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Overcoming Resistance to EGFR Inhibitors in EGFR Mutant NSCLC

Overcoming Resistance to EGFR Inhibitors in EGFR Mutant NSCLC
  • Author : Anthony Faber
  • Publisher :Unknown
  • Release Date :2021-03-15
  • Total pages :250
  • ISBN : 0128228334
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Summary : Overcoming Resistance to EGFR Inhibitors in EGFR Mutant NSCLC, Volume 17 presents updated information on how EGFR mutant lung cancers evolve to evade EGFR inhibitors, clinical strategies that identify these mechanisms, and how to implement newer therapeutic strategies to combat resistance and improve patient survival. As resistance to EGFR inhibitors is often through re-activation of MEK/ERK and PI3K pathways, or through loss of cell death responses, there is much overlap with resistance to targeted therapies in other paradigms, such as BRAF inhibitors in BRAF mutant melanoma, and HER2 inhibitors in HER2 amplified breast cancer. This book is a valuable resource for cancer researchers, clinicians, graduate students and other members of the biomedical field who are interested in promising treatments for lung cancer. Presents historical context on how NSCLC and SCLC has been treated, with an emphasis on NSCLC and how the concept of EGFR inhibitors has been implemented Discusses critical resistant mechanisms seen in the clinic to 1st, 2nd and 3rd generation EGFR inhibitors Encompasses the current state of affairs in clinical trials to address resistance

Third Generation EGFR Inhibitors

Third Generation EGFR Inhibitors
  • Author : Harun M. Patel,Rahul Pawara,Sanjay J. Surana
  • Publisher :Unknown
  • Release Date :2018-11-27
  • Total pages :208
  • ISBN : 9780081026625
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Summary : Third Generation EGFR Inhibitors: Overcoming EGFR Resistance and Toxicity Problems reviews current issues relating to the design of reversible and irreversible third generation EGFR inhibitors, highlighting the types of mutation responsible for resistance, and providing different chemical starting points for researchers to optimize and develop in designing the next generation of drugs. Beginning with an introduction to EGFR inhibitors and a review of inhibitors currently approved or in clinical trials, the book goes on to discuss current approaches in the development of both covalent irreversible and covalent reversible EGFR Inhibitors. In addition, mechanisms of resistance to third generation inhibitors, and discovery of fourth generation allosteric C797S inhibitors are explored before a discussion of potential future trends. This comprehensive coverage of the design and development of improved analogues to overcome the problems of resistance and toxicity associated with third generation EGFR inhibitors makes Third Generation EGFR Inhibitors a crucial resource for medicinal chemists, drug developers, and researchers investigating cancer therapeutics. Includes full synthetic schemes of all approved and in-trial third generation inhibitors Highlights the emergence of fourth generation EGFR inhibitors and the possibilities of them overcoming constraints of third generation compounds Provides a structural correlation of third and fourth generation EGFR inhibitors, reviewing both their design strategies and typical anticancer activity

Resistance to Tyrosine Kinase Inhibitors

Resistance to Tyrosine Kinase Inhibitors
  • Author : Daniele Focosi
  • Publisher :Unknown
  • Release Date :2016-11-07
  • Total pages :188
  • ISBN : 9783319460918
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Summary : The volume will serve as a primer on tyrosine kinase signaling and its importance in cancer. The volume will first introduce the common denominators of small-molecule and antibody-derived inhibitors, as well as the general phenomenon of resistance. The volume will then detail resistance to the most commonly used classes of tyrosine kinase inhibitors, and will focus specific chapters on resistance to BCR-ABL1, FLT3, angiokinase family members, and ALK inhibitors.

Guide to Targeted Therapies: Treatment Resistance in Lung Cancer

Guide to Targeted Therapies: Treatment Resistance in Lung Cancer
  • Author : Federico Cappuzzo
  • Publisher :Unknown
  • Release Date :2015-10-15
  • Total pages :67
  • ISBN : 9783319207414
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Summary : This text is a concise and up-to-date review, which discusses the background, development and mechanisms of resistance, testing methods and technology, current and emerging therapies and resources that clinicians can provide to their patients. Busy healthcare professionals who want a quick review of treatment resistance in lung cancer as well as a summary of current therapies will benefit from this succinct guide.

