Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor‐selective treatment ...approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado‐trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first‐generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.
Fight together: Antibody–drug conjugates (ADCs) are an emerging new class of targeted cancer therapeutics, with validation provided by the recent marketing approvals of the ADCs brentuximab vedotin and ado‐trastuzumab emtansine. Key considerations in the design of ADCs, pre‐clinical and clinical data of various ADCs in development, along with the current status and emerging advances are reviewed.
The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop ...novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody−drug conjugates and shows how the lessons learned from the first generation of conjugates has guided the development of more effective antitumor agents. The three components of antibody−drug conjugates, that is, the monoclonal anitbody, the cytotoxic drug, and the linker connecting the drug to the antibody, have been methodically studied and optimized. The antimitotic drug maytansine was chosen for use in the targeted delivery approach because of its high in vitro potency. Analogues of maytansine bearing a disulfide substituent that allowed linkage to monoclonal antibodies via disulfide bonds were prepared. These analogues retain the high potency of the parent drug. The stability of the disulfide link in antibody−maytansinoid conjugates was varied by introduction of methyl substituents on the carbon atoms geminal to the disulfide link. The optimized disulfide linker was stable in circulation in vivo. The circulation half-life of the cytotoxic drug was increased from just a few hours for the unconjugated drug to several days for the conjugate. Upon binding of the conjugate to the tumor cell, internalization and lysosomal processing released the potent cytotoxic agent inside the cell. These conjugates displayed high target-specific cytotoxicity in vitro. The antitumor activity of these targeted agents was superior to that of the antibodies alone or the standard anticancer drugs in human tumor xenograft models. Several conjugates from this new class of tumor-targeted anticancer agents are currrently undergoing clinical evaluation. The progress made in the targeted delivery approach and initial clinical results opens the door to the future development of highly potent drugs that were too toxic on their own to be therapeutically useful.
Electronics packaging type and its size have an effect on product wastes in stamping, molding and plating operations. Waste streams from these operations like copper, polymerized thermoset plastic, ...caustic and acidic effluents have non-recyclable hazardous content that are detrimental to cause of environment. Eco-efficiency that stands for reducing the environmental impact added, while increasing value of output produced, assumes great importance in this context. There are a number of barriers that affect eco-efficiency in electronics packaging industries. Existing models have focused on diagnosing these barriers independently and thus lack a holistic view in understanding those hindering eco-efficiency. The ten barriers under consideration in this study have been identified from literature review and opinion of experts, both from electronics packaging industry and academia. Through a nation wide questionnaire survey on Indian electronic packaging industries, the influences of these barriers on eco-efficiency has been identified using interpretive structural modeling. By use of this model, crucial barriers affecting implementation of eco-efficiency programs in an organization can be identified. Through the survey and its results, it is found that barriers like lack of awareness about environmental and sustainability issues, lack of commitment by top management and short-term decision making perspectives are strategic level attributes affecting implementation of eco-efficiency programs. Policy decision makers in a company need to take more concerns about these barriers as they possess high driver power. One of the main managerial implications of this model is that top management of companies must take effective steps on developing strategies to create awareness about eco-efficiency and its related benefits such that desired objectives in eco-efficiency could be achieved.
•The interactions among major barriers of eco-efficiency in electronics packaging industry have been analyzed in this research.•The driving power and dependence of each barrier are found out using interpretive structural modeling.•Those barriers with high driver power may be treated as the root cause for the remaining barriers.•Lack of awareness about environmental and other sustainability issues is a very significant barrier affecting eco-efficiency.
Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, ...with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
Suppliers can be considered as inevitable sources of external risks in modern supply chains. In this context, resilience that stands for the adaptive capability to respond to disruptions and ...recovering from it needs to be considered in supplier selection. But selection of suppliers is a challenging issue that involves the evaluation of both qualitative and quantitative attributes, in usual have imprecise and limited information. Grey relational analysis based on linguistic assessment of supplier rating and attribute weightings could judiciously be used under these situations to obtain a set of possibility values for prioritizing supplier selection. In this research, a supplier to be selected in the context of a resilient supply chain is termed as a resilient supplier. Taking electronic supply chain as a case study, with six alternative suppliers, grey possibility values for supplier selection were calculated and the suppliers were prioritized. Sensitivity analysis was also conducted to identify how far the selection priorities of suppliers change by varying the weightings given to each of the resilience attributes. This helps us in identifying the attributes of resilience where a particular supplier performs well. A comparison of proposed grey methodology with analytic hierarchy process (AHP) and analytic network process (ANP) was also conducted to comprehend extent of out-performance. The results of the proposed research could help top management in taking strategic level decision making with respect to selection of suppliers in a resilient supply chain.
This paper presents a comprehensive review of the work done, during the 1968–2005, in the application of statistical and intelligent techniques to solve the bankruptcy prediction problem faced by ...banks and firms. The review is categorized by taking the type of technique applied to solve this problem as an important dimension. Accordingly, the papers are grouped in the following families of techniques: (i) statistical techniques, (ii) neural networks, (iii) case-based reasoning, (iv) decision trees, (iv) operational research, (v) evolutionary approaches, (vi) rough set based techniques, (vii) other techniques subsuming fuzzy logic, support vector machine and isotonic separation and (viii) soft computing subsuming seamless hybridization of all the above-mentioned techniques. Of particular significance is that in each paper, the review highlights the source of data sets, financial ratios used, country of origin, time line of study and the comparative performance of techniques in terms of prediction accuracy wherever available. The review also lists some important directions for future research.
