Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding

The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. Mutation of T507 to alanine (T507A) enhanced the biological activity of Cdc25A. Cdc25A(T507A) was more efficient in binding to cyclin B1, activating cyclin B1-Cdk1, and promoting premature entry into mitosis. We propose that the Chk1/Cdc25A/14-3-3 pathway functions to prevent cells from entering into mitosis prior to replicating their genomes to ensure the fidelity of the cell division process

Core Gas Sloshing in Abell 1644

We present an analysis of a 72 ks Chandra observation of the double cluster Abell 1644 (z = 0.047). The X-ray temperatures indicate that the masses are M 500 = (2.6 ± 0.4) × 1014 h –1 M ☉ for the northern sub-cluster and M 500 = (3.1 ± 0.4) × 1014 h –1 M ☉ for the southern, main cluster. We identify a sharp edge in the radial X-ray surface brightness of the main cluster, which we find to be a cold front, with a jump in temperature of a factor of ~3. This edge possesses a spiral morphology characteristic of core gas sloshing around the cluster potential minimum. We present observational evidence, supported by hydrodynamic simulations, that the northern sub-cluster is the object that initiated the core gas sloshing in the main cluster at least 700 Myr ago. We discuss reheating of the main cluster\u27s core gas via two mechanisms brought about by the sloshing gas: first, the release of gravitational potential energy gained by the core\u27s displacement from the potential minimum, and second, a dredging inward of the outer, higher entropy cluster gas along finger-shaped streams. We find that the available gravitational potential energy is small compared to the energy released by the cooling gas in the core

Deep Chandra Observations of Abell 2199: the Interplay between Merger-Induced Gas Motions and Nuclear Outbursts in a Cool Core Cluster

We present new Chandra observations of Abell 2199 that show evidence of gas sloshing due to a minor merger, as well as impacts of the radio source, 3C 338, hosted by the central galaxy, NGC 6166, on the intracluster gas. The new data are consistent with previous evidence of a Mach 1.46 shock 100" from the cluster center, although there is still no convincing evidence for the expected temperature jump. Other interpretations of this feature are possible, but none is fully satisfactory. Large scale asymmetries, including enhanced X-ray emission 200" southwest of the cluster center and a plume of low entropy, enriched gas reaching 50" to the north of the center, are signatures of gas sloshing induced by core passage of a merging subcluster about 400 Myr ago. An association between the unusual radio ridge and low entropy gas are consistent with this feature being the remnant of a former radio jet that was swept away from the AGN by gas sloshing. A large discrepancy between the energy required to produce the 100" shock and the enthalpy of the outer radio lobes of 3C 338 suggests that the lobes were formed by a more recent, less powerful radio outburst. Lack of evidence for shocks in the central 10" indicates that the power of the jet now is some two orders of magnitude smaller than when the 100" shock was formed.Comment: 17 pages, 20 figures, accepted for publication in Ap

Denying renal transplantation to an adolescent medical cannabis user: An ethical case study

Medical cannabis is now legal in over half of the United States. As more patients adopt this unconventional therapy, it is inevitable that potential transplant recipients will disclose their cannabis use during transplant evaluation. Transplant teams are tasked with the decision to utilize a pressure resource, often with little guidance from international and national professional organizations. Many healthcare providers remain uniformed or misinformed about the risks of cannabis use and organ transplantation. In order to illustrate the multifaceted and complex evaluation of transplant patients using medical cannabis, this article presents the case of a 20‐year‐old woman recommended for renal transplant who was originally denied active listing due to her medical cannabis use. A review of the literature explores the perceived and actual risks of cannabis use in the immunocompromised patient. Furthermore, a discussion of the ethics of medical cannabis use and organ transplantation is included with recommendations for multidisciplinary transplant teams.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150568/1/petr13467.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150568/2/petr13467_am.pd

Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis

Despite advances in treatment, cancer remains the 2nd most common cause of death in the United States. Poor cure rates may result from the ability of cancer to recur and spread after initial therapies have seemingly eliminated detectable signs of disease. A growing body of evidence supports a role for cancer stem cells (CSCs) in tumor regrowth and spread after initial treatment. Thus, targeting CSCs in combination with traditional induction therapies may improve treatment outcomes and survival rates. Unfortunately, CSCs tend to be resistant to chemo- and radiation therapy, and a better understanding of the mechanisms underlying CSC resistance to treatment is necessary. This paper provides an update on evidence that supports a fundamental role for CSCs in cancer progression, summarizes potential mechanisms of CSC resistance to treatment, and discusses classes of drugs currently in preclinical or clinical testing that show promise at targeting CSCs

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease