st second (FEV1), forced vital capacity (FVC), and vital capacity (VC) were measured. Echocardiographic indices, including pulmonary artery systolic pressure (PASP), the ratio of early ventricular filling flow velocity to the septal mitral annulus tissue velocity (E/e'), and left ventricular mass (LVM), were recorded. National Death Registry was linked for the identification of mortality. A total of 1194 patients (72.4±13.2 years, 59% men) were enrolled. PASP, E/e' and LVM were associated with either obstructive (RV/TLC, FEV1 and FEF25-75) or restrictive (VC and TLC) ventilatory indices. During a mean follow-up of 23.0±12.8 months, 182 patients died. Subjects with COPD had a lower survival rate than those without COPD. While VC, FVC, RV/TLC, and FEV1 were all independently associated with all-cause mortality in patients without COPD, only FEF25-75 was predictive of outcomes in those with COPD. The abnormalities of pulmonary function were related to the cardiac hemodynamics in patients with HFpEF. In addition, these ventilatory indices were independently associated with long-term mortality, especially in those without COPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer chemotherapy can significantly impair the bone formation and cause myelosuppression; however, their recovery potentials and mechanisms remain unclear. This study investigated the roles of the ...β‐catenin signaling pathway in bone and bone marrow recovery potentials in rats treated with antimetabolite methotrexate (MTX) (five once‐daily injections, 0.75 mg/kg) with/without β‐catenin inhibitor indocyanine green (ICG)‐001 (oral, 200 mg/kg/day). ICG alone reduced trabecular bone volume and bone marrow cellularity. In MTX‐treated rats, ICG suppressed bone volume recovery on Day 11 after the first MTX injection. ICG exacerbated MTX‐induced decreases on Day 9 osteoblast numbers on bone surfaces, their formation in vitro from bone marrow stromal cells (osteogenic differentiation/mineralization), as well as expression of osteogenesis‐related markers Runx2, Osx, and OCN in bone, and it suppressed their subsequent recoveries on Day 11. On the other hand, ICG did not affect MTX‐induced increased osteoclast density and the level of the osteoclastogenic signal (RANKL/OPG expression ratio) in bone, suggesting that ICG inhibition of β‐catenin does nothing to abate the increased bone resorption induced by MTX. ICG also attenuated bone marrow cellularity recovery on Day 11, which was associated with the suppressed recovery of CD34+ or c‐Kit+ hematopoietic progenitor cell contents. Thus, β‐catenin signaling is important for osteogenesis and hematopoiesis recoveries following MTX chemotherapy.
Acute intense chemotherapy with antimetabolite methotrexate (MTX) causes trabecular bone loss and bone marrow cell depletion, which can recover after chemotherapy in rats. Inhibition of β‐catenin signaling using inhibitor (ICG‐001) suppresses the recovery of trabecular bone volume and bone marrow cellularity following MTX chemotherapy. β‐catenin signaling was important for bone marrow cell osteogenesis and hematopoietic progenitor cell content recovery.
Injectable hydrogel allows irregular surgical defects to be completely filled, lessens the risk of implant migration, and minimizes surgical defects due to the solution–gel state transformation. ...Here, we first propose a method for preparing oxidized hyaluronic acid/adipic acid dihydrazide (oxi-HA/ADH) injectable hydrogel by chemical cross-linking under physiological conditions. Fourier transform infrared spectrometry and trinitrobenzene sulfonate assay were used to confirm the oxidation of hyaluronic acid. Rheological properties were measured to evaluate the working ability of the hydrogel for further clinical application. The oxi-HA/ADH in situ forming hydrogel can transform from liquid form into a gel-like matrix within 3–8min, depending on the operational temperature. Furthermore, hydrogel degradation and cell assessment is also a concern for clinical application. Injectable oxi-HA/ADH8 hydrogel can maintain its gel-like state for at least 5weeks with a degradation percentage of 40%. Importantly, oxi-HA/ADH8 hydrogel can assist in nucleus pulposus cell synthesis of type II collagen and aggrecan mRNA gene expression according to the results of real-time PCR analysis, and shows good biocompatibility based on cell viability and cytotoxicity assays. Based on the results of the current study, oxi-HA/ADH hydrogel may possess several advantages for future application in nucleus pulposus regeneration.
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