Pollution responsibility allocation in supply networks: A game-theoretic approach and a case study

This study introduces a cooperative game theory approach aimed at addressing the problem of allocating pollution responsibility across partners collaborating in supply networks. The proposed framework includes three different allocation rules through which companies can share pollution responsibility across complex supply networks. A case study in the context of a supply network for the manufacturing of construction materials is illustrated for demonstrating the real-world applicability of the approach

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

Single-lap joints of similar and dissimilar adherends bonded with a polyurethane adhesive used in the automotive industry

The mechanical performances of single-lap joints between similar and dissimilar adherends bonded with a bi-component polyurethane adhesive have been studied in the present work. The substrate materials include both carbon fibre reinforced composite material (CRFP) and painted metal substrates (PMS). The following substrate combinations were tested: CFRP/CFRP, PMS/PMS, and CFRP/PMS. Two adhesive overlaps, 12 mm and 24 mm, with a fixed thickness were studied to assess the mechanical behaviour of the adhesive joints. The experimental results have been used to construct a finite element model of the single lap joint tests. The objective is to determine the material cohesive properties, in particular the maximum shear stress and the corresponding energy release rate, of the adhesive layer for each retained combination of substrates. An optimization scheme based on transient nonlinear finite element analysis has been here considered, where cohesive parameters of the adhesive layer are handled as design variables. Material parameters are firstly identified for the 12 mm overlap, minimizing the discrepancy between the experimental and numerical force-displacement curves. Then, to validate the obtained properties, results of the 24 mm overlap single lap joint tests are used. The comparison between the experimental and numerical results shows a very good agreemen

A comparison between TOPSIS and SAW methods

The Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) and Simple Additive Weighting (SAW) are among the most employed approaches for aggregating performances in Multi-Criteria Decision-Making (MCDM). TOPSIS and SAW are two MCDM methods based on the value function approach and are often used in combination with other MCDM methods in order to produce rankings of alternatives. In this paper, first, we analyse some common features of these two MCDM methods with a specific reference to the additive properties of the value function and to the sensitivity of the value function to trade-off weights. Based on such methodological insights, an experimental comparison of the results provided by these two aggregation methods across a computational test is performed. Specifically, similarities in rankings of alternatives produced by TOPSIS and SAW are evaluated under three different Minkowski distances (namely, the Euclidean, Manhattan and Tchebichev ones). Similarities are measured trough a set of statistical indices. Results show that TOPSIS, when used in combination with a Manhattan distance, produces rankings which are extremely similar to the ones resulting from SAW. Similarities are also Experimental results confirm that rankings produced by TOPSIS methods are closer to SAW ones when similar formal properties are satisfied

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

Vandetanib for the Treatment of Metastatic Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) represents an aggressive form of thyroid malignancy. Some may occur spontaneously or can be associated with Multiple Endocrine Neoplasia syndromes, or Familial Medullary Thyroid Cancer syndrome. In these patients, the protooncogene RET (rearranged during transfection) is mutated. In patients who have unresectable or metastatic disease, the long term prognosis is poor. New treatments for this disease have focused on the use of targeted agents that inhibit the receptor tyrosine kinase of RET. One of these treatments, Vandetanib (Caprelsa, Astra Zeneca), recently has received approval from the Food and Drug Administration for the treatment of patients with progressive locally advanced and/or metastatic disease. This review highlights the studies that led to the drug’s approval, and discusses on the potential financial costs of treatment and side effects of this therapy. The main clinical studies evaluating Vandetanib for the treatment of other solid tumors will also be reviewed

experimental investigation on adhesively bonded u shaped metallic joints using the arcan test

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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

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