Energy composition of the Universe: time-independent internal symmetry

The energy composition of the Universe, as emerged from the Type Ia supernova observations and the WMAP data, looks preposterously complex, -- but only at the first glance. In fact, its structure proves to be simple and regular. An analysis in terms of the Friedmann integral enables to recognize a remarkably simple time-independent covariant robust recipe of the cosmic mix: the numerical values of the Friedmann integral for vacuum, dark matter, baryons and radiation are approximately identical. The identity may be treated as a symmetry relation that unifies cosmic energies into a regular set, a quartet, with the Friedmann integral as its common genuine time-independent physical parameter. Such cosmic internal (non-geometrical) symmetry exists whenever cosmic energies themselves exist in nature. It is most natural for a finite Universe suggested by the WMAP data. A link to fundamental theory may be found under the assumption about a special significance of the electroweak energy scale in both particle physics and cosmology. A freeze-out model developed on this basis demonstrates that the physical nature of new symmetry might be due to the interplay between electroweak physics and gravity at the cosmic age of a few picoseconds. The big `hierarchy number' of particle physics represents the interplay in the model. This number quantifies the Friedmann integral and gives also a measure to some other basic cosmological figures and phenomena associated with new symmetry. In this way, cosmic internal symmetry provides a common ground for better understanding of old and recent problems that otherwise seem unrelated; the coincidence of the observed cosmic densities, the flatness of the co-moving space, the initial perturbations and their amplitude, the cosmic entropy are among them.Comment: 32 page

Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level

Background: Increasing data indicate that HER2-positive (HER2 +) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms. Methods: A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated. Results: Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients. Conclusion: In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered

Bulk Scale Factor at Very Early Universe

In this paper we propose a higher dimensional Cosmology based on FRW model and brane-world scenario. We consider the warp factor in the brane-world scenario as a scale factor in 5-dimensional generalized FRW metric, which is called as bulk scale factor, and obtain the evolution of it with space-like and time-like extra dimensions. It is then showed that, additional space-like dimensions can produce exponentially bulk scale factor under repulsive strong gravitational force in the empty universe at a very early stage.Comment: 7 pages, October 201

Evolving DNA repair synthetic lethality targets in cancer

DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, upregulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair targeted investigations culminating in clinically viable precision oncology strategy using PARP inhibitors in breast, ovarian, pancreatic and prostate cancers. Whilst PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense pre-clinical and clinical investigation. Here we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors and other emerging DNA repair inhibitors for synthetic lethality in cancer

Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia

© 2020 The Authors Ibrutinib positively modulates many T-cell subsets in chronic lymphocytic leukemia (CLL). To understand ibrutinib\u27s effects on the broader landscape of immune cell populations, we comprehensively characterized changes in circulating counts of 21 immune blood cell subsets throughout the first year of treatment in patients with relapsed/refractory (R/R) CLL (n = 55, RESONATE) and previously untreated CLL (n = 50, RESONATE-2) compared with untreated age-matched healthy donors (n = 20). Ibrutinib normalized abnormal immune cell counts to levels similar to those of age-matched healthy donors. Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes. T-cell function was assessed in response to T-cell receptor stimulation in patients with R/R CLL (n = 21) compared with age-matched healthy donors (n = 18). Ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets. These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function

Genetics of Human and Canine Dilated Cardiomyopathy

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed

Targeting DNA damage repair precision medicine strategies in cancer

DNA repair targeted therapeutics is a promising precision medicine strategy in cancer. The development and clinical use of PARP inhibitors has transformed lives for many patients with BRCA germline deficient breast and ovarian cancer as well as platinum sensitive epithelial ovarian cancers. However, lessons learnt from the clinical use of PARP inhibitors also confirm that not all patients respond either due to intrinsic or acquired resistance. Therefore, the search for additional synthetic lethality approaches is an active area of translational and clinical research. Here, we review the current clinical state of PARP inhibitors and other evolving DNA repair targets including ATM, ATR, WEE1 inhibitors and others in cancer

Period-doubling bifurcation in strongly anisotropic Bianchi I quantum cosmology

We solve the Wheeler-DeWitt equation for the minisuperspace of a cosmological model of Bianchi type I with a minimally coupled massive scalar field $\phi$ as source by generalizing the calculation of Lukash and Schmidt [1]. Contrarily to other approaches we allow strong anisotropy. Combining analytical and numerical methods, we apply an adiabatic approximation for $\phi$, and as new feature we find a period-doubling bifurcation. This bifurcation takes place near the cosmological quantum boundary, i.e., the boundary of the quasiclassical region with oscillating $\psi$-function where the WKB-approximation is good. The numerical calculations suggest that such a notion of a ``cosmological quantum boundary'' is well-defined, because sharply beyond that boundary, the WKB-approximation is no more applicable at all. This result confirms the adequateness of the introduction of a cosmological quantum boundary in quantum cosmology.Comment: Latest update of the paper at http://www.physik.fu-berlin.de/~mbach/publics.html#