Checkpoint

This book is a critical exploration of Israel's curfew-closure policy in the Occupied Palestinian Territories through the eyes of CheckpointWatch, an organization of Israeli women monitoring human rights abuses. The book combines observers' daily reports from the checkpoints and along the Separation Wall, with analysis of the bureaucracy that supports the ongoing occupation. Keshet demonstrates the link between Israeli bureaucracy and the closure system as integral to a wider project of ethnic cleansing. As co-founder of the group, Keshet critically reviews the organisation's transformation from a feminist, radical protest movement to one both reclaimed by, and reclaiming, the consensus. Illustrating the nature of Israeli mainstream discourse as both anodyne and cruel, the book also analyses Israeli media representation of Checkpoint Watch and human rights activism in general. Keshet contends that the dilemmas of these Israeli women, torn between opposition to the Occupation and their loyalty to the state, reflects political divisions within Israel society as a whole.

Intracellular checkpoint controls constitute a network of signal transd- tion pathways that protect cells from external stresses and internal errors. Ext- nal stresses can be generated by the continuous assault of DNA-damaging agents, such as environmental mutagens, ultraviolet (UV) light, ionizing radiation, or the reactive oxygen species that can arise during normal cellular metabolism. In response to any of these assaults on the integrity of the genome, the activation of the network of checkpoint control pathways can lead to diverse cellular responses, such as cell cycle arrest, DNA repair, or elimination of the cell by cell death (apoptosis) if the damage cannot be repaired. Moreover, internal errors can occur during the highly orchestrated replication of the cellular genome and its distribution into daughter cells. Here, the temporal order of these cell cycle events must be strictly enforced—for example, to ensure that DNA replication is c- plete and occurs only once before cell division, or to monitor mitotic spindle assembly, and to prevent exit from mitosis until chromosome segregation has been completed. Thus, well functioning checkpoint mechanisms are central to the maintenance of genomic integrity and the basic viability of cells and, the- fore, are essential for proper development and survival. The importance of proper functioning of checkpoints becomes plainly obvious under conditions in which this control network malfunctions and fails. Depending on the severity and timing, failure of this machinery can lead to embryonic lethality, genetic diseases, and cancer.

Extensive research has uncovered a set of molecular surveillance mechanisms – commonly called “checkpoints” – which tightly monitor cell-cycle processes. Today’s anticancer drug development has identified many of these cell-cycle checkpoint molecules as effective targets. Research now promises to uncover a new generation of anticancer drugs with improved therapeutic indices based on their ability to target emerging checkpoint components. Checkpoint Responses in Cancer Therapy summarizes the advances made over the past 20 years, identifying components of cell-cycle checkpoints and their molecular regulation during checkpoint activation and validating the use of checkpoint proteins as targets for the development of anticancer drugs. This book’s distinguished panel of authors takes a close look at topics ranging from the major molecular players affecting DNA synthesis and the response to DNA damage to advances made in the identification of chemical compounds capable of inhibiting individual mitotic kinases. Illuminating and authoritative, Checkpoint Responses in Cancer Therapy offers a critical summary of findings for researchers in the pharmaceutical and biotechnology industries and a valuable resource for academic scientists in cancer research and the study of cell-cycle regulation, signal transduction and apoptosis.

From the award-winning Serbian author David Albahari comes a devastating and Kafkaesque war fable about an army unit sent to guard a military checkpoint with no idea where they are or who the enemy might be. Atop a hill, deep in the forest, an army unit is dropped off to guard a checkpoint. The commander doesn’t know where they are, what border they’re protecting, or why. Their map is useless. The radio crackles with a language no one can recognize. A soldier is found dead in a latrine and the unit vows vengeance—but the killer, like the enemy, is unknown. Amid orgies and massacres, the commander struggles to maintain order and keep his soldiers alive, but he can’t be sure whether they’re fighting a war or caught in some bizarre military experiment. Equal parts Waiting for Godot and Catch-22, David Albahari’s Checkpoint is a haunting and hysterical confrontation with the absurdity of war. Praise for Checkpoint: "A satirical take on war in the vein of Catch-22 and Slaughterhouse Five, Serbian author David Albahari’s Checkpointis shocking and comic in equal turns, skillfully pulled together by the force of Albahari’s wit.... Visceral, wild, and often hilarious, Checkpoint is a dark delight." —Ho Lin, Foreword Reviews, Starred Review “A worthy descendant of The Good Soldier Svejk and Catch-22.” —Kirkus Reviews “Checkpoint is a tornado of a book. David Albahari, a noted Serbian author who lives in Canada, muscles this Kafkaesque short novel into the war-is-absurd literary tradition in one tremendous 183-page paragraph…. Stylistically, JP Donleavy and Gary Shteyngart come to mind at times, while imagistically one might think of Goya, Picasso, or the Surrealists. But Albahari has a distinctive voice, and it comes through vividly in Ellen Elias-Bursać’s able translation from the Serbian.” —Jon Sobel, Blogcritics “Between adventure and apocalypse... Kafka and Kubrick...combining in grotesque-comical manner all the ridiculousness, beauty, horror, subtlety and extravagance that literature can hold.“ —Neue Zürcher Zeitung