PI3K signalling

PI3K signalling
  • Author : Klaus Okkenhaug,Martin Turner, Michael R Gold
  • Publisher :Unknown
  • Release Date :2015-03-05
  • Total pages :229
  • ISBN : 9782889194193
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Summary : The PI3Ks control many key functions in immune cells. PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3. Initially, PI3K inhibitors such as Wortmannin, LY294002 and Rapamycin were used to establish a central role for Pi3K pathway in immune cells. Considerable progress in understanding the role of this pathway in cells of the immune system has been made in recent years, starting with analysis of various PI3K and Pten knockout mice and subsequently mTOR and Foxo knockout mice. Together, these experiments have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell development and function, B cell and T cell trafficking, immunoglobulin class switching and much, much more. The PI3Kd inhibitor idelalisib has recently been approved for the treatment of B cell lymphoma. Clinical trials of other PI3K inhibitors in autoimmune and inflammatory diseases are also in progress. This is an opportune time to consider a Research Topic considering when what we have learned about the PI3K signalling module in lymphocyte biology and how this is making an impact on clinical immunology and haematology.

Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners

Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners
  • Author : Marianne Davies,Beth Eaby-Sandy
  • Publisher :Unknown
  • Release Date :2019-07-16
  • Total pages :120
  • ISBN : 9783030165505
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Summary : This book aims to educate nurses and advanced practice providers (APP’s) about known mutations, availability of targeted therapy and the management of patients with non-small cell lung cancer (NSCLC). It will educate nurses and practitioners about the scope of therapy to assure safe and effective lung cancer treatment. In this era of personalized medicine, nurses and APP’s are responsible for guiding patients from diagnosis through treatment. This starts with the identification of patients that can benefit from these therapies, the key role of biopsy acquisition (ie. what to test, when and how often) and treatment selection based on the mutation identified. Readers will learn about the mechanisms of action, administration, potential adverse side effects and unique management strategies for these targeted agents. Lung cancer continues to be the leading cause of cancer death in the United States and worldwide. Recent advances in the identification of specific oncogenic mutations that drive cancer development, growth and metastasis have led to major paradigm shifts in lung cancer treatment. Sophisticated methods are required to identify specific mutations at the time of diagnosis. This book explains how molecularly targeted therapies have been developed that target these drivers. To date, several tyrosine kinase inhibitors have been approved to target the epidermal growth factor receptor (EGFR), EML4-ALK ,ROS1 and BRAF. Most recently, immune checkpoint inhibitors have been approved with some indication that efficacy may be enhanced for patients who overexpress PD-L1. While some driver mutations have been identified, there is ongoing investigation into additional mutations. In the case of driver mutations, lung cancers will develop resistance to therapy. This book provides nurses and APP’s with the mechanisms of resistance that have been identified such as T790 mutation and many others in the EGFR mutation, and shows how the next level of drug development is focused on identifying mechanisms of resistance and development of new agents that overcome these mutations. With this book in hand, nurses and practitioners will be able to navigate patients through this ever expanding field of lung cancer treatment.

Advances in Molecular Oncology

Advances in Molecular Oncology
  • Author : Fabrizio d'Adda di Fagagna,Susanna Chiocca,Fraser McBlane,Ugo Cavallaro
  • Publisher :Unknown
  • Release Date :2007-07-18
  • Total pages :276
  • ISBN : 9780387691169
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Summary : Proceedings of the 2nd Annual IFOM-IEO Meeting on Cancer. This is a new meeting, it has about 200 attendees from Australia, Austria, Belgium, Brazil, Canada, England, France, Germany, Greece, Ireland, Italy, Japan, Netherlands, Spain, Sweden, Switzerland, and the USA. The 2nd IFOM-IEO international meeting on cancer will provide a forum in which the world’s leading cancer researchers and young scientists will discuss the latest advances in molecular oncology. The impact of recent breakthroughs in basic research and of emerging technologies on molecular medicine in cancer will be highlighted.

