A unified element stiffness matrix model for variable cross-section flexure hinges in compliant mechanisms for micro/nano positioning

This paper presents a unified analytical model of element stiffness matrix for variable cross-section flexure hinges in plane deformation which is most frequently employed in planar-motion compliant mechanisms for micro/nano positioning. The unified analytical model is derived for flexure hinges in plane deformation based on the principle of virtual work. The derivation is generalized such that it can be applied to various geometries. To optimize and simplify element stiffness matrix model, four coefficients with curve integral are introduced. The results of the analysis were validated in part by modeling several previously investigated configurations, namely flexible beam hinge and right circular hinge. To further validate the proposed analytical model, finite element analysis and experimental testing were used. And the experimental testing shows the proposed unified model is more precise than pseudo-rigid-body method. The proposed model provides a concise and generalized solution to derive the element stiffness matrices of flexible hinges in plane deformation, which will have excellent applications in design and analysis of variable cross-section flexible hinges in compliant mechanisms

Adjuvant therapy with Jianpi Huayu decoction improves overall and recurrence-free survival after hepatectomy for hepatocellular carcinoma: a retrospective propensity score-matching study

Hepatocellular carcinoma (HCC) patients experience high rates of recurrence following hepatectomy. Many herbal preparations used in traditional Chinese medicine have been shown to improve the postoperative condition of cancer patients. This retrospective study examined the efficacy and safety of Jianpi Huayu decoction (JPHYD) as adjuvant therapy for HCC following hepatectomy. HCC patients received postoperative management according to Chinese Society of Clinical Oncology recommendations, either alone (Control group) or in addition to daily JPHYD (1 week in hospital and 3 months after release). To reduce selection bias, we performed 1:1 propensity score matching between the Control and JPHYD groups. The main endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS) and adverse event frequency. A total of 207 patients meeting inclusion criteria were enrolled, 127 in the Control group and 80 in the JPHYD group. Patients were then propensity score-matched, yielding each group of 80. Recurrence-free survival rate was significantly higher in the JPHYD group than in the Control group at 1 year (67.9% vs. 38.1%), 2 years (39.1% vs. 26.2%), and 3 years (31.3% vs. 26.2%) following hepatectomy (HR 0.5666 [95%CI, 0.3655 to 0.8784]; p = 0.0066). Additionally, OS was significantly higher in the JPHYD group than the Control group at 1 year (94.3% vs. 81.9%), 2 years (76.4% vs. 58.8%), and 3 years (66.3% vs. 51.4%) following hepatectomy (HR 0.5199 [95%CI, 0.2849 to 0.9490]; p = 0.027). Adverse events frequencies did not differ between the two groups. In conclusion, JPHYD can safely improve RFS and OS following hepatectomy for HCC

IL-2 and IL-6 cooperate to enhance the generation of influenza-specific CD8 T cells responding to live influenza virus in aged mice and humans

An age-related decline in cytolytic activity has been described in CD8+ T cells and we have previously shown that the poor CD8+ effector T cell responses to influenza A/H3N2 challenge result from a decline in the proportion and function of these cytolytic T lymphocytes (CTL). Here, we describe that addition of exogenous cytokines to influenza-stimulated PBMC from both aged mice and humans, enhances the generation of influenza specific CD8 CTL by increasing their proliferation and survival. Our data show that the addition of IL-2 and IL-6 to splenocytes from mice previously infected with influenza virus restores the aged CD8+ T cell response to that observed in young mice. In humans, IL-2 plus IL-6 also reduces the proportion of apoptotic effector CD8+ T cells to levels resembling those of younger adults. In HLA-A2+ donors, MHC Class I tetramer staining showed that adding both exogenous IL-2 and IL-6 resulted in greater differentiation into influenza-specific effector CD8+ T cells. Since this effect of IL-2/IL-6 supplementation can be reproduced with the addition of Toll-like receptor agonists, it may be possible to exploit this mechanism and design new vaccines to improve the CD8 T cell response to influenza vaccination in older adults

Design of a flexure-based mechanism possessing low stiffness and constant force

This paper presents a novel design of a flexure-based constant force mechanism with a long travel stroke. Unlike the conventional force control method using a force sensor and feedback controller to obtain constant force output, the proposed compliant mechanism provides a constant force utilizing the unique mechanical property of the mechanical structure. The constant force is generated by using the combination of a negative-stiffness and a positive-stiffness mechanism. In order to achieve a low driving force, the negative stiffness is realized by a special bistable beam, which is a step beam with structural holes. Meanwhile, the positive stiffness is generated by the leaf flexure hinges with structural holes. The regular structural holes can reduce the mass and stiffness of the whole mechanism. Furthermore, the elliptic integral method and the pseudo-rigid-body approach are utilized to establish the model of the constant force mechanism. Based on the established model, the performance of the constant force mechanism is evaluated computationally. Additionally, the parametric model of the proposed mechanism is investigated using the nonlinear finite element analysis. Finally, a prototype is fabricated using 3D printing technique. The open-loop and the closed-loop experimental tests are implemented to investigate the performance of the developed constant force mechanism. It is noted that the constant force mechanism can be robustly controlled by a proportional-integral-derivative control method. Experimental results demonstrate that the developed constant force mechanism has a constant force with slight fluctuation with a range of 500 μm

Design of a novel 3D tip-based nanofabrication system with high precision depth control capability

The design, analysis, and experimental investigation of a novel 3D tip-based nanofabrication system with high precision depth control capability is presented in this paper. Based on this system, a new depth control method, namely tip displacement-based closed-loop (DC) depth control methodology is proposed to improve the depth control capability. As the force-depth prediction with the commonly-used depth control method, i.e. the normal force-based closed-loop (FC) method, may depend on the machining speed, the machining direction, and the material properties, etc. Compared with the FC method, the DC method decreases the complexity and the high uncertainty. The tip feed system utilizes a non-contact force, i.e. the electromagnetic force, to adjust the tip displacement. Therefore, the tip support mechanism can be used to accomplish the tip-sample contact detection. Additionally, an active compensation method is proposed to eliminate the tilt angle between the sample surface and the horizontal plane. Otherwise the machining depth will change gradually, i.e. getting deeper or lower. Furthermore, a series of patterns have been fabricated on silicon sample surface with the proposed system and method. The maximum machining depth of a single scan reaches 300 nm, which is much larger than that of an atomic force microscope (AFM)-based nanofabrication system. The experimental results demonstrate that the system has advantages of distinguished depth control capability, high machining accuracy, and excellent repeatability, which diminishes the influence of above-mentioned factors on the machining depth. Also, the method has the potential of machining arbitrary 2D/3D patterns with well-controlled depth and high accuracy

Oncogenic Function of DACT1 in Colon Cancer through the Regulation of β-catenin

The Wnt/β-catenin signaling pathway plays important roles in the progression of colon cancer. DACT1 has been identified as a modulator of Wnt signaling through its interaction with Dishevelled (Dvl), a central mediator of both the canonical and noncanonical Wnt pathways. However, the functions of DACT1 in the WNT/β-catenin signaling pathway remain unclear. Here, we present evidence that DACT1 is an important positive regulator in colon cancer through regulating the stability and sublocation of β-catenin. We have shown that DACT1 promotes cancer cell proliferation in vitro and tumor growth in vivo and enhances the migratory and invasive potential of colon cancer cells. Furthermore, the higher expression of DACT1 not only increases the nuclear and cytoplasmic fractions of β-catenin, but also increases its membrane-associated fraction. The overexpression of DACT1 leads to the increased accumulation of nonphosphorylated β-catenin in the cytoplasm and particularly in the nuclei. We have demonstrated that DACT1 interacts with GSK-3β and β-catenin. DACT1 stabilizes β-catenin via DACT1-induced effects on GSK-3β and directly interacts with β-catenin proteins. The level of phosphorylated GSK-3β at Ser9 is significantly increased following the elevated expression of DACT1. DACT1 mediates the subcellular localization of β-catenin via increasing the level of phosphorylated GSK-3β at Ser9 to inhibit the activity of GSK-3β. Taken together, our study identifies DACT1 as an important positive regulator in colon cancer and suggests a potential strategy for the therapeutic control of the β-catenin-dependent pathway

Clinical Response to T-DM1 in HER2-Amplified, KRAS-Mutated Metastatic Colorectal Cancer

HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient's response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non-HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC

Presence of Concurrent TP53 Mutations Is Necessary to Predict Poor Outcomes within the SMAD4 Mutated Subgroup of Metastatic Colorectal Cancer

Prior studies have resulted in conflicting conclusions on the value of SMAD4 mutations as a prognostic biomarker in metastatic colorectal cancer. In this study, the impact of coexisting mutations with SMAD4 on overall survival was evaluated retrospectively in 433 patients with metastatic colorectal cancer. SMAD4 mutation was found in 16.2% (70/433) of tumors. A systemic univariate and multivariate survival analysis model including age, gender, sidedness of primary tumor, RAS, BRAFV600E, APC, TP53 and SMAD4 status showed that SMAD4 mutations were not associated with worse prognosis (multivariate HR = 1.25, 95% CI 0.90–1.73, p = 0.18). However, coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival (multivariate HR = 2.5, 95% CI 1.44–4.36, p = 0.001). The median overall survival of patients with coexisting SMAD4 and TP53 mutation was 24.2 months, compared to 42.2 months for the rest of the population (p = 0.002). Concurrent SMAD4 and TP53 defines a new subgroup of patients of metastatic colorectal cancer with poor clinical outcomes

Metastatic pattern is a prognostic factor in BRAFV600E mutant colorectal cancer

Background: Despite recent advancements in the treatment of metastatic BRAFV600E colorectal cancer (CRC), prognosis remains poor. However, a some patients with BRAFV600E disease have superior outcomes compared to the overall cohort and the prognostic factors associated with this improved survival are not well understood. Methods: We conducted a single center retrospective review of patients with metastatic CRC and available next generation sequencing data. Patients with confirmed BRAFV600E disease were selected for the final analysis. We collected baseline demographic characteristics, concurrent mutations, and metastatic pattern. The primary endpoint was overall survival (OS). Univariate and multivariable logistic regression was used to examine the association between baseline concurrent somatic mutations and sites of metastatic disease with survival. Results: Of 466 patients with metastatic CRC, 50 harbored BRAFV600E disease and 42 were included in the final analysis. The median OS in this cohort was 18.7 months (95% CI: 5.55–31.8). There was no association between baseline concurrent somatic mutations and OS. On univariate analysis, patients with lymph node only disease at the time of metastatic disease were more likely to have longer OS (hazard ratio [HR] = 0.30, 95% CI: 0.09–0.98, p = 0.047) and patients with peritoneal disease were more likely to have shorter OS (HR = 2.78, 95% CI: 1.12–6.88, p = 0.03). However, these associations did not retain statistical significance on multivariable analysis. Conclusions: The pattern of metastatic disease in BRAFV600E CRC may be a prognostic factor and future studies are needed to better understand the underlying mechanisms and potentially change clinical practice for a select patient population. MicroAbstract: Select patients with metastatic BRAFV600E colorectal cancer may have better than expected survival but are not well characterized. We conducted a retrospective review of 42 patients with metastatic BRAFV600E colorectal cancer and showed that lymph node only disease at the time of metastatic disease was associated with superior survival