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Purpose of Review: For patients with metastatic melanoma, immune checkpoint inhibition has drastically changed outcomes. Here, we review the current and next generations of immune-based anti-cancer therapeutics for patients with metastatic melanoma. Recent Findings: The need for new anti-cancer therapeutics in patients with metastatic melanoma who have progression of disease despite immune checkpoint blockade is evident. Several novel agents are expected to have FDA approval within the next few years, as they have yielded impressive responses. Despite these optimistic agents, the field of immuno-oncology continues to expand and produce agents with novel mechanisms of action. Summary: The next generation of immunotherapy is based upon years of thoroughly researched immuno-oncology. Many of these agents are currently being evaluated in early phase clinical trials, and much of the preliminary data looks promising. [ABSTRACT FROM AUTHOR]

Abstract Background Cell cycle regulation is a complex system consisting of growth-promoting and growth-restricting mechanisms, whose coordinated activity is vital for proper division and propagation. Alterations in this regulation may lead to uncontrolled proliferation and genomic instability, triggering carcinogenesis. Here, we conducted a comprehensive bioinformatic analysis of cell cycle-related genes using data from CRISPR/Cas9 loss-of-function screens performed in four cancer cell lines and in human embryonic stem cells (hESCs). Results Cell cycle genes, and in particular S phase and checkpoint genes, are highly essential for the growth of cancer and pluripotent cells. However, checkpoint genes are also found to underlie the differences between the cell cycle features of these cell types. Interestingly, while growth-promoting cell cycle genes overlap considerably between cancer and stem cells, growth-restricting cell cycle genes are completely distinct. Moreover, growth-restricting genes are consistently less frequent in cancer cells than in hESCs. Here we show that most of these genes are regulated by the tumor suppressor gene TP53, which is mutated in most cancer cells. Therefore, the growth-restriction system in cancer cells lacks important factors and does not function properly. Intriguingly, M phase genes are specifically essential for the growth of hESCs and are highly abundant among hESC-enriched genes. Conclusions Our results highlight the differences in cell cycle regulation between cell types and emphasize the importance of conducting cell cycle studies in cells with intact genomes, in order to obtain an authentic representation of the genetic features of the cell cycle.

The hospitality industry in modern conditions is developing rapidly, infrastructure is being improved and expanded, many hotels and restaurants, recreation centers are appearing, the network of sanatorium-resort facilities and services, communications, etc., is expanding that satisfy the needs of national and foreign consumers. Hospitality is becoming a major sector of the economy in regions with significant tourism and recreation resources. Typically, these resources are not used to the fullest extent without the effective support of local authorities and local governments. The aim of the article is to evaluate the resource provision of hospitality development. The methodology of the study was based on research methods: forecasting, analysis, synthesis, comparison, graphic, systematization and generalization. The research study considers the resource potential of the hospitality industry. The system of hospitality resources is formulated, which includes tourist resources of the region, as well as ancillary resources: human, financial, information, marketing, natural-climatic, administrative, institutional, innovative. It has been proposed, in order to improve the situation that exists in the tourism, hotel, spa industry of the region, the use of its capabilities, to create a cluster of hospitality. The cluster will create more favorable conditions for the active development of congress tourism in the region, that is, the development of a tourist destination aimed at serving various congresses, seminars, meetings and conferences of both national and international importance. The necessity of opening new border crossing points as an element of the hospitality infrastructure has been justified, because the number of foreign tourists entering the region is constantly increasing. The scientific novelty of the study is to justify and solve the problems of systematizing the resources of hospitality and on their possibilities of creating a cluster of hospitality. The practical significance of the results lies in the possibility of using scientifically based guidelines and suggestions for the effective use of the resource potential of the hospitality sector in the regions of Ukraine in the development of relevant strategies and regional programs

Cancer immunotherapy moderates the immune system’s ability to fight cancer. Due to its extreme complexity, scientists are working to put together all the puzzle pieces to get a clearer picture of the immune system. Shreds of available evidence show the connection between cancer and the immune system. Immune responses to tumors and lymphoid malignancies are influenced by B cells, γδT cells, NK cells, and dendritic cells (DCs). Cancer immunotherapy, which encompasses adoptive cancer therapy, monoclonal antibodies (mAbs), immune checkpoint therapy, and CART cells, has revolutionized contemporary cancer treatment. This article reviews recent developments in immune cell regulation and cancer immunotherapy. Various options are available to treat many diseases, particularly cancer, due to the progress in various immunotherapies, such as monoclonal antibodies, recombinant proteins, vaccinations (both preventative and curative), cellular immunotherapies, and cytokines.