Second Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological and Molecular Aspects of Novel Promising Drugs

Second Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological and Molecular Aspects of Novel Promising Drugs
  • Author : Umberto Malapelle,Pierlorenzo Pallante
  • Publisher :Unknown
  • Release Date :2017-08-29
  • Total pages :229
  • ISBN : 9782889452637
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Summary : Lung cancer still remains a challenging disease with a higher mortality rate in comparison to other cancers. The discovery of oncogene addicted tumours and targeted therapies responsive to these targets lead to a meaningful change in the prognosis of these diseases. Unfortunately, these newer therapeutic options are reserved to a minor part of lung cancer patients harbouring specific mutations. In the so called wild type population, the first line options bring the median overall survival to go beyond 1 year, and in the population receiving the maintenance therapy over 16 months. Given these results, more than 60% of patients may receive a second line therapy with further opportunities to improve the length and quality of life. For patients not harbouring targetable DNA mutations newer options will be available for second line therapeutic schemes and two major assets seem to be promising: immune modulation and anti-angiogenetic agents. In particular, anti PD1/PDL1 antibodies, VEGFR antibodies and TKIs, these latter combined with standard chemotherapy docetaxel advance the median overall survival of 12 months. These drugs have a different mechanism of action, various adverse events and their activity is different depending on the types of population. However, the biomarkers’ activity and efficacy prediction are not fully or totally understood. In addition, also for patients with DNA targetable mutations new drugs seems to be promising for the use in the second line therapeutic protocols. In particular, drugs selectively directed against ALK translocation and mutational events and EGFR T790M secondary mutations seems to be very promising. In this Research Topic we critically discuss the older therapies and the historical development of second line, putting in to perspective the new agents available in clinical practice. We discuss their importance from a clinical point of view, but also consider and exploit the complex molecular mechanisms responsible of their efficacy or of the subsequently observed resistance phenomena. In this perspective, the undercovering and characterization of novel predictive biomarkers by NGS technology, the characterization of novel actors in the signal transduction pathway modulating the response of the cells, the optimization of new diagnostic tool as the evaluation of liquid biopsy and the implementation of more suitable pre-clinical models are crucial aspects dissected too. Nivolumab, nintedanib and ramucirumab probably will give the opportunity to improve the efficacy outcomes for the treatment of wild type tumours in second line therapeutic schemes, but many aspects should be debated in order that these agents are made available to patients, planning ahead a therapeutic strategy, beginning from the first line therapy, to the subsequent ones in a logical and affordable manner. As well, for treatment of mutated tumours, mutated EGFR irreversible inhibitors such as rociletinib and AZD9291, and ALK targeting drugs ceritinib and alectinib will also play an important role in the immediate future. Probably the right way is to give all the available opportunities to patients, but challenges and pitfalls should be carefully debated, and by launching this Research Topic we tried to give some practical insights in this changing landscape.

Successes and Limitations of Targeted Cancer Therapy

Successes and Limitations of Targeted Cancer Therapy
  • Author : S. Peters,R.A. Stahel
  • Publisher :Unknown
  • Release Date :2014-02-19
  • Total pages :124
  • ISBN : 9783318025422
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Summary : The treatment of patients with advanced malignancies has undergone remarkable change in the last few years. While in the past decisions about systemic therapy were largely based on the performance status of a patient, oncologists today also take into account the pathological and molecular characteristics of the patient’s tumor. Targeting specific molecular pathways important for tumorigenesis has become the preferred way of treatment for many types of malignancies. With these advances come new challenges including the optimization of therapy, recognizing and dealing with side effects and, importantly, the development of resistance. This book provides an up-to-date overview of the advances and limitations of targeted therapy for several tumor entities including breast cancer, colon cancer, gastrointestinal stromal tumors, lung cancer, melanoma, ovarian cancer and renal cell carcinoma. Written by over a dozen internationally renowned scientists, the book is suitable for advanced students, postdoctoral researchers, scientists and clinicians who wish to update their knowledge of the latest approaches to targeted cancer therapies.

