Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor.

Using homogeneous CCD photometric data from the 105 cm Kiso Schmidt telescope covering a 50 × 50 field, we study the mass functions (MFs) of nine open clusters. The ages and Galactocentric distances of the target clusters vary from 16-2000 Myr and 9-10.8 kpc, respectively. The values of MF slopes vary from −1.1 to −2.1. The classical value derived by Salpeter in 1955 for the slope of the initial mass function (IMF) is Γ = −1.35. The MFs in the outer regions of the clusters are found to be steeper than in the inner regions, indicating the presence of mass segregation in the clusters. The MF slopes (in the outer region as well as the whole cluster) undergo an exponential decay with the evolutionary parameter τ (=age/relaxation time). It seems that the evaporation of low-mass members from outer regions of the clusters is not significant at larger Galactocentric distances. It is concluded that IMF in the anti-center direction of the Galaxy might have been steeper than the IMF in the opposite direction. A comparison of the observed color-magnitude diagrams (CMDs) of the clusters with synthetic CMDs gives a photometric binary content of ∼40%.

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The evolution of an X2.7 solar flare, that occurred in a complex βγ δ magnetic configuration region on 3 November 2003 is discussed by utilizing a multi-wavelength data set. The very first signature of pre-flare coronal activity is observed in radio wavelengths as a type III burst that occurred several minutes prior to the flare signature in Hα. This type III burst is followed by the appearance of a loop-top source in hard X-ray (HXR) images obtained from RHESSI. During the main phase of the event, Hα images observed from ARIES solar tower telescope, Nainital, reveal well-defined footpoint (FP) and loop-top (LT) sources. As the flare evolves, the LT source moves upward and the separation between the two FP sources increases. The co-alignment of Hα with HXR images shows spatial B. Joshi et al. correlation between Hα and HXR footpoints, whereas the rising LT source in HXR is always located above the LT source seen in Hα. The evolution of LT and FP sources is consistent with the reconnection models of solar flares. The EUV images at 195 Å taken by SOHO/EIT reveal intense emission on the disk at the flaring region during the impulsive phase. Further, slow-drifting type IV bursts, observed at low coronal heights at two time intervals along the flare period, indicate rising plasmoids or loop systems. The intense type II radio burst at a time in between these type IV bursts, but at a relatively greater height, indicates the onset of CME and its associated coronal shock wave. The study supports the standard CSHKP model of flares, which is consistent with nearly all eruptive flare models. More importantly, the results also contain evidence for breakout reconnection before the flare phase.

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Surface texturing has emerged as a viable option for enhancing the surface properties. The present study analyzes the effect of full and partial micro-textured surface, at different locations and different kinds of dimple geometries, on the dynamic characteristics of hydrodynamic journal bearings and made a comparative study with the non-textured bearings. Three different kinds of dimple geometries, namely, circular texture, square texture, and densely distributed square texture have been adopted for study. The important dynamic characteristics of bearings were evaluated and stability charts were plotted. Location of the texture was found as an important parameter for improved dynamic characteristics though the extent of improvement depends largely on the geometry of texture. The partial textured bearing with proper geometry and location was found to be more stable. Stability margin of such bearings was more in comparison to the plain journal bearings and the relative improvement was found to be the maximum for circular texture and minimum for square texture. The study also shows the potential of surface texturing to make contribution in the accomplishment of the objectives of green tribology.