Gut microbiota in cancer: insights on microbial metabolites and therapeutic strategies.

In recent years, the role of gut microbiota in cancer treatment has attracted substantial attention. It is now well established that gut microbiota and its metabolites significantly contribute to the incidence, treatment, and prognosis of various cancers. This review provides a comprehensive review on the pivotal role of gut microbiota and their metabolites in cancer initiation and progression. Furthermore, it evaluates the impact of gut microbiota on the efficacy and associated side effects of anticancer therapies, including radiotherapy, chemotherapy, and immunotherapy, thus emphasizing the clinical importance of gut microbiota reconstitution in cancer treatment.

Activation of aldehyde dehydrogenase-2 improves ischemic random skin flap survival in rats.

Objective: Random skin flaps have many applications in plastic and reconstructive surgeries. However, distal flap necrosis restricts wider clinical utility. Mitophagy, a vital form of autophagy for damaged mitochondria, is excessively activated in flap ischemia/reperfusion (I/R) injury, thus inducing cell death. Aldehyde dehydrogenase-2 (ALDH2), an allosteric tetrameric enzyme, plays an important role in regulating mitophagy. We explored whether ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) could reduce the risk of ischemic random skin flap necrosis, and the possible mechanism of action. Methods: Modified McFarlane flap models were established in 36 male Sprague-Dawley rats assigned randomly to three groups: a low-dose Alda-1 group (10 mg/kg/day), a high-dose Alda-1 group (20 mg/kg/day) and a control group. The percentage surviving skin flap area, neutrophil density and microvessel density (MVD) were evaluated on day 7. Oxidative stress was quantitated by measuring the superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Blood perfusion and skin flap angiogenesis were assessed via laser Doppler flow imaging and lead oxide-gelatin angiography, respectively. The expression levels of inflammatory cytokines (IL-1ß, IL-6, and TNF-α), vascular endothelial growth factor (VEGF), ALDH2, PTEN-induced kinase 1 (PINK1), and E3 ubiquitin ligase (Parkin) were immunohistochemically detected. Indicators of mitophagy such as Beclin-1, p62, and microtubule-associated protein light chain 3 (LC3) were evaluated by immunofluorescence. Results: Alda-1 significantly enhanced the survival area of random skin flaps. The SOD activity increased and the MDA level decreased, suggesting that Alda-1 reduced oxidative stress. ALDH2 was upregulated, and mitophagy-related proteins (PINK1, Parkin, Beclin-1, p62, and LC3) were downregulated, indicating that ALDH2 inhibited mitophagy through the PINK1/Parkin signaling pathway. Treatment with Alda-1 reduced neutrophil infiltration and expressions of inflammatory cytokines. Alda-1 significantly upregulated VEGF expression, increased the MVD, promoted angiogenesis, and enhanced blood perfusion. Conclusion: ALDH2 activation can effectively enhance random skin flap viability via inhibiting PINK1/Parkin-dependent mitophagy. Moreover, enhancement of ALDH2 activity also exerts anti-inflammatory and angiogenic properties.

The Effect of Cutting Fluid on Machined Surface Integrity of Ultra-High-Strength Steel 45CrNiMoVA.

The surface integrity of ultra-high-strength steel has a significant influence on service performance, and cutting fluid plays an important role in maintaining surface integrity in production. In this paper, the surface integrity of ultra-high-strength steel 45CrNiMoVA was investigated under three cutting fluids: HY-103 (micro-emulsion), TRIM E709 (emulsion), and Vasco 7000 (micro-emulsion) from the aspects of cutting force, surface morphology, residual stress, micro hardness, microstructure, etc. The results showed that the changing trend of the cutting forces in three directions is HY-103 > Vasco 7000 > TRIM E709. The TRIM E709 contains the maximum lubricants, which reduce cutting force and Sa roughness, while the Vasco 7000 contains the minimum corrosive elements, which results in the least pitting. Both tangential and axial stresses under cutting fluid are tensile stresses. TRIM E709 and Vasco 7000 are reduced axially by 4.45% and 7.60% relative to HY-103, respectively. The grain refinement layer depths of HY-103, TRIM E709, and Vasco 7000 are 9 µm, 4 µm, and 8 µm, respectively, and TRIM E709 can induce recrystallized grains to grow along {001} of the sample cross section, which results from the lowest cooling rate. This work may provide an innovative control strategy for cutting fluid to improve surface integrity and service performance.