Targeted Therapies for Lung Cancer

Targeted Therapies for Lung Cancer
  • Author : Ravi Salgia
  • Publisher :Unknown
  • Release Date :2019-06-26
  • Total pages :238
  • ISBN : 9783030178321
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Summary : This book contextualizes translational research and provides an up to date progress report on therapies that are currently being targeted in lung cancer. It is now well established that there is tremendous heterogeneity among cancer cells both at the inter- and intra-tumoral level. Further, a growing body of work highlights the importance of targeted therapies and personalized medicine in treating cancer patients. In contrast to conventional therapies that are typically administered to the average patient regardless of the patient’s genotype, targeted therapies are tailored to patients with specific traits. Nonetheless, such genetic changes can be disease-specific and/or target specific; thus, the book addresses these issues manifested in the somatically acquired genetic changes of the targeted gene. Each chapter is written by a leading medical oncologist who specializes in thoracic oncology and is devoted to a particular target in a specific indication. Contributors provide an in-depth review of the literature covering the mechanisms underlying signaling, potential cross talk between the target and downstream signaling, and potential emergence of drug resistance.

Current Applications for Overcoming Resistance to Targeted Therapies

Current Applications for Overcoming Resistance to Targeted Therapies
  • Author : Myron R. Szewczuk,Bessi Qorri,Manpreet Sambi
  • Publisher :Unknown
  • Release Date :2019-07-15
  • Total pages :320
  • ISBN : 9783030214777
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Summary : Targeted therapies were initially developed to exploit the upregulation and dependence on key oncogenic pathways critical to cancer progression. Additionally, they also presented as a method to overcome chemoresistance by supplementing conventional therapeutic regimens with targeted therapies. However, the development of resistance to these combinatorial approaches has led to the reassessment of currently available therapeutic options to overcome resistance to targeted therapy. This book aims to provide an update on the advancements in the therapeutic arms race between cancer, clinicians and scientists alike to overcome resistance to targeted therapies. Subject experts provide a comprehensive overview of the challenges and solutions to resistance to several conventional targeted therapies in addition to providing a discussion on broad topics including targeting components of the tumor microenvironment, emerging therapeutic options, and novel areas to be explored concerning nanotechnology and the epigenome.

Molecular Pathology of Lung Cancer

Molecular Pathology of Lung Cancer
  • Author : Philip T. Cagle,Timothy Craig Allen,Mary Beth Beasley,Lucian R. Chirieac,Sanja Dacic,Alain C. Borczuk,Keith M. Kerr
  • Publisher :Unknown
  • Release Date :2012-06-14
  • Total pages :216
  • ISBN : 9781461431978
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Summary : As with other books in the Molecular Pathology Library Series, Molecular Pathology of Lung Cancer bridges the gap between the molecular specialist and the clinical practitioner, including the surgical pathologist who now has a key role in decisions regarding molecular targeted therapy for lung cancer. Molecular Pathology of Lung Cancer provides the latest information and current insights into the molecular basis for lung cancer, including precursor and preinvasive lesions, molecular diagnosis, molecular targeted therapy, molecular prognosis, molecular radiology and related fields for lung cancer generally and for the specific cell types. As many fundamental concepts about lung cancer have undergone revision in only the past few years, this book will likely be the first to comprehensively cover the new molecular pathology of lung cancer. It provides a foundation in this field for pathologists, medical oncologists, radiation oncologists, thoracic surgeons, thoracic radiologists and their trainees, physician assistants, and nursing staff.

Targeted Therapies in Cancer

Targeted Therapies in Cancer
  • Author : Manfred Dietel
  • Publisher :Unknown
  • Release Date :2007-06-10
  • Total pages :262
  • ISBN : 9783540460916
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Summary : From its introduction, oncological chemotherapy has been encumbered by poor selectivity because antiproliferative drugs are often toxic not only to tumor cells but also to important populations of the body’s non-neoplastic cells. Modern targeted therapies interact with defined molecules present on cancer cells, adding increased selectivity to their toxic effects. This book presents an integrated critical view on the theories, mechanisms, problems and pitfalls of the targeted therapy approach.