I present an optical characterization of the Galactic X-ray transient source MAXI J1957+032. This system flares by a factor of 104 every few hundred days, with each flare lasting ∼5 days. I identify ...its quiescent counterpart to be a late-K/early-M dwarf star at a distance of 5 2 kpc. This implies that the peak luminosity of the system is erg s−1. As found by Mata Sanchez et al. the outburst properties of MAXI J1957+032 are most consistent with the sample of accreting millisecond pulsars. However, the low inferred accretion rate, and the lack of evidence for a hydrogen-rich accretion flow, are difficult to reconcile with the late-K/early-M dwarf counterpart being the mass donor. Instead, the observations are best described by a low-mass hydrogen- and possibly helium-poor mass donor, such as a carbon-oxygen white dwarf, forming a tight interacting binary with a neutron star. The observed main-sequence counterpart would then likely be in a wide orbit around the inner binary.
•Constructed causal–effect diagrams among enablers of risk mitigation.•Grey theory and DEMATEL have been employed to effectively quantify enablers.•One enabler can be the cause/effect of one or more ...enablers.•Steps for instigating causal enablers can in turn initiate effect enablers.•Most prominent enablers coming under ‘zone 3’ needs imperative attention.
Supply chains are becoming perpetually complex and potentially vulnerable due to increased globalization and vertical integration. Supply chain managers are conscious that the success of any supply chain lies in its proficiency to manage risks efficiently and effectively. Supply chain risk management (SCRM) signifies proactive practices of managing vulnerability of supply chains. Various firms espouse strategic level measures for risk mitigation and implement practices for enhancing supply chain resilience. In order to enhance supply chain resilience, the enablers of supply chain risk mitigation need to be acknowledged and implemented into practice. This research emphasizes on ascertaining the major enablers of supply chain risk mitigation with emblematic focus on electronic supply chains. A blend of Grey theory and DEMATEL approaches has been employed in this research to find out cause/effect relationships among the enablers of supply chain risk mitigation. This exercise helps to find which can be the driver to initiate the effects of other driven enablers. Sensitivity analysis was also conducted of the results to ensure reliability of solutions. The results show that that the enablers of supply chain risk mitigation are intertwined and one enabler can be the cause/effect of one or more enablers of supply chain risk mitigation. Dynamic assortment planning is found to be the decisive causal enabler, as it initiates the effects of many other enablers of supply chain risk mitigation, followed by accurate demand forecasting and flexible supply contracts. Cause–effect relationships plotted facilitate managers to ascertain primary causal enablers that need imperative attention in dealing with vulnerability issues of supply chain. Managers can take proactive steps to address and implement primary causal enables of risk mitigation into practice for reducing total risk impacts of the supply chain.
We examined the contribution of the amygdala to value signals within orbital prefrontal cortex (OFC) and medial prefrontal cortex (MFC). On each trial, monkeys chose between two stimuli that were ...associated with different quantities of reward. In intact monkeys, as expected, neurons in both OFC and MFC signaled the reward quantity associated with stimuli. Contrasted with MFC, OFC contained a larger proportion of neurons encoding reward quantity and did so with faster response latencies. Removing the amygdala eliminated these differences, mainly by decreasing value coding in OFC. Similar decreases occurred in OFC immediately before and after reward delivery. Although the amygdala projects to both OFC and MFC, we found that it has its greatest influence over reward-value coding in OFC. Notably, amygdala lesions did not abolish value coding in OFC, which shows that OFC’s representations of the value of objects, choices, and outcomes depends, in large part, on other sources.
•Neurons in OFC and MFC differentially encode the reward value of stimuli•Lesions of the amygdala reduce reward coding in OFC but not in MFC•Amygdala lesions abolish differences between OFC and MFC in reward coding•Amygdala input is not necessary for reward coding in either OFC or MFC
Rudebeck et al. used combined electrophysiology and lesion methods to show that removing the amygdala input to the primate prefrontal cortex reduces reward-value encoding in the orbital, but not medial, prefrontal cortex.
Since their discovery in 2007
, much effort has been devoted to uncovering the sources of the extragalactic, millisecond-duration fast radio bursts (FRBs)
. A class of neutron stars known as ...magnetars is a leading candidate source of FRBs
. Magnetars have surface magnetic fields in excess of 10
gauss, the decay of which powers a range of high-energy phenomena
. Here we report observations of a millisecond-duration radio burst from the Galactic magnetar SGR 1935+2154, with a fluence of 1.5 ± 0.3 megajansky milliseconds. This event, FRB 200428 (ST 200428A), was detected on 28 April 2020 by the STARE2 radio array
in the 1,281-1,468 megahertz band. The isotropic-equivalent energy released in FRB 200428 is 4 × 10
times greater than that of any radio pulse from the Crab pulsar-previously the source of the brightest Galactic radio bursts observed on similar timescales
. FRB 200428 is just 30 times less energetic than the weakest extragalactic FRB observed so far
, and is drawn from the same population as the observed FRB sample. The coincidence of FRB 200428 with an X-ray burst
favours emission models that describe synchrotron masers or electromagnetic pulses powered by magnetar bursts and giant flares
. The discovery of FRB 200428 implies that active magnetars such as SGR 1935+2154 can produce FRBs at extragalactic distances.
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