Infections, due to a dysfunctional immune response, pose a great risk to patients with decompensated cirrhosis and herald the beginning of the terminal phase of this disease. Infections typically result from breaches in innate immune barriers and inadequate clearance by immune cells. This leads to bacterial and bacterial product translocation to the systemic circulation, which is already primed by ongoing hepatic inflammation in patients with cirrhosis, who are particularly prone to developing organ failure in the presence of an infection. Early identification of bacterial infection, along with the prompt use of appropriate antibiotics, have reduced the mortality associated with certain infections in patients with decompensated cirrhosis. Judicious use of antibiotic therapy remains imperative given the emergence of multidrug-resistant infections in the cirrhotic population. Important research over the last few years has identified molecular targets on immune cells that may enhance their function, and theoretically prevent infections. Clinical trials are ongoing to delineate the beneficial effects of targeted molecules from their off-target effects. Herein, we review the mechanisms that predispose patients with cirrhosis to bacterial infections, the clinical implications of infections and potential targets for the prevention or treatment of infections in this vulnerable population. [ABSTRACT FROM AUTHOR]

The objective of this article is to bring Palestinian women to the centre of a discussion about the gendered dimensions of Israel's convoluted permit system and checkpoint security infrastructure. Drawing on fieldwork close to one of the largest checkpoint terminals in the West Bank, Checkpoint 300 between Bethlehem and Jerusalem, the article develops knowledge about checkpoints in three important ways: i) as gendered spaces that regulate women's mobility differently from that of men; ii) as spaces that produce particular embodied experiences for women; and iii) as security mechanisms that disrupt and regulate relations of care. This knowledge builds towards the main argument of the article: Palestinian women's lives are profoundly affected by Israel's imposition of permit systems and checkpoints in terms of highly gendered impositions of (im)mobility, embodied experience and relations of care. The research presented here thus makes two wider contributions to research on security to do with how the checkpoint brings the politics of gender and occupation to the fore, and how security infrastructure connects to the politics of care under military occupation. [ABSTRACT FROM AUTHOR]

Uncertainty is often approached as an undesired condition that needs to be confronted and mitigated. This is particularly the case at the intersection of two key governance domains, mobility and security, where state actors concern themselves with minimalizing risk and uncertainty by streamlining the safe movement of people, goods and capital. But can uncertainty, in some cases, be also a condition desired by state security actors? This article proposes that uncertainty can be employed as a mode of governance, in which it is deliberately crafted in order to pursue controversial policies which differentiate and discriminate between different population groups. Using ethnographic data collected in 11 months of fieldwork at checkpoints in and around Jerusalem Jerusalem, I examine the role of (un)certainty in facilitating the mobility of some residents, while severely limiting the movement of others. I then proceed to analyse three distinct dimensions of (un)certainty as a mode of governance at the checkpoints: the opaque and interchangeable roles of public and private security actors; the parallel existence of unimpeded and streamlined mobility to designated populations; and the spatiotemporal movement of borders and their significance. I propose that uncertainty can be strategically employed and adjusted by means of irregular operation, managerial obfuscation, lack of accountability and contradictory or oft-altered directives, and regulatory framework by public and private security actors. I continue to explore how such a strategy can lead to a differentiall (re)distribution of rights, resources and privileges between different citizens and residents. [ABSTRACT FROM AUTHOR]