Much work over the last two decades has firmly established that loss of cell cycle checkpoint regulation, and resultant unabated cellular proliferation, is an inherent characteristic of cancer. This loss may occur through aberration in any single component involved in signal transduction pathways that orchestrate checkpoint regulation, which may manifest through either a failure to activate the checkpoint or a failure to respond to the activated checkpoint. In normal cells, checkpoint pathways are activated when genetic or cellular homeostasis is compromised, and signals are then transduced to re-stabilize homeostasis, and, failing this, to activate the apoptotic machinery to induce a cellular suicidal response. This implies that both survival and cell death pathways are induced following checkpoint activation, and that the final decision is dependant on the net result of integrating the two sets of signals. It is intriguing that checkpoint pathways are also critical in cancer therapy to provide an apoptotic stimulus when cellular damage induced by the therapeutic agent is detected by the sensor system. Therefore, it is not surprising that failure in pro-survival checkpoint response will render tumor cells hypersensitive to cytotoxics and, conversely, failure in pro-apoptotic checkpoint response will induce genetic instability and/or therapeutic resistance. Understanding the intricacies of checkpoint response is, therefore, central to the design of therapeutic regimen that will enhance antitumor effects. Although early versions of this design entail combination of cytotoxic agents with cell cycle or checkpoint inhibitors, a greater understanding of the concepts could make such combinations clinically more effective. The contributions in this book will consolidate the current state of knowledge on checkpoint responses that may lay the foundation for hypothesis-driven rational approaches in advancing the management of cancer. The immediate attraction of the book to the scientific community is that it represents a timely opportunity to build upon existing concepts of checkpoints to expand our understanding of the inner workings of the critical checkpoint machinery. The present understanding has provided ample appreciation that response to checkpoint activation is manifested through coordinated inhibition of cyclin-dependent kinase (CDK) complexes in G1, S and/or the G2 phase in order to arrest the cell cycle. Kinase inhibition can occur through several mechanisms, including inhibitory phosphorylation of CDK, destruction of the cognate cyclins, and recruitment of CDK inhibitors from the INK and WAF1/CIP1 families. However, the wealth of information from recent discoveries needs to be examined critically to consolidate our conceptual knowledge of checkpoints. At the same time, there is acute awareness in the diversity of checkpoint response between cytotoxic agents, and this serves as a reminder of the magnitude of complexity that is inherent in checkpoint regulation. This volume is intended to bring the cancer research community closer toward an improved understanding of this regulation, how checkpoint abnormalities can impact negatively on cancer therapy, and emerging strategies to target checkpoint response as a therapeutic end-point.

A “constantly captivating…well-researched and often moving” (The Wall Street Journal) history of Checkpoint Charlie, the famous military gate on the border of East and West Berlin where the United States confronted the USSR during the Cold War. In the early 1960s, East Germany committed a billion dollars to the creation of the Berlin Wall, an eleven-foot-high barrier that consisted of seventy-nine miles of fencing, 300 watchtowers, 250 guard dog runs, twenty bunkers, and was operated around the clock by guards who shot to kill. Over the next twenty-eight years, at least five thousand people attempt to smash through it, swim across it, tunnel under it, or fly over it. In 1989, the East German leadership buckled in the face of a civil revolt that culminated in half a million East Berliners demanding an end to the ban on free movement. The world’s media flocked to capture the moment which, perhaps more than any other, signaled the end of the Cold War. Checkpoint Charlie had been the epicenter of global conflict for nearly three decades. Now, “in capturing the essence of the old Cold War [MacGregor] may just have helped us to understand a bit more about the new one” (The Times, London)—the mistrust, oppression, paranoia, and fear that gripped the world throughout this period. Checkpoint Charlie is about the nerve-wracking confrontation between the West and USSR, highlighting such important global figures as Eisenhower, Stalin, JFK, Nikita Khrushchev, Mao Zedung, Nixon, Reagan, and other politicians of the period. He also includes never-before-heard interviews with the men who built and dismantled the Wall; children who crossed it; relatives and friends who lost loved ones trying to escape over it; military policemen and soldiers who guarded the checkpoints; CIA, MI6, and Stasi operatives who oversaw operations across its borders; politicians whose ambitions shaped it; journalists who recorded its story; and many more whose living memories contributed to the full story of Checkpoint Charlie.

The field of cell cycle regulation is based on the observation that the life cycle of a cell progresses through several distinct phases, G1, M, S, and G2, occurring in a well-defined temporal order. Details of the mechanisms involved are rapidly emerging and appear extraordinarily complex. Furthermore, not only is the order of the phases important, but in normal eukaryotic cells one phase will not begin unless the prior phase is completed successfully. Che- point control mechanisms are essentially surveillance systems that monitor the events in each phase, and assure that the cell does not progress prematurely to the next phase. If conditions are such that the cell is not ready to progress—for example, because of incomplete DNA replication in S or DNA damage that may interfere with chromosome segregation in M—a transient delay in cell cycle progression will occur. Once the inducing event is properly handled— for example, DNA replication is no longer blocked or damaged DNA is repaired—cell cycle progression continues. Checkpoint controls have recently been the focus of intense study by investigators interested in mechanisms that regulate the cell cycle. Furthermore, the relationship between checkpoint c- trol and carcinogenesis has additionally enhanced interest in these cell cycle regulatory pathways. It is clear that cancer cells often lack these checkpoints and exhibit genomic instability as a result. Moreover, several tumor suppressor genes participate in checkpoint control, and alterations in these genes are as- ciated with genomic instability as well as the development of cancer.