Central Nervous System Metastases

Central Nervous System Metastases
  • Author : Manmeet Ahluwalia,Philippe Metellus,Riccardo Soffietti
  • Publisher :Unknown
  • Release Date :2019-11-05
  • Total pages :421
  • ISBN : 9783030234171
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Summary : This book provides a comprehensive overview of brain metastases, from the molecular biology aspects to therapeutic management and perspectives. Due to the increasing incidence of these tumors and the urgent need to effectively control brain metastatic diseases in these patients, new therapeutic strategies have emerged in recent years. The volume discusses all these innovative approaches combined with new surgical techniques (fluorescence, functional mapping, integrated navigation), novel radiation therapy techniques (stereotactic radiosurgery) and new systemic treatment approaches such as targeted- and immunotherapy. These combination strategies represent a new therapeutic model in brain metastatic patients in which each medical practitioner (neurosurgeon, neurologist, medical oncologist, radiation oncologist) plays a pivotal role in defining the optimal treatment in a multidisciplinary approach. Written by recognized experts in the field, this book is a valuable tool for neurosurgeons, neuro-oncologists, neuroradiologists, medical oncologists, radiation oncologists, cognitive therapists, basic scientists and students working in the area of brain tumors.

Lung Cancer and Personalized Medicine

Lung Cancer and Personalized Medicine
  • Author : Aamir Ahmad,Shirish Gadgeel
  • Publisher :Unknown
  • Release Date :2015-12-14
  • Total pages :228
  • ISBN : 9783319242231
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Summary : This, the first of two volumes on personalized medicine in lung cancer, touches on the core issues related to the understanding of lung cancer—statistics and epidemiology of lung cancer—along with the incidence of lung cancer in non-smokers. A major focus of this volume is the state of current therapies against lung cancer—immune, targeted therapies against EGFR TKIs, KRAS, ALK, angiogenesis; the associated challenges, especially resistance mechanisms; and recent progress in targeted drug development based on metal chemistry. Chapters are written by some of the leading experts in the field, who provide a better understanding of lung cancer, the factors that make it lethal, and current research focused on developing personalized treatment plans. With a unique mix of topics, this volume summarizes the current state-of-knowledge on lung cancer and the available therapies.

Cancer Evolution

Cancer Evolution
  • Author : Charles Swanton
  • Publisher :Unknown
  • Release Date :2017
  • Total pages :350
  • ISBN : 1621821439
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Summary : Tumor progression is driven by mutations that confer growth advantages to different subpopulations of cancer cells. As a tumor grows, these subpopulations expand, accumulate new mutations, and are subjected to selective pressures from the environment, including anticancer interventions. This process, termed clonal evolution, can lead to the emergence of therapy-resistant tumors and poses a major challenge for cancer eradication efforts. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine examines cancer progression as an evolutionary process and explores how this way of looking at cancer may lead to more effective strategies for managing and treating it. The contributors review efforts to characterize the subclonal architecture and dynamics of tumors, understand the roles of chromosomal instability, driver mutations, and mutation order, and determine how cancer cells respond to selective pressures imposed by anticancer agents, immune cells, and other components of the tumor microenvironment. They compare cancer evolution to organismal evolution and describe how ecological theories and mathematical models are being used to understand the complex dynamics between a tumor and its microenvironment during cancer progression. The authors also discuss improved methods to monitor tumor evolution (e.g., liquid biopsies) and the development of more effective strategies for managing and treating cancers (e.g., immunotherapies). This volume will therefore serve as a vital reference for all cancer biologists as well as anyone seeking to improve clinical outcomes for patients with cancer.

Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy

Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy
  • Author : Benjamin Bonavida
  • Publisher :Unknown
  • Release Date :2013-07-04
  • Total pages :260
  • ISBN : 9781461470700
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Summary : ​​​​​This volume gives the latest developments in on the mechanisms of cancer cell resistance to apoptotic stimuli, which eventually result in cancer progression and metastasis. One of the main challenges in cancer research is to develop new therapies to combat resistant tumors. The development of new effective therapies will be dependent on delineating the biochemical, molecular, and genetic mechanisms that regulate tumor cell resistance to cytotoxic drug-induced apoptosis. These mechanisms should reveal gene products that directly regulate resistance in order to develop new drugs that target these resistance factors and such new drugs may either be selective or common to various cancers. If successful, new drugs may not be toxic and may be used effectively in combination with subtoxic conventional drugs to achieve synergy and to reverse tumor cell resistance. The research developments presented in this book can be translated to produce better clinical responses to resistant tumors.