Summary: Distributed Stream Processing Systems (DSPS) are very popular to process unbounded data streams in real‐time. Low processing latency is a fundamental requirement for DSPS applications to maintain the real‐time response. This requirement of low processing latency for DSPS is badly affected due to inevitable failures in computing systems. Generally, DSPS grapple with these inevitable failures by triggering periodic checkpoints. The periodic checkpoints pessimistically persist the application state so that the execution may be resumed after the failure. These periodic checkpoints incur high overheads due to the high frequency of checkpoints triggering, which increases the overall execution time. On the other hand, failure occurrences in real‐world systems are not periodic. This sharp contrast between the periodic checkpoints and failure distributions in the real‐world systems makes the periodic checkpoints inefficient. We propose a failure‐aware adaptive fault tolerance model called FATM which triggers the checkpoints inline with the underlying failure rate. Further, we design a model for utility factor and checkpoint overheads to evaluate the performance of fault tolerance models for DSPS. We implement the FATM atop Apache Flink and perform a series of experiments. To validate the effectiveness of FATM, experiment results are compared with the existing checkpoint‐based models of DSPS. The results show that the FATM significantly reduces the checkpoint frequency, increases the utility factor, and reduces the checkpoint overheads by 28%. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a life-threatening syndrome with complex pathophysiology and great clinical heterogeneity which complicates the delivery of personalized therapies. Our goals were to demonstrate that some biomarkers identified as regulatory immune checkpoints in preclinical studies could 1)improve sepsis prognostication based on clinical variables and 2)guide the stratification of septic patients in subgroups with shared characteristics of immune response or survival outcomes., Methods: We assayed the soluble counterparts of 12 biomarkers of immune response in 113 internal medicine patients with bacterial sepsis., Results: IL-1 receptor-associated kinase M (IRAK-M) exhibited the highest hazard ratios (HRs) for increased 7-day (1.94 [1.17-3.20]) and 30-day mortality (1.61 [1.14-2.28]). HRs of IRAK-M and Galectin-1 for predicting 1-year mortality were 1.52 (1.20-1.92) and 1.64 (1.13-2.36), respectively. A prognostic model including IRAK-M, Galectin-1, and clinical variables (Charlson Comorbidty Index, multiple source of sepsis, and SOFA score) had high discrimination for death at 7 days and 30 days (area under the curve 0.90 [0.82-0.99]) and 0.86 [0.79-0.94], respectively). Patients with elevated serum levels of IRAK-M and Galectin-1 had clinical traits of immune suppression and low survival rates. None of the 12 biomarkers were independent predictors of 2-year mortality., Conclusions: Two inhibitory immune checkpoint biomarkers (IRAK-M and Galectin-1) helped identify 3 distinct sepsis phenotypes with distinct prognoses. These biomarkers shed light on the interplay between immune dysfunction and prognosis in patients with bacterial sepsis and may prove to be useful prognostic markers, therapeutic targets, and biochemical markers for targeted enrollment in targeted therapeutic trials., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. Methods. From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. Results. The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (HAVCR2/TIM3, CD27, CD70, CTLA4, ICOS, IDO1, LAG3, PDCD1, TNFRSF9, PVRIG, CD274/PDL1, and TIGIT) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs versus non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. Conclusion. Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.

Checkpoints maintain the order of cell cycle events during DNA damage or incomplete replication. How the checkpoint response is tailored to different phases of the cell cycle remains poorly understood. The S-phase checkpoint for example results in the slowing of replication, which in budding yeast occurs by Rad53-dependent inhibition of the initiation factors Sld3 and Dbf4. Despite this, we show here that Rad53 phosphorylates both of these substrates throughout the cell cycle at the same sites as in S-phase, suggesting roles for this pathway beyond S-phase. Indeed, we show that Rad53-dependent inhibition of Sld3 and Dbf4 limits re-replication in G2/M, preventing gene amplification. In addition, we show that inhibition of Sld3 and Dbf4 in G1 prevents premature initiation at all origins at the G1/S transition. This study redefines the scope of the ‘S-phase checkpoint’ with implications for understanding checkpoint function in cancers that lack cell cycle controls.

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. Most of these patients with non-small cell lung cancer (NSCLC) present with the advanced stage of the disease at the time of diagnosis, and thus decrease the 5-year survival rate to about 5%. Immune checkpoint inhibitors (ICIs) can act on the inhibitory pathway of cancer immune response, thereby restoring and maintaining anti-tumor immunity. There are already ICIs targeting different pathways, including the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway. Since March 2015, the US Food and Drug Administration (FDA) approved nivolumab (anti-PD-1 antibody) as the second-line option for treatment of patients with advanced squamous NSCLC. Additionally, a series of inhibitors related to PD-1/PD-L1 immune-checkpoints have helped in the immunotherapy of NSCLC patients, and modified the original treatment model. However, controversies remain regarding the use of ICIs in a subgroup with targeted oncogene mutations is a problem that we need to solve. On the other hand, there are continuous efforts to find biomarkers that effectively predict the response of ICIs to screen suitable populations. In this review, we have reviewed the history of the continuous developments in cancer immunotherapy, summarized the mechanism of action of the immune-checkpoint pathways. Finally, based on the results of the first-line recent trials, we propose a potential first-line immunotherapeutic strategy for the treatment of the patients with NSCLC.

