Dynamic behaviour of polyolefin thermoplastic hot melt adhesive under impact loading conditions

Dynamic behavior of polyolefin thermoplastic hot melt adhesive under impact loading conditions R. Ciardiello1, A. Tridello1, G. Belingardi1, L. Goglio1. 1 Politecnico di Torino, Department of Mechanical and Aerospace Engineering, Torino, 10129, IT. The mechanical behaviour of adhesive joints under impact loadings is an active area of research due to significant industrial interests. Furthermore, the absence of a unique adopted standard for the study of bonded joints under impact loading increases the academic interests for this topic [1]. In this work, the static and the dynamic response of adhesive joints, bonded with a polyolefin hot-melt adhesive (HMA), were investigated by means of Single Lap Joint (SLJ) tests. The adhesive studied in this work is used in automotive application for bonding plastic internal and external plastic components [2], such as plastic bumpers that can be subjected to impacts during its life. The mechanical and thermal properties of this adhesive are presented in [3]. The main aim of this study is to test standard specimens, SLJ, under dynamic impacts with the use of a modified Charpy pendulum in order to compare the differences between static and dynamic behaviour. The substrate used in this activity are made of a polypropylene copolymer with 10% in weight of talc. Figure 1 shows the testing machine with the clamping system of the specimen. These special fixtures were designed by Goglio et al. [4] with the aim to apply a dynamic load on the tested SLJ. The specimen is fixed to the hammer at the front end, as shown in the right part of Figure 1; the back end is connected to a transverse tail, which hits the two stoppers fixed on the pendulum base, shown in the red circle of Figure 1. The fixtures hold the specimen during the fall of the hammer and transmit the load. A tail in aluminium alloy with T cross section was used, in order to guarantee a high stiffness during the impact, without adding excessive inertia to the system. The system is able to perform dynamic tests for SLJ specimens up to 3.75 m/s. Figure 1: Charpy pendulum used for the experimental tests. Mechanical tests show that there is a clear influence of the load rate on force-displacement diagram and on the maximum force for the tested adhesive. Figure 2 illustrates the differences between a representative curve of quasi-static test and dynamic tests with two different velocities. Figure 2: Force vs linear displacement: comparison between quasi-static and dynamic tests. Figure 3 shows the average values of the peak force and absorbed energies. This Figure illustrates that the velocity increase leads to an increase of the maximum force while the adsorbed energy significantly decreases by comparing quasi-static and dynamic tests. Figure 3: Peak loads and absorbed energy of the quasi-static and dynamic tests. Finally, the fracture surfaces of the SLJ specimens were assessed by means of visual inspection. This analysis showed that the joint separation in the quasi-static tests is mostly cohesive, whereas it becomes completely adhesive in dynamic tests. [1] J.J.M. Machado, E.A.S. Marques and L.F.M. da Silva, J. Adhes., (2017). https://doi.org/10.1080/00218464.2017.1282349. [2] G. Belingardi, V. Brunella, B. Martorana and R. Ciardiello, in Adhesives applications and properties, Cap.13, p.341, A. Rudawska Ed. (INTECH, Rijeca, 2016). [3] E. Koricho, E. Verna, G. Belingardi, B. Martorana, and V. Brunella, Int. J. Adhes. Adhes. 68, 169–181 (2016). [4] L. Goglio and M. Rossetto, in Proceedings of ESDA2006 8th Biennial ASME Conference on Engineering Systems Design and Analysis, 637-643 (2006)

Interactions between the epidermal growth factor receptor and type I protein kinase A: biological significance and therapeutic implications.

Peptide growth factors regulate normal cellular proliferation and differentiation through autocrine and paracrine pathways and are involved in cancer development and progression. Among the endogenous growth factors, the epidermal growth factor (EGF)-related proteins play an important role in the pathogenesis of human cancer. In fact, overexpression of EGF-related growth factors such as transforming growth factor alpha and amphiregulin and/or their specific receptor, the EGF receptor (EGFR), has been detected in several types of human cancers, including breast, lung, and colorectal cancers. Therefore, the blockade of EGFR activation by using anti-EGFR monoclonal antibodies (MAbs) has been proposed as a potential anticancer therapy. The cAMP-dependent protein kinase (PKA) is an intracellular enzyme with serine-threonine kinase activity that plays a key role in cell growth and differentiation. Two PKA isoforms with identical catalytic (C) subunits but different cAMP-binding regulatory (R) subunits (defined as RI in PKAI and RII in PKAII) have been identified. Predominant expression of PKAII is found in normal nonproliferating tissues and in growth-arrested cells, whereas enhanced levels of PKAI are detected steadily in tumor cells and transiently in normal cells exposed to mitogenic stimuli. Overexpression of PKAI has been correlated recently with poor prognosis in breast cancer patients. Inhibition of PKAI expression and function by specific pharmacological agents such as the selective cAMP analogue 8-chloro-cAMP (8-Cl-cAMP) induces growth inhibition in various human cancer cell lines in vitro and in vivo. We have provided experimental evidence of a functional cross-talk between ligand-induced EGFR activation and PKAI expression and function. In fact, PKAI is overexpressed and activated following transforming growth factor alpha-induced transformation in several rodent and human cell line models. Furthermore, PKAI is involved in the intracellular mitogenic signaling following ligand-induced EGFR activation. We have shown that an interaction between EGFR and PKAI occurs through direct binding of the RI subunit to the Grb2 adaptor protein. In this respect, PKAI seems to function downstream of the EGFR, and experimental evidence suggests that PKAI is acting upstream of the mitogen-activated protein kinase pathway. We have also demonstrated that the functional interaction between the EGFR and the PKAI pathways could have potential therapeutic implications. In fact, the combined interference with both EGFR and PKAI with specific pharmacological agents, such as anti-EGFR blocking MAbs and cAMP analogues, has a cooperative antiproliferative effect on human cancer cell lines in vitro and in vivo. The antitumor activity of this combination could be explored in a clinical setting because both the 8-Cl-cAMP analogue and the anti-EGFR blocking MAb C225 have entered human clinical trial evaluation. Finally, both MAb C225 and 8-Cl-cAMP are specific inhibitors of intracellular mitogenic signaling that have different mechanisms of action compared with conventional cytotoxic drugs. In this respect, a cooperative growth-inhibitory effect in combination with several chemotherapeutic agents in a large series of human cancer cell lines in vitro and in vivo has been demonstrated for anti-EGFR blocking MAbs or for 8-Cl-cAMP. Therefore, the combination of MAb C225 and 8-Cl-cAMP following chemotherapy could be investigated in cancer patients

Debonding of adhesive joints by means of microwave and induction heating processes

In this work, an innovative technique for adhesive joint separation that combines the use of a hybrid-modified adhesive with microwave (MW) or induction heating (IH) [1-3] processes is presented. Graphene nanoplatelets (GnPs) and iron oxide particles were used to modify a thermoplastic adhesive, polyolefin hot-melt adhesive by mean of a twin-screw extruder. This thermoplastic adhesive, already used for bonding automotive applications, was modified with both iron oxide and GnPs in order to enhance the electrical properties and the sensitivity to MW and IH. The mechanical and electrical properties together with the sensitivity of the modified adhesives to microwave or induction heating processes are investigated. Single Lap Joint (SLJ) specimens were used to evaluate the mechanical properties of the pristine and the modified adhesive. The mechanical tests illustrate that the maximum loads of modified adhesives decrease slightly. Tests conducted with microwave and induction heating processes showed that these two systems are able to melt the modified adhesive. Thus, the separation of bonded joints is possible with both systems. The temperature increase of the induction heating system is found to be more rapid than the microwaves but the latter system is energetically more efficient. Scanning Electron Microscope (SEM) was used to measure the particle distribution and to evaluate the differences between the manual mixed mode and the tween extruder system as preliminary analysis

Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs

We investigated the antitumour effect and ability to overcome the resistance to anti-EGFR drugs of enzastaurin, an inhibitor of VEGFR-dependent PKCβ signalling. Enzastaurin was evaluated alone and in combination with the EGFR inhibitor gefitinib, on growth and signalling protein expression in human cancer cells sensitive and resistant to anti-EGFR drugs, both in vitro and in nude mice. We demonstrated the marked inhibitory activity of enzastaurin against GEO colon and PC3 prostate cancer cells and their gefitinib-resistant counterparts GEO-GR and PC3-GR, accompanied by inhibition of pAkt and its effector pp70S6K, pGSK3β and VEGF expression and secretion. Moreover, enzastaurin showed a cooperative effect with gefitinib in parental and in gefitinib-resistant cells. Remarkably, these results were confirmed in vivo, where enzastaurin showed antitumour activity and cooperativity with gefitinib in mice grafted with GEO and GEO-GR tumours, incrementing their median survival and inhibiting the aforesaid protein expression and secretion in tumour specimens. In conclusion, enzastaurin by interfering with signalling proteins implicated in EGFR drug resistance markedly cooperates with gefitinib in sensitive and gefitinib-resistant tumours, thus overcoming and reverting such resistance and providing a rational basis for its development in patients resistant to anti-EGFR drugs

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients

Cutaneous metastasis from colorectal cancer: Making light on an unusual and misdiagnosed event