Effect of Cutting Fluid on Milled Surface Quality and Tool Life of Aluminum Alloy.

The machining process of aluminum alloy usually produces built-up edge and tool sticking problems due to their low hardness and large plastic deformation, which may further affect the machined surface quality and tool life. This paper aims to investigate the influence of different cutting fluids on the machined surface quality and tool life during the milling process of 7050 aluminum alloy. A novel cutting fluid (QC-2803) was considered in the study, which is synthesized by addition of alkyl alcohol amide and chlorinated polyolefin, and the traditional cutting fluid (CCF-10) was used as the control group. The physical and chemical properties of two cutting fluids were characterized. The milling process of 7050 aluminum alloy was carried out under two different cutting fluid conditions. The machined surface morphology, cutting force and tool wear morphology were observed during the process. Results show that the surface tension of the novel cutting fluid is significantly lower than that of the traditional cutting fluid, which makes it easier to produce a lubricating film between the aluminum alloy and tool, and further benefits the machined surface quality and tool life. As a result, the surface roughness and cutting force are reduced by ~20.0% and ~42.9%, respectively, and the tool life is increased by 25.6% in the case of the novel cutting fluid (QC-2803). The results in this paper revealed the important laws of cutting fluid with metal surface quality, cutting performance and tool wear, which helps to control the machined surface quality and tool life by the selection of cutting fluid during metal milling.

Effect of Cutting Fluid on Machined Surface Integrity and Corrosion Property of Nickel Based Superalloy.

Superalloy parts place high demands on machined surface integrity and serviceability. In the machining process of superalloys, the cutting fluid is usually used to improve the machining performance. Cutting fluids with cooling and lubrication functions have a relatively large effect on the surface microstructure and residual stress as well. The corrosion damage caused by cutting fluid to the machined surface, during machining and residual, are also worth considering. In this paper, the machining performance of typical binary Ni Cr solid solution, age-hardened, nickel-based superalloy NiCr20TiAl T6, under two commonly used cutting fluids, Blasocut and E709, was analyzed, including cutting performance, surface quality, machining surface corrosion characteristics, and so on. The results showed that the surface residual stress could be improved by adding both cutting fluids compared with the deionized water. Blasocut had better lubrication properties, which could reduce friction and heat production. Pitting holes were found on the polished surface after 45 days with E709 cutting fluid, which was more corrosive than Blasocut. According to this research, a reasonable cutting fluid can be selected to reduce the surface corrosion and improve the service life and performance of parts.

A Novel Multi-Task Learning Model with PSAE Network for Simultaneous Estimation of Surface Quality and Tool Wear in Milling of Nickel-Based Superalloy Haynes 230.

For data-driven intelligent manufacturing, many important in-process parameters should be estimated simultaneously to control the machining precision of the parts. However, as two of the most important in-process parameters, there is a lack of multi-task learning (MTL) model for simultaneous estimation of surface roughness and tool wear. To address the problem, a new MTL model with shared layers and two task-specific layers was proposed. A novel parallel-stacked auto-encoder (PSAE) network based on stacked denoising auto-encoder (SDAE) and stacked contractive auto-encoder (SCAE) was designed as the shared layers to learn deep features from cutting force signals. To enhance the performance of the MTL model, the scaled exponential linear unit (SELU) was introduced as the activation function of SDAE. Moreover, a dynamic weight averaging (DWA) strategy was implemented to dynamically adjust the learning rate of different tasks. Then, the time-domain features were extracted from raw cutting signals and low-frequency reconstructed wavelet packet coefficients. Frequency-domain features were extracted from the power spectrum obtained by the Fourier transform. After that, all features were combined as the input vectors of the proposed MTL model. Finally, surface roughness and tool wear were simultaneously predicted by the trained MTL model. To verify the superiority and effectiveness of the proposed MTL model, nickel-based superalloy Haynes 230 was machined under different cutting parameter combinations and tool wear levels. Some other intelligent algorithms were also implemented to predict surface roughness and tool wear. The results showed that compared with the support vector regression (SVR), kernel extreme learning machine (KELM), MTL with SDAE (MTL_SDAE), MTL with SCAE (MTL_SCAE), and single-task learning with PSAE (STL_PSAE), the estimation accuracy of surface roughness was improved by 30.82%, 16.67%, 14.06%, 26.17%, and 16.67%, respectively. Meanwhile, the prediction accuracy of tool wear was improved by 46.74%, 39.57%, 41.51%, 38.68%, and 39.57%, respectively. For practical engineering application, the dimensional deviation and surface quality of the machined parts can be controlled through the established MTL model.