In-memory databases (IMDBs) are gaining increasing popularity in big data applications, where clients commit updates intensively. Specifically, it is necessary for IMDBs to have efficient snapshot performance to support certain special applications (e.g., consistent checkpoint, HTAP). Formally, the in-memory consistent snapshot problem refers to taking an in-memory consistent time-in-point snapshot with the constraints that 1) clients can read the latest data items and 2) any data item in the snapshot should not be overwritten. Various snapshot algorithms have been proposed in academia to trade off throughput and latency, but industrial IMDBs such as Redis adhere to the simple fork algorithm. To understand this phenomenon, we conduct comprehensive performance evaluations on mainstream snapshot algorithms. Surprisingly, we observe that the simple fork algorithm indeed outperforms the state-of-the-arts in update-intensive workload scenarios. On this basis, we identify the drawbacks of existing research and propose two lightweight improvements. Extensive evaluations on synthetic data and Redis show that our lightweight improvements yield better performance than fork, the current industrial standard, and the representative snapshot algorithms from academia. Finally, we have opensourced the implementation of all the above snapshot algorithms so that practitioners are able to benchmark the performance of each algorithm and select proper methods for different application scenarios. [ABSTRACT FROM AUTHOR]

Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. Methods. From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. Results. The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in Ml macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (HAVCR2/TIM3, CD27, CD70, CTLA4, ICOS, IDO1, LAG3, PDCD1, TNFRSF9, PVRIG, CD274/PDL1, and TIGIT) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs versus non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. Conclusion. Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials. [ABSTRACT FROM AUTHOR]

This article brings women to the fore of a discussion of checkpoints in Palestine to understand better the ways that Palestinian women's lives—even as they may not regularly cross checkpoints—are affected by Israeli security infrastructure. Drawing on fieldwork near Checkpoint 300 between Bethlehem and Jerusalem, we examine women's lives in the context of a gendered system of permits and the nearby checkpoint that makes men's days of labour both long and exhausting, a fact that has profound effects on the family home in terms of restricted mobilities and the division of domestic labour. The article thus builds an account of checkpoints that: (1) situates women's everyday lives in Palestine in the context of Israel's military occupation; (2) extends the temporality of checkpoints beyond the checkpoint itself; and, therefore, (3) enables an understanding of the effects of borders beyond the immediate space of the border. [ABSTRACT FROM AUTHOR]

Eukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance because of the requirement for SPO11-induced programmed double-strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is crucial for eliminating not only oocytes defective in meiotic DSB repair (e.g., Trip13Gt mutants), but also Spo112/2 oocytes that are defective in homologous chromosome synapsis and accumulate a threshold level of spontaneous DSBs. However, rescue of such oocytes by Chk2 deficiency was incomplete, raising the possibility that a parallel checkpoint pathway(s) exists. Here, we show that mouse oocytes lacking both p53 (TRP53) and the oocyte-exclusive isoform of p63, TAp63, protects nearly all Spo112/2 and Trip13Gt/Gt oocytes from elimination. We present evidence that checkpoint kinase I (CHK1; CHEK1), which is known to signal to TRP53, also becomes activated by persistent DSBs in oocytes, and to an increased degree when CHK2 is absent. The combined data indicate that nearly all oocytes reaching a threshold level of unrepaired DSBs are eliminated by a semiredundant pathway of CHK1/CHK2 signaling to TRP53/TAp63. [ABSTRACT FROM AUTHOR]

The problem of online checkpointing is a classical problem with numerous applications that has been studied in various forms for almost 50 years. In the simplest version of this problem, a user has to maintain k memorized checkpoints during a long computation, where the only allowed operation is to move one of the checkpoints from its old time to the current time, and his goal is to keep the checkpoints as evenly spread out as possible at all times. Bringmann, Doerr, Neumann, and Sliacan studied this problem as a special case of an online/offline optimization problem in which the deviation from uniformity is measured by the natural discrepancy metric of the worst case ratio between real and ideal segment lengths. They showed this discrepancy is smaller than 1.59 - o(1) for all k and smaller than ln 4 - o(1) 1.39 for the sparse subset of k's, which are powers of 2. In addition, they obtained upper bounds on the achievable discrepancy for some small values of k. In this article, we solve the main problems left open in the above-mentioned paper by proving that ln 4 is a tight upper and lower bound on the asymptotic discrepancy for all large k and by providing tight upper and lower bounds (in the form of provably optimal checkpointing algorithms, some of which are in fact better than those of Bringmann et al.) for all the small values of k = 10. In the last part of the article, we describe some new applications of this online checkpointing problem. [ABSTRACT FROM AUTHOR]

DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and anomalies. If the damage occurs in the germline, it can potentially lead to infertility or chromosomal and genetic aberrations in the developing embryo. Mammalian oocytes, the female germ cells, are produced before birth, remaining arrested at the prophase stage of meiosis over a long period of time. During this extensive state of arrest the oocyte may be exposed to different DNA-damaging insults for months, years or even decades. Therefore, it is of great importance to understand how these cells respond to DNA damage. In this review, we summarize the most recent developments in the understanding of the DNA damage response mechanisms that function in fully grown mammalian oocytes.