Integrative Oncology

Integrative Oncology
  • Author : Donald Abrams,Andrew Weil
  • Publisher :Unknown
  • Release Date :2009-03-09
  • Total pages :624
  • ISBN : 9780199885855
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Summary : People facing a new diagnosis of cancer are unsettled by their prognosis and treatment options, and they often seek to integrate complementary modalities into their conventional care plan, hoping to improve their chances of cure and decrease side effects. Many do so without informing their oncologist, for fear of alienating them or not convinced that their physician would be informed about complementary therapies. Integrative Oncology, the first volume in the Weil Integrative Medicine Library, provides a wealth of information for both practitioners and consumers on the emerging field of integrative oncology. Noted oncologist Donald Abrams and integrative medicine pioneer Andrew Weil and their international panel of experts present up-to-date and extensively referenced chapters on a wide spectrum of issues and challenges, bound in one comprehensive, reader-friendly text in a format featuring key points, sidebars, tables, and a two-color design for ease of use. It is destined to emerge as the definitive resource in this emerging field.

A Global Scientific VisionPrevention, Diagnosis, and Treatment of Lung Cancer

A Global Scientific VisionPrevention, Diagnosis, and Treatment of Lung Cancer
  • Author : Marta Adonis
  • Publisher :Unknown
  • Release Date :2017-03-01
  • Total pages :230
  • ISBN : 9789535129653
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Summary : Lung cancer is the number one cause of cancer deaths around the world. This devastating disease takes strength not only in people who smoke but also in poor people that eat polluted food and use heating sources, and in those exposed naturally to toxic compounds present in indoor and outdoor environments. Lung cancer patients and their families wait actions from the science that give not only answer to their demands but also a light of hope at the moment of receiveing the diagnosis. This book meets the experience of several researchers who dedicate many hours a day to find not only the cure of lung cancer but also the way to convert the pathology of this chronic disease. In 12 chapters, the lectures will give information related to the relationship of lung cancer and smoking habit, the crucial role of the image technology for diagnosis of lung cancer, and a molecular vision of prevention, diagnosis, and treatment of lung cancer. The authors with a clinic and/or lab vision and with a great spirit to collaborate with the science and with each past, present, and future patient and their families have dedicated many hours to write each chapter. Probably, the final answer to find the cure of lung cancer is not in this book. However, the lectures will give scientific information that will contribute in the near future improvement to the life quality of the patients.

Colorectal Cancer

Colorectal Cancer
  • Author : Luis Rodrigo
  • Publisher :Unknown
  • Release Date :2016-09-07
  • Total pages :440
  • ISBN : 9789535125440
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Summary : Colorectal cancer (CRC) is a major health problem because it represents around 10% of all cancers and achieves a worldwide estimate of 1.4 million newly diagnosed cases annually, resulting in approximately 700,000 deaths. Approximately 19-31% of patients present liver metastases. At diagnosis, a further 23-38% will develop extra-hepatic disease. Over the past decade, the widespread use of modern chemotherapeutic and biological agents, combined with laparoscopic surgical techniques, has improved the prognosis of metastatic CRC. A better understanding of the biology of the tumor, along with high efficiency of diagnostic and therapeutic methods, as well as the spread of screening programs, will improve the survival of the CRC patients in the near future.

Molecular Targeted Therapy of Lung Cancer

Molecular Targeted Therapy of Lung Cancer
  • Author : Yuichi Takiguchi
  • Publisher :Unknown
  • Release Date :2017-01-24
  • Total pages :327
  • ISBN : 9789811020025
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Summary : This book discusses the latest molecular targeted therapy of lung cancer including its evaluation and future directions. It clearly illustrates the initial dramatic effectiveness of molecular targeted therapy, recurrence of the disease, overcoming the wide variety of resistance mechanisms using new-generation molecular targeted agents and potential novel approaches. It also outlines the increasing necessity for new diagnostic technology and strategies for managing different adverse effects and novel methods for evaluating effectiveness and safety. Edited and authored by opinion leaders, Molecular Targeted Therapy of Lung Cancer provides a comprehensive overview of the disease and its treatments. It is a valuable resource for graduate students, post-doctoral fellows and faculty staff, as well as researchers involved in clinical and translational research on lung cancer, helping promote new ideas for further advances.