Cutaneous metastasis from solid tumors is a rare event and usually represents a late occurrence in the natural history of an advanced visceral malignancy. Rarely, cutaneous metastasis has been described in colorectal cancer patients. The most frequent cutaneous site of colorectal metastasis is the surgical scar in the abdomen following the removal of the primary malignancy, followed by the extremities, perineum, head, neck, and penis. Metastases to the thigh and back of the trunk are anecdotical. Dermatological diagnosis of cutaneous metastasis can be quite complex, especially in unusual sites, such as in the facial skin or thorax and in cases of single cutaneous lesions since metastasis from colorectal cancer is not usually the first clinical hypothesis, leading to misdiagnosis. To date, due to the rarity of cutaneous metastasis from colorectal cancer, little evidence, most of which is based on case reports and very small case series, is currently available. Therefore, a better understanding of the clinic-pathological characteristics of this unusual metastatic site represents an unmet clinical need. We present a large series of 29 cutaneous metastases from colorectal cancer with particular concerns regarding anatomic localization and the time of onset with respect to primitive colorectal cancer and visceral metastases

RenalGuard system in high-risk patients for contrast-induced acute kidney injury.

BACKGROUND: High urine flow rate (UFR) has been suggested as a target for effective prevention of contrast-induced acute kidney injury (CI-AKI). The RenalGuard therapy (saline infusion plus furosemide controlled by the RenalGuard system) facilitates the achievement of this target. METHODS: Four hundred consecutive patients with an estimated glomerular filtration rate ≤30 mL/min per 1.73 m(2) and/or a high predicted risk (according to the Mehran score ≥11 and/or the Gurm score >7%) treated by the RenalGuard therapy were analyzed. The primary end points were (1) the relationship between CI-AKI and UFR during preprocedural, intraprocedural, and postprocedural phases of the RenalGuard therapy and (2) the rate of acute pulmonary edema and impairment in electrolytes balance. RESULTS: Urine flow rate was significantly lower in the patients with CI-AKI in the preprocedural phase (208 ± 117 vs 283 ± 160 mL/h, P 0.32 mg/kg (HR 5.03, 95% CI 2.33-10.87, P < .001) were independent predictors of CI-AKI. Pulmonary edema occurred in 4 patients (1%). Potassium replacement was required in 16 patients (4%). No patients developed severe hypomagnesemia, hyponatremia, or hypernatremia. CONCLUSIONS: RenalGuard therapy is safe and effective in reaching high UFR. Mean intraprocedural UFR ≥450 mL/h should be the target for optimal CI-AKI prevention

Expression of Wnt5a is downregulated by extracellular matrix and mutated c-Ha-ras in the human mammary epithelial cell line MCF-10A

Wnt genes are involved in tumour growth and regulate cell adhesion. Some (Wnt5a and Wnt7b) are more highly expressed in human breast cancer compared to normal tissues. Wnt5a is involved in the regulation of cell movement in Xenopus and is upregulated in several human cancers. Factors regulating Wnt gene expression in human breast epithelium are poorly understood, but c-erbB2 is amplified in many breast cancers and associated with rapid growth and metastasis, as is high expression of c-Ha-ras. To further understand the regulation of Wnt gene expression, this study investigated the effect of proto-oncogenes c-Ha-ras and c-erbB2, and collagen on Wnt mRNA expression, in a normal spontaneously immortalised human mammary epithelial cell line MCF-10A. Out of nine human Wnt genes investigated, Wnt5a and Wnt7b were expressed in the parental cell line, and neomycin-, c-Ha-ras- and c-erbB2-transfected cell lines. The level of Wnt5a mRNA expression was decreased 40-fold and 3-fold when parental cells were grown on collagen and in collagen, respectively. This downregulation correlated with cell branching. However, Wnt7b was not regulated by collagen. In the presence of activated c-Ha-ras, the level of Wnt5a mRNA expression was markedly decreased (> 200-fold) and cell growth rate was elevated. When treated with p21ras inhibitor, BZA-5B, there was a moderate reversal of Wnt5a mRNA expression (2-fold) with a parallel decrease in cell growth. The data indicate that c-Ha-ras is an upstream inhibitory regulator of Wnt5a, and provide further evidence of an inverse relationship between Wnt5a mRNA expression and cell branching. This demonstrates selectivity of regulation of individual members of the Wnt gene family by the ras pathway. Overexpression of c-erbB2 had no effect on Wnt5a or Wnt7b mRNA expression. Thus, extracellular matrix and ras regulate Wnt5a, providing a mechanism for feedback of morphogenetic movements, which is relevant also to cancer biology