The current view of the involvement of PI3-kinases in checkpoint responses after DNA damage is that ATM is the key regulator of G1-, S- or G2-phase checkpoints, that ATR is only partly involved in the regulation of S- and G2-phase checkpoints and that DNA-PKcs is not involved in checkpoint regulation. However, further analysis of the contributions of these kinases to checkpoint responses in cells exposed to ionizing radiation (IR) recently uncovered striking integrations and interplays among ATM, ATR and DNA-PKcs that adapt not only to the phase of the cell cycle in which cells are irradiated, but also to the load of DNA double-strand breaks (DSBs), presumably to optimize their processing. Specifically, we found that low IR doses in G2-phase cells activate a G2-checkpoint that is regulated by epistatically coupled ATM and ATR. Thus, inhibition of either kinase suppresses almost fully its activation. At high IR doses, the epistatic ATM/ATR coupling relaxes, yielding to a cooperative regulation. Thus, single-kinase inhibition suppresses partly, and only combined inhibition suppresses fully G2-checkpoint activation. Interestingly, DNA-PKcs integrates with ATM/ATR in G2-checkpoint control, but functions in its recovery in a dose-independent manner. Strikingly, irradiation during S-phase activates, independently of dose, an exclusively ATR-dependent G2 checkpoint. Here, ATM couples with DNA-PKcs to regulate checkpoint recovery. In the present work, we extend these studies and investigate organization and functions of these PI3-kinases in the activation of the G1 checkpoint in cells irradiated either in the G0 or G1 phase. We report that ATM is the sole regulator of the G1 checkpoint after exposure to low IR doses. At high IR doses, ATM remains dominant, but contributions from ATR also become detectable and are associated with limited ATM/ATR-dependent end resection at DSBs. Under these conditions, only combined ATM + ATR inhibition fully abrogates checkpoint and resection. Contributions of DNA-PKcs and CHK2 to the regulation of the G1 checkpoint are not obvious in these experiments and may be masked by the endpoint employed for checkpoint analysis and perturbations in normal progression through the cell cycle of cells exposed to DNA-PKcs inhibitors. The results broaden our understanding of organization throughout the cell cycle and adaptation with increasing IR dose of the ATM/ATR/DNA-PKcs module to regulate checkpoint responses. They emphasize notable similarities and distinct differences between G1-, G2- and S-phase checkpoint regulation that may guide DSB processing decisions.

Computation offloading effectively expands the usability of mobile terminals beyond their physical limits, and also greatly extends their battery charging intervals. Offloading or cyber foraging is a technique by which large and complex computational jobs are relocated from lightweight portable devices (such as smartphones) called offloadee to powerful servers (such as nearby laptops/desktops or cloud server over the Internet) called surrogates, and getting the output back at the offloadee. Many research works have been done so far on the architecture of offloading systems, but only few works can be found on fault detection and tolerance. So this paper concentrates on categorizing different failures that may affect the benefit of offloading computation and proposes a fault-tolerance approach to alleviate those faults. The checkpoint based fault-tolerance approach proposed in this paper is able to handle crash, omission and transient failures altogether. Fault prevention is obtained by utilizing historical data for choosing worthy surrogate from known neighborhood. This fault tolerance model is evaluated by applying a real application named π calculator and Scimark benchmark suite. The system is implemented and the proposed approach is found to be effective with respect to energy consumption and resource utilization even in case of crash and omission failure. [ABSTRACT FROM AUTHOR]

Background: Cell cycle regulation is a complex system consisting of growth-promoting and growth-restricting mechanisms, whose coordinated activity is vital for proper division and propagation. Alterations in this regulation may lead to uncontrolled proliferation and genomic instability, triggering carcinogenesis. Here, we conducted a comprehensive bioinformatic analysis of cell cycle-related genes using data from CRISPR/Cas9 loss-of-function screens performed in four cancer cell lines and in human embryonic stem cells (hESCs). Results: Cell cycle genes, and in particular S phase and checkpoint genes, are highly essential for the growth of cancer and pluripotent cells. However, checkpoint genes are also found to underlie the differences between the cell cycle features of these cell types. Interestingly, while growth-promoting cell cycle genes overlap considerably between cancer and stem cells, growth-restricting cell cycle genes are completely distinct. Moreover, growth-restricting genes are consistently less frequent in cancer cells than in hESCs. Here we show that most of these genes are regulated by the tumor suppressor gene TP53, which is mutated in most cancer cells. Therefore, the growth-restriction system in cancer cells lacks important factors and does not function properly. Intriguingly, M phase genes are specifically essential for the growth of hESCs and are highly abundant among hESC-enriched genes. Conclusions: Our results highlight the differences in cell cycle regulation between cell types and emphasize the importance of conducting cell cycle studies in cells with intact genomes, in order to obtain an authentic representation of the genetic features of the cell cycle. [ABSTRACT FROM AUTHOR]

