Recent advances in understanding the role of Cdk1 in the Spindle Assembly Checkpoint

The goal of mitosis is to form two daughter cells each containing one copy of each mother cell chromosome, replicated in the previous S phase. To achieve this, sister chromatids held together back-to-back at their primary constriction, the centromere, have to interact with microtubules of the mitotic spindle so that each chromatid takes connections with microtubules emanating from opposite spindle poles (we will refer to this condition as bipolar attachment). Only once all replicated chromosomes have reached bipolar attachments can sister chromatids lose cohesion with each other, at the onset of anaphase, and move toward opposite spindle poles, being segregated into what will soon become the daughter cell nucleus. Prevention of errors in chromosome segregation is granted by a safeguard mechanism called Spindle Assembly Checkpoint (SAC). Until all chromosomes are bipolarly oriented at the equator of the mitotic spindle, the SAC prevents loss of sister chromatid cohesion, thus anaphase onset, and maintains the mitotic state by inhibiting inactivation of the major M phase promoting kinase, the cyclin B-cdk1 complex (Cdk1). Here, we review recent mechanistic insights about the circuitry that links Cdk1 to the SAC to ensure correct achievement of the goal of mitosi

Exploiting immune-dependent effects of microtubule-targeting agents to improve efficacy and tolerability of cancer treatment

Microtubule-targeting agents (MTAs), like taxanes and vinca alkaloids, are tubulin-binding drugs that are very effective in the treatment of various types of cancers. In cell cultures, these drugs appear to affect assembly of the mitotic spindle and to delay progression through mitosis and this correlates with their ability to induce cell death. Their clinical efficacy is, however, limited by resistance and toxicity. For these reasons, other spindle-targeting drugs, affecting proteins such as certain kinesins like Eg5 and CENP-E, or kinases like Plk1, Aurora A and B, have been developed as an alternative to MTAs. However, these attempts have disappointed in the clinic since these drugs show poor anticancer activity and toxicity ahead of positive effects. In addition, whether efficacy of MTAs in cancer treatment is solely due to their ability to delay mitosis progression remains controversial. Here we discuss recent findings indicating that the taxane paclitaxel can promote a proinflammatory response by activation of innate immunity. We further describe how this can help adaptive antitumor immune response and suggest, on this basis and on the recent success of immune checkpoint inhibitors in cancer treatment, that a combination therapy based on low doses of taxanes and immune checkpoint inhibitors may be of high clinical advantage in terms of wide applicability, reduced toxicity, and increased antitumor response

A method for spreading and cutting flexible sheet materials

Accordingly with the invention, during the spreading phase, plies stacked in each cutting position can be sep- arated into different groups by applying one flexible film ply, called "separator film" between groups. The appli- cation of the separator film is provided by means of a "separating spreader". It is desirable to provide an appa- ratus for separating plies that is efficient and does not increase sheet material spreading time. It is an object of the present invention in its preferred embodiment at least to provide a method for applying separating film that min- imize the time required for spread separating film. It is a further object of the present invention in its preferred em- bodiment at least to provide a method for accommodates a separating film at different heights at different cutting positions in the lay-up. It is a another object of the present invention in its preferred embodiment at least to provide a method that ensure that the separating film is applied without both stopping the sheet material spreading and requiring a spreader set-up operation. Moreover in ac- cordance with the present invention, the spreader is pro- vided by an innovative operating method oriented to the minimization of the number of lay-ups formed Indeed, the lower are the spreading time and the cutting time spent to process the current workload, the higher are the productivity performance of the system. Since the cutting patterns are pre-established, it is an object of the present invention to provide a method to compose single lay-up in order to maximize the length of spread plies (i.e. to minimize supply roll changes and the number of distinct spreading operations) as well as to maximize cutting po- sitions heights (i.e. minimize of the number of cutting po- sitions)

Sustaining the Spindle Assembly Checkpoint to improve cancer therapy

To prevent chromosome segregation errors, the spindle assembly checkpoint (SAC) delays mitosis exit until proper spindle assembly. We found that the FCP1 phosphatase and its downstream target WEE1 kinase oppose the SAC, promoting mitosis exit despite malformed spindles. We further showed that targeting this pathway might be useful for cancer therapy

Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword

Major currently used anticancer therapeutics either directly damage DNA or target and upset basic cell division mechanisms like DNA replication and chromosome segregation. These insults elicit activation of cell cycle checkpoints, safeguard mechanisms that cells implement to correctly complete cell cycle phases, repair damage or eventually commit suicide in case damage is unrepairable. Although cancer cells appear to be advantageously defective in some aspects of checkpoint physiology, recent acquisitions on the biochemical mechanisms of the various checkpoints are offering new therapeutic approaches against cancer. Indeed, chemical manipulation of these mechanisms is providing new therapeutic strategies and tools to increase the killing efficacy of major cancer therapeutics as well as to directly promote cancer cell death. In this review we summarize developing concepts on how targeting cell cycle checkpoints may provide substantial improvement to cancer therapy

An exact solution to the TLP problem in a NC Machine

This paper considers a job sequencing problem for a single numerical controlled machining center. It is assumed that all the considered jobs must be processed on a single machine provided with a tool magazine with C positions, that no job requires more than C tools to be completely machined and that the tools may be loaded and unloaded from the tool magazine only when the machining operations for each job are completed. The decisional problem is referred to as the tool loading problem (TLP) and it determines the jobs machining sequence as well as the tools to load in the machine tool magazine before the machining operations on each job may start. In industrial cases where the tool switching time is both significant relative to job processing time and proportional to the number of tool switches, the performance criterion is the minimization of the number of tool switches. This paper demonstrates that the TLP is a symmetric sequencing problem. The authors enrich a branch-and-bound algorithm proposed in literature for the TLP with the new symmetric formulation. Computational experiments show the significant improvement obtained by the novel symmetric formulation of the TLP

cGAS-dependent proinflammatory and immune homeostatic effects of the microtubule-targeting agent paclitaxel

: Taxanes are Microtubule-Targeting Agents (MTAs) that exert potent anticancer activity by directly killing cancer cells. However, recent evidence suggests that they may also stimulate inflammation and anticancer adaptive immunity and that these actions strongly contribute to their therapeutic efficacy. Details on how Taxanes may modulate inflammation and anticancer immunity are, nevertheless, still missing. We show here that at very low doses the Taxane Paclitaxel (Pxl) indeed induces a potent proinflammatory response in various cancer cell types in a cyclic GMP-AMP (cGAMP) synthase (cGAS)- and Stimulator of Interferon Genes (STING)-dependent manner, leading to interferon (IFN) signaling. However, we find that Pxl treatment also strongly upregulates the expression of the immune checkpoint protein Programmed Death-Ligand 1 (PD-L1) in cancer cells, therefore, inducing an inhibitory response to adaptive immunity potentially attenuating anticancer immunity and therapeutic success. These observations provide a mechanistic explanation of why clinical benefit may derive from the combination of Pxl with Immune Checkpoint Inhibitors (ICIs) and suggest that more accurately tailoring dosage and schedule of this combination therapy may provide benefit in the management of a larger number of cancer types and stages