Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors

Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance

Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion

Conventional cytotoxic chemotherapy is highly effective in certain cancers, but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise (‘exhaustion’), which limits the use of chemotherapy and success of cancer therapy. Here, we show that the co-administration of G1T28 (trilaciclib), a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects murine hematopoietic stem cells (HSCs) from chemotherapy-induced exhaustion in a serial 5-fluorouracil (5FU) treatment model. Consistent with a cell intrinsic effect, we show directly preserved HSC function resulting in a more rapid recovery of peripheral blood counts, enhanced serial transplantation capacity and reduced myeloid skewing. When administered to healthy human volunteers, G1T28 demonstrated excellent in vivo pharmacology and transiently inhibited bone marrow (BM) HSPC proliferation. These findings suggest that the combination of CDK4/6 inhibitors (CDK4/6i) with cytotoxic chemotherapy should provide a means to attenuate therapy-induced BM exhaustion in patients with cancer

Mapping threatened Thai bovids provides opportunities for improved conservation outcomes in Asia

Wild bovids provide important ecosystem functions as seed dispersers and vegetation modifiers. Five wild bovids remain in Thailand: gaur (Bos gaurus), banteng (Bos javanicus), wild water buffalo (Bubalus arnee), mainland serow (Capricornis sumatraensis) and Chinese goral (Naemorhedus griseus). Their populations and habitats have declined substantially and become fragmented by land-use change. We use ecological niche models to quantify how much potential suitable habitat for these species remains within protected areas in Asia and then specifically Thailand. We combined species occurrence data from several sources (e.g. mainly camera traps and direct observation) with environmental variables and species-specific and single, large accessible areas in ensemble models to generate suitability maps, using out-of-sample predictions to validate model performance against new independent data. Gaur, banteng and buffalo models showed reasonable model accuracy throughout the entire distribution (greater than or equal to 62%) and in Thailand (greater than or equal to 80%), whereas serow and goral models performed poorly for the entire distribution and in Thailand, though 5 km movement buffers markedly improved the performance for serow. Large suitable areas were identified in Thailand and India for gaur, Cambodia and Thailand for banteng and India for buffalo. Over 50% of suitable habitat is located outside protected areas, highlighting the need for habitat management and conflict mitigation outside protected areas

Neutrino astronomy with the MACRO detector

High energy gamma ray astronomy is now a well established field and several sources have been discovered in the region from a few GeV up to several TeV. If sources involving hadronic processes exist, the production of photons would be accompanied by neutrinos too. Other possible neutrino sources could be related to the annihilation of WIMPs at the center of galaxies with black holes. We present the results of a search for point-like sources using 1100 upward-going muons produced by neutrino interactions in the rock below and inside the MACRO detector in the underground Gran Sasso Laboratory. These data show no evidence for a possible neutrino point-like source or for possible correlations between gamma ray bursts and neutrinos. They have been used to set flux upper limits for candidate point-like sources which are in the range 10^-14-10^-15 cm-2 s-1.Comment: 37 pages, 15 figures, replacement due to a typo in tab. 6, AASLaTex, submitted to Ap

The Murchison Widefield Array: The Square Kilometre Array Precursor at Low Radio Frequencies

The Murchison Widefield Array (MWA) is one of three Square Kilometre Array Precursor telescopes and is located at the Murchison Radio-astronomy Observatory in the Murchison Shire of the mid-west of Western Australia, a location chosen for its extremely low levels of radio frequency interference. The MWA operates at low radio frequencies, 80–300 MHz, with a processed bandwidth of 30.72 MHz for both linear polarisations, and consists of 128 aperture arrays (known as tiles) distributed over a ~3-km diameter area. Novel hybrid hardware/software correlation and a real-time imaging and calibration systems comprise the MWA signal processing backend. In this paper, the as-built MWA is described both at a system and sub-system level, the expected performance of the array is presented, and the science goals of the instrument are summarised

The Sun-Earth Connection near Solar Minimum: Placing it into Context

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Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy

Cyclin-dependent kinases (CDKs) regulate cell proliferation and coordinate the cell cycle checkpoint response to DNA damage. Although inhibitors with varying selectivity to specific CDK family members have been developed, selective CDK4/6 inhibitors have emerged as the most attractive antineoplastic agents because of the importance of CDK4/6 activity in regulating cell proliferation and the toxic effects associated with inhibition of other CDKs (eg, CDK1 and CDK2)