The recent successes of new cancer immunotherapy approaches have led to investigate their relevance in the context of the Endometrial Carcinoma (EC). These therapies, that take the tumor-induced immunosuppressive microenvironment into account, target the tumor immune escape, in particular the inhibitory receptors involved in the regulation of the effector T cells' activity (immune checkpoints). The aim of this study was to identify, in ECs, differences in intergrades immune status that could contribute to the differences in tumor aggressiveness, and could also be used as theranostic tools. The immune status of tumors was assessed by quantitative real-time PCR. We analyzed the expression of specific genes associated to specific leukocytes subpopulations and the expression of reporting genes associated with the tumor escape/resistance. This study highlights significant differences in the EC intergrades immune status especially the tumor-infiltrating cell types and their activation status as well as in the molecular factors produced by the environment. The immune microenvironment of grade 1 ECs hints at a robust tumoricidal milieu while that of higher grades is more evocative of a tolerogenic milieu. This genes-based immunological monitoring of tumors that easily highlights significant intergrade differences relating to the density, composition and functional state of the leukocyte infiltrate, could give solid arguments for choosing the best therapeutic options, especially those targeting immune checkpoints. Moreover it could enable an easy adaptation of individual treatment approaches for each patient. [ABSTRACT FROM AUTHOR]

Cyclins are central engines of cell cycle progression in conjunction with cyclin‐dependent kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but instead forms via its F‐box domain an SCF (Skp1‐Cul1‐F‐box)‐type E3 ubiquitin ligase module. Although various substrates of cyclin F have been identified, the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging them with more than 180 different kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. Replication catastrophe depends on accumulation of the transcription factor E2F1 in cyclin F‐depleted cells. We find that SCF‐cyclin F controls E2F1 ubiquitylation and degradation during the G2/M phase of the cell cycle and upon challenging cells with Chk1 inhibitors. Thus, Cyclin F restricts E2F1 activity during the cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors. Synopsis: A kinase inhibitor screen for synthetic lethality in cells lacking the ubiquitin ligase adaptor Cyclin F leads to the identification of E2F1 as new SCF‐Cyclin F substrate, whose unrestricted activity promotes catastrophic replication stress upon checkpoint suppression with Chk1 inhibitors. A screen to identify vulnerabilities of cells lacking cyclin F identifies Chk1 inhibitors as primary hits.Cyclin F loss predisposes cells to the toxic effect of Chk1i by inducing DNA replication catastrophe.Aberrant accumulation of E2F1 upon cyclin F loss promotes DNA damage upon Chk1 inhibition.Lack of cyclin F prevents degradation of E2F1 in G2/M and upon Chk1 inhibitors.A non‐degradable E2F1 lacking a CY motif induces cell death and DNA replication stress upon Chk1 inhibition. [ABSTRACT FROM AUTHOR]

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As a part of the architecture of the Israeli occupation of the Palestinian Territories, the Israeli government introduced in 2005 a series of so‐called terminal checkpoints as "neutral border crossings", to minimise the impact of these barriers on Palestinian lives through a different design and the use of several machines, such as turnstiles and metal detectors. In this article, we analyse terminal Checkpoint 300 in Bethlehem, framing it as a spatial political technology aimed at controlling the movement of Palestinians. More specifically, we investigate the interactions between Palestinian commuters, Israeli soldiers/security guards and the machines operating inside Checkpoint 300. We conclude by suggesting that Checkpoint 300 is a porous barrier whose regime is produced, reproduced but also challenged by such interactions, and that, despite the new "neutral design", Checkpoint 300 is a place still filled with tension and violence, often exercised by the machines and their "decisions". [ABSTRACT FROM AUTHOR]