Structural and advanced imaging in predicting MGMT promoter methylation of primary glioblastoma: a region of interest based analysis.

BACKGROUND: The methylation status of oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with treatment response in glioblastoma(GBM). Using pre-operative MRI techniques to predict MGMT promoter methylation status remains inconclusive. In this study, we investigated the value of features from structural and advanced imagings in predicting the methylation of MGMT promoter in primary glioblastoma patients. METHODS: Ninety-two pathologically confirmed primary glioblastoma patients underwent preoperative structural MR imagings and the efficacy of structural image features were qualitatively analyzed using Fisher's exact test. In addition, 77 of the 92 patients underwent additional advanced MRI scans including diffusion-weighted (DWI) and 3-diminsional pseudo-continuous arterial spin labeling (3D pCASL) imaging. Apparent diffusion coefficient (ADC) and relative cerebral blood flow (rCBF) values within the manually drawn region-of-interest (ROI) were calculated and compared using independent sample t test for their efficacies in predicting MGMT promoter methylation. Receiver operating characteristic curve (ROC) analysis was used to investigate the predicting efficacy with the area under the curve (AUC) and cross validations. Multiple-variable logistic regression model was employed to evaluate the predicting performance of multiple variables. RESULTS: MGMT promoter methylation was associated with tumor location and necrosis (P <  0.05). Significantly increased ADC value (P <  0.001) and decreased rCBF (P <  0.001) were associated with MGMT promoter methylation in primary glioblastoma. The ADC achieved the better predicting efficacy than rCBF (ADC: AUC, 0.860; sensitivity, 81.1%; specificity, 82.5%; vs rCBF: AUC, 0.835; sensitivity, 75.0%; specificity, 78.4%; P = 0.032). The combination of tumor location, necrosis, ADC and rCBF resulted in the highest AUC of 0.914. CONCLUSION: ADC and rCBF are promising imaging biomarkers in clinical routine to predict the MGMT promoter methylation in primary glioblastoma patients.

Development of new method of δ13C measurement for trace hydrocarbons in natural gas using solid phase micro-extraction coupled to gas chromatography isotope ratio mass spectrometry.

Compound specific isotope analysis (CSIA) of normal-level hydrocarbons (C1-C4) in natural gas is often successfully used in natural gas origin identification and classification, but little progress so far has been made for trace level hydrocarbons (C5-C14) in natural gas. In this study, we developed a method for rapid analysis of carbon isotopic ratios for trace hydrocarbons in natural gas samples. This method can be described as a combined approach characterized by solid phase micro-extraction (SPME) technique coupled to gas chromatography isotope ratio mass spectrometry (GC/IRMS). In this study, the CAR-PDMS fiber was chosen as the SPME adsorptive material after comparative experiments with other four fibers, and the parameters, including equilibration time, extraction temperature and desorption time, for efficient extraction of trace hydrocarbons were systematically optimized. The results showed the carbon isotopic fractionation was not observed as a function of equilibration time and extraction temperature. And the δ13C signatures determined by SPME-GC/IRMS were in good agreement with the known δ13C values of C5-C14 measured by GC-IRMS, and the accuracy is generally within ±0.5‰. Five natural gas samples were analyzed using this method, and the δ13C values for C5-C14 components were obtained with satisfied repeatability. The SPME-GC/IRMS approach fitted with CAR-PDMS fiber is well suited for the preconcentration of trace hydrocarbons and provides so far the most reliable carbon isotopic analysis for trace compounds in natural gas.

The primary site of the acrocephalic feature in Apert Syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling.

Activation of osteoblastic bone anabolism in the calvarial sutures is considered to be the essential pathologic condition underlying mutant FGFR2-related craniofacial dysostosis. However, early clinical investigations indicated that abnormal cartilage development in the cranial base was rather a primary site of abnormal feature in Apert Syndrome (AS). To examine the significance of cartilaginous growth of the cranial base in AS, we generated a transgenic mouse bearing AS-type mutant Fgfr2IIIc under the control of the Col2a1 promoter-enhancer (Fgfr2IIIc(P253R) mouse). Despite the lacking expression of Fgfr2IIIc(P253R) in osteoblasts, exclusive disruption of chondrocytic differentiation and growth reproduced AS-like acrocephaly accompanied by short anterior cranial base with fusion of the cranial base synchondroses, maxillary hypoplasia and synostosis of the calvarial sutures with no significant abnormalities in the trunk and extremities. Gene expression analyses demonstrated upregulation of p21, Ihh and Mmp-13 accompanied by modest increase in expression of Sox9 and Runx2, indicating acceleration of chondrocytic maturation and hypertrophy in the cranial base of the Fgfr2IIIc(P253R) mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIc(P253R) receptor with FGF2 and FGF10 is suggested as a mechanism of activation of FGFR2 signaling selectively in the cranial base. In this report, we strongly suggest that the acrocephalic feature of AS is not alone a result of the coronal suture synostosis, but is a result of the primary disturbance in growth of the cranial base with precocious endochondral ossification.

[Relationship between initial stability and infected loosening of total hip arthroplasty prosthesis].

OBJECTIVE: To investigate the relationship between the initial stability and infected loosening of the total hip arthroplasty (THA) prosthesis. METHODS: From January 2000 to December 2008, 110 cases (110 hips) were treated with THA revision. Among them, 15 cases (15 hips) were confirmed infected loosening. There were 8 males and 7 females with an average age of 62 years (range 42-75 years). The infected signs were found from 6 months to 2 years after initial THA. All of them had Tsukayama type IV and late infection, including 6 cases of acetabular infected loosening (5 cases of one-stage and 1 case of two-stage acetabular revision), 7 cases of simple infected loosening of femoral prosthesis (4 cases of one-stage and 3 cases of two-stage femoral prosthesis revision), and 2 cases of joint capsule infection and sinus without prosthesis loosening (debridement and continuous irrigation). RESULTS: All incisions healed by first intention. Fifteen patients were followed up for 12 to 36 months (average 24 months). In 13 cases of revision, postoperative X-ray films showed that femoral acetabular prostheses were in good position, and had no clinical and imaging infective signs of loosening. In 2 cases of joint capsule infection, sinus recurred 6 months postoperation without hip joint pain, the function of weight-bearing and walking of hip joint was normal. Harris score increased from preoperative average of 42 to postoperative average of 85; the results were excellent in 4 cases, good in 7 cases, and fair in 4 cases. CONCLUSION: The infection of THA may occur in the whole joint, half-joint or just in joint capsule. The initial stability of the prosthesis would affect the long-term survival of the prosthesis. If the prosthesis initial stability is obtained, even if there are infective factors, infections would also be limited.

Characterization of the non-collagenous proteins in avian cortical and medullary bone.