NK cells are innate lymphocytes critical for immune surveillance, particularly in eradication of metastatic cancer cells and acute antiviral responses. In contrast to T cells, NK cell‐mediated immunity is rapid, with spontaneous cytotoxicity and cytokine/chemokine production upon pathogen detection. The renaissance in cancer immunology has cast NK cell biology back into the spotlight with an urgent need for deeper understanding of the regulatory networks that govern NK cell antitumor activity. To this end, we have adapted and refined a series of quantitative cellular calculus methods, previously applied to T and B lymphocytes, to dissect the biologic outcomes of NK cells following stimulation with cytokines (IL‐15, IL‐12, IL‐18) or deletion of genes that regulate NK cell proliferation (Cish), survival (Bcl2l11), and activation‐induced‐cell‐death (AICD; Fas). Our methodology is well suited to delineate effects on division rate, intrinsic apoptosis, and AICD, permitting variables such as population half‐life, rate of cell division, and their combined influence on population numbers in response to stimuli to be accurately measured and modelled. Changes in these variables that result from gene deletion, concentration of stimuli, time, and cell density give insight into the dynamics of NK cell responses and serve as a platform to dissect the mechanism of action of putative checkpoints in NK cell activation and novel NK cell immunotherapy agents. [ABSTRACT FROM AUTHOR]

This introductory article revisits cross-border shadow exchanges in a comparative perspective and reflects on their theoretical implications. It explores the diversities and complexities of shadow operations and critically examines the concept of informality that is commonly used to describe such non-state-sanctioned practices. It further underlines the key role played by checkpoint politics in border governance. Border checkpoints serve both as a state institution in regulating border crossings as well as a political site where material and power exchanges among state and non-state actors are negotiated. Such negotiation of selective passage through state-controlled gateways is often predicated upon the skilful manipulation of time and space by experienced traders and brokers. [ABSTRACT FROM AUTHOR]

Marked in part by a narrow river, the border between the neighbouring provinces of Loei in Thailand and Sayaboury in the Lao PDR appears to be porous and unregulated. While a Friendship Bridge regulates large-scale international trade, an extensive amount of informal, small-scale trade continues to flow across smaller checkpoints and other parts of the river. Trade along these sites is not only highly organised, most of it also happens under the gaze of border officials. This article examines the material and power exchanges that occur at local checkpoints between the different actors involved in the facilitation and restriction of trade. Between Loei and Sayaboury, trade is regulated according to a spectrum of licitness that is constantly negotiated and renegotiated between traders and officials. Negotiations rely on the social relations between these actors and involve practices of gift-giving and bribery, which blur the boundaries between reciprocity and corruption. By focusing on the interactions between state and non-state actors, this article sheds light on the way the informal economy is configured by checkpoint politics. [ABSTRACT FROM AUTHOR]

Immunotherapies have revolutionized cancer treatment. Immunotherapy is effective for the treatment of a wide range of cancer types and can mediate complete and durable tumor regression. Nonetheless, the field still faces many significant challenges, such as the need for personalized therapeutic strategies and better biomarkers, the difficulty of selecting the right combination therapy, and resistance to currently available immunotherapies. Both cancer and host immunity comprise significantly diverse and complex ecosystems, making immunogenomics an ideal field for functional genomics analysis. In this review, we describe the cancer–immunity cycle, how cancer cells manage to evade immune attack and the current hurdles in the path of cancer immunotherapy. Then, we discuss how functional genomics approaches can pave the way for more successful cancer immunotherapies. [ABSTRACT FROM AUTHOR]

With the success of immunosuppressive checkpoint in tumor therapy, the corresponding adverse response and drug resistance defects have been exposed. T cells and NK cells are the body's immune system of the two substantial main forces. in recent years, study of T cell checkpoints appeared a certain block, such as PD-1 the effect not benign, on the distribution of NK cell surface excitatory and inhibitory receptors under normal conditions to maintain steady, could be targeted in the tumor treatment blockade have therapeutic effect. This paper reviews the function of NK cells and the effects of corresponding receptors in various types of tumors, providing a direction for the selection of appropriate gate control sites for future treatment. [ABSTRACT FROM AUTHOR]

Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) DNA damage response (DDR) kinases contain elastic domains. ATM also responds to reactive oxygen species (ROS) and ATR to nuclear mechanical stress. Mre11 mediates ATM activation following DNA damage; ATM mutations cause ataxia telangiectasia (A-T). Here, using in vivo imaging, electron microscopy, proteomic, and mechano-biology approaches, we study how ATM responds to mechanical stress. We report that cytoskeleton and ROS, but not Mre11, mediate ATM activation following cell deformation. ATM deficiency causes hyper-stiffness, stress fiber accumulation, Yes-associated protein (YAP) nuclear enrichment, plasma and nuclear membrane alterations during interstitial migration, and H3 hyper-methylation. ATM locates to the actin cytoskeleton and, following cytoskeleton stress, promotes phosphorylation of key cytoskeleton and chromatin regulators. Our data contribute to explain some clinical features of patients with A-T and pinpoint the existence of an integrated mechano-response in which ATM and ATR have distinct roles unrelated to their canonical DDR functions. [Display omitted] • ATM kinase is activated by mechanical stress • ATM binds to cytoskeleton and controls cell stiffness and migration • ATM promotes Kap1 S473 phosphorylation following cell stretching • ATM defects compromise chromatin remodeling in response to mechanical stress Cells adapt to mechanical forces by activating specific mechano-transduction pathways that control chromatin organization, nuclear integrity, and cytoskeleton properties. Bastianello et al. show that the ATM kinase, also involved in the DNA damage response, is activated by mechanical stress through a ROS-dependent mechanism and promotes cytoskeleton and chromatin remodeling. [ABSTRACT FROM AUTHOR]

The mechanisms for identification of DNA damage and repair usually manage DNA damage very efficiently. If damaged cells manage to bypass the checkpoints where the integrity of the genome is assessed and the decisions whether to proceed with the cell cycle are made, they may evade the imperative to stop dividing and to die. As a result, cancer may develop. Warding off the potential sequence-altering effects of DNA damage during the life of the individual or the existence span of the species is controlled by a set of larger checkpoints acting on a progressively increasing scale, from systematic removal of damaged cells from the proliferative pool by means of repair of DNA damage/programmed cell death through ageing to, finally, cancer. They serve different purposes and act at different levels of the life cycle, safeguarding the integrity of the genetic backup of the individual, the genetic diversity of the population, and, finally, the survival of the species and of life on Earth. In the light of the theory that cancer is the final checkpoint or the nature's manner to prevent complex organisms from living forever at the expense of genetic stagnation, the eventual failure of modern anti-cancer treatments is only to be expected. Nevertheless, the medicine of today and the near future has enough potential to slow down the progression to terminal cancer so that the life expectancy and the quality of life of cancer-affected individuals may be comparable to those of healthy aged individuals.

The purpose of this study was to identify and analyze inns and churches of the historical Bucharest, based on diachronic cartography on historical maps from 1789 up to the present. The importance and the spatial development of the inns and churches throughout history were identified using modern GIS techniques for spatial representation. A major goal was to identify connections between churches and inns. Routes and checkpoints of the passersby and inhabitants were established. Results showed that there were strong connections between churches and inns, represented as patterns of the past.

The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.

The few previous studies testing whether or not microexpressions are indicators of deception have produced equivocal findings, which may have resulted from restrictive operationalizations of microexpression duration. In this study, facial expressions of emotion produced by community participants in an initial screening interview in a mock crime experiment were coded for occurrence and duration. Various expression durations were tested concerning whether they differentiated between truthtellers and liars concerning their intent to commit a malicious act in the future. We operationalized microexpressions as expressions occurring less than the duration of spontaneously occurring, non-concealed, non-repressed facial expressions of emotion based on empirically documented findings, that is ≤0.50 s, and then more systematically ≤0.40, ≤0.30, and ≤0.20 s. We also compared expressions occurring between 0.50 and 6.00 s and all expressions ≤6.00 s. Microexpressions of negative emotions occurring ≤0.40 and ≤0.50 s differentiated truthtellers and liars. Expressions of negative emotions occurring ≤6.00 s also differentiated truthtellers from liars but this finding did not survive when expressions ≤1.00 s were filtered from the data. These findings provided the first systematic evidence for the existence of microexpressions at various durations and their possible ability to differentiate truthtellers from liars about their intent to commit an act of malfeasance in the future.

The current study examined the psychological experience of Palestinians who daily cross an Israel Defense Forces (IDF) checkpoint to reach their schools or places of employment. The study employed an interpretative phenomenological analysis of semi-structured interviews and drawings to capture a depth insight regarding the psychological meaning of crossing the Qalandia checkpoint on a daily basis among 20 adult participants (10 males, 10 females). Three themes emerged. The first theme described deep feelings of distress and desperation and included the categories of humiliation and dehumanization, non-existence, rage, and pessimism and helplessness. The second theme concentrated on the participants’ coping strategies of avoidance and dissociation, which usually characterize maladaptive trauma coping style, as well as exhibited aggressiveness toward their fellow community members, while the third theme described the social fragmentation of the Palestinians’ solidarity. Furthermore, three pictorial phenomena emerged from the participants’ drawings: squared restricted drawings, the use of multiple black tiny objects, and the use of split drawings. These phenomena supported and validated participants’ verbal expressions. We suggest understanding these findings in light of the term “social suffering.”