Northern blotting, RT-PCR, and Western blotting techniques were used to characterize the matrix constituents of avian cortical and medullary bone. Extracts of bone tissue were found to contain multiple isoforms of bone sialoprotein (BSP), osteopontin (OPN), osteonectin (ON), osteocalcin (OC), and dentin matrix protein-1 (DMP-1). Only single transcripts were observed with Northern blotting; therefore it was concluded that the isoforms were due to differences in post-translational modifications. Since medullary bone is rich in keratan sulfate (KS), RT-PCR was used to investigate the expression of known keratan sulfate-containing proteoglycans (KSPGs). Although this tissue was found to express lumican and osteoglycin/mimecan, there was little evidence to suggest that these proteoglycans were a major source of the keratan sulfate glycosaminoglycans. Treatment of medullary bone extracts with keratanase resulted in the appearance of a BSP immunoactive band of approximately 59 kDa. However, it was not possible to isolate and identify the intact keratan sulfate proteoglycan.

Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage.

OBJECTIVE: To understand the molecular mechanisms that lead to increased MMP-13 expression and cartilage degeneration during the progression of osteoarthritis (OA), we have investigated the expression of the transcription factor RUNX2 in OA cartilage and the regulation of MMP-13 expression by RUNX2 and FGF2 in articular chondrocytes. DESIGN: RUNX2 and MMP-13 expression in human OA and control cartilage was analyzed by immunohistochemistry. The effects of RUNX2 over-expression, with or without FGF2 treatment, on MMP-13 promoter activity and enzyme accumulation were measured in articular chondrocytes. Inhibitors of MEK/ERK were assayed for their ability to block FGF2 and RUNX2 up-regulation of the MMP-13 promoter. We analyzed RUNX2 phosphorylation in response to FGF2. RESULTS: Fibrillated OA cartilage exhibited increased RUNX2 immunoreactivity when compared to control cartilage. RUNX2 co-localized with MMP-13 in clusters of chondrocytes in fibrillated OA cartilage. RUNX2 over-expression in cultured chondrocytes increased their responsiveness to FGF2 treatment, which led to increased MMP-13 expression. Inhibitors of MEK/ERK signaling blocked up-regulation of the MMP-13 promoter by RUNX2 and FGF2, and also blocked the activation of RUNX2 by FGF2. FGF2 treatment of articular chondrocytes increased RUNX2 phosphorylation approximately 2-fold. CONCLUSIONS: Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. However, it is unlikely that RUNX2 is a substrate of ERK1/2. RUNX2 expression and activation may be a significant step in the progression of OA by promoting changes in gene expression and chondrocyte differentiation.

Smad signaling in mesenchymal and chondroprogenitor cells.

BACKGROUND: Bone morphogenetic proteins (BMPs) are pleiotropic differentiation factors that regulate cell fate determination by orchestrating the activities of downstream signal transducers. Although BMP ligands can elicit signal transduction from heterodimeric combinations of several type-I and type-II receptors, cytoplasmic transducers of the BMP signal include only three known BMP-specific regulatory Smad proteins: Smad1, 5, and 8. In order to determine the combination of signals that regulate chondrogenesis by BMPs, we analyzed the functions of BMP Smad subtypes. METHODS: Multipotential mesenchymal C3H10T1/2 cells and monopotential chondroprogenitor MC615 cells were placed in micromass culture in the presence or absence of BMP4. Chondrogenic differentiation was assayed by measuring Sox9 and type-II collagen gene expression and by alcian blue staining. Transactivation of type-II collagen by regulatory Smads singly, or in combination with Smad4, which partners with regulatory Smads, was assayed by luciferase activity. RESULTS: In the absence of BMP4, mesenchymal cells did not exhibit chondrogenic differentiation, whereas chondroprogenitor cells showed increased cartilage marker expression. In the presence of BMP4, the rate and extent of chondrogenesis increased in a dose-dependent manner for both cell types. We further determined that Smad1 or Smad5, but not Smad8, synergized with Smad4 in the transactivation of the type-II collagen promoter in chondroprogenitor cells. In contrast, Smad8 and Smad4 presented modest synergy in mesenchymal cells. CONCLUSIONS: Taken together, our data suggest that uncommitted mesenchymal cells do not have the cellular competence to respond to the rate-limiting chondroinductive factor BMP. However, in chondroprogenitor cells, BMP stimulates differentiation through mechanisms mediated by Smad1 or Smad5 in combination with Smad4.