Antiangiogenic Steroids in Human Cancer Therapy

Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers. This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na(+)/H(+) exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell–cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies, including ovarian, non-small cell lung and breast cancers. Clinical trials with squalamine alone or combined with standard chemotherapies or other biologic therapies, including antiangiogenic agents, should be considered for selected cancer patients, and further study of the mechanism of action and bioactivity of squalamine is warranted

GATA1 (GATA binding protein 1 (globin transcription factor1))

We provide a survey of the disease entities associated with GATA1 mutations

Mixed phenotype acute leukemia (MPAL)

Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of all acute leukemias (Weinberg OK et al., 2010)...e World Health Organization (WHO) classification of hematopoietic and lymphoid tumors proposed a simpler diagnostic algorithm, which relies on fewer and more lineage-specific markers to define MPAL. MPAL with t(9;22) and MLL rearrangement are now separate subtypes of MPAL and considered as distinct entities (Weir EG et al., 2010). Recent molecular studies demonstrates frequent epigeneti

Automated System for Early Breast Cancer Detection in Mammograms

The increasing demand on mammographic screening for early breast cancer detection, and the subtlety of early breast cancer signs on mammograms, suggest an automated image processing system that can serve as a diagnostic aid in radiology clinics. We present a fully automated algorithm for detecting clusters of microcalcifications that are the most common signs of early, potentially curable breast cancer. By using the contour map of the mammogram, the algorithm circumvents some of the difficulties encountered with standard image processing methods. The clinical implementation of an automated instrument based on this algorithm is also discussed

Refining the scalar and tensor contributions in τ→πππντ\tau\to \pi\pi\pi\nu_\tau decays

In this article we analyze the contribution from intermediate spin-0 and spin-2 resonances to the $\tau\to\nu \pi\pi\pi$ decay by means of a chiral invariant Lagrangian incorporating these mesons. In particular, we study the corresponding axial-vector form-factors. The advantage of this procedure with respect to previous analyses is that it incorporates chiral (and isospin) invariance and, hence, the partial conservation of the axial-vector current. This ensures the recovery of the right low-energy limit, described by chiral perturbation theory, and the transversality of the current in the chiral limit at all energies. Furthermore, the meson form-factors are further improved by requiring appropriate QCD high-energy conditions. We end up with a brief discussion on its implementation in the Tauola Monte Carlo and the prospects for future analyses of Belle's data.Comment: 32 pages, 13 figures. Extended discussion on the numerical importance of the tensor and scalar resonances and the parametrization of the scalar propagator. Version published in JHE

Diagnostic Potential of Cosmic-Neutrino Absorption Spectroscopy

Annihilation of extremely energetic cosmic neutrinos on the relic-neutrino background can give rise to absorption lines at energies corresponding to formation of the electroweak gauge boson $Z^{0}$. The positions of the absorption dips are set by the masses of the relic neutrinos. Suitably intense sources of extremely energetic ($10^{21}$ -- $10^{25}$-eV) cosmic neutrinos might therefore enable the determination of the absolute neutrino masses and the flavor composition of the mass eigenstates. Several factors--other than neutrino mass and composition--distort the absorption lines, however. We analyze the influence of the time-evolution of the relic-neutrino density and the consequences of neutrino decay. We consider the sensitivity of the lineshape to the age and character of extremely energetic neutrino sources, and to the thermal history of the Universe, reflected in the expansion rate. We take into account Fermi motion arising from the thermal distribution of the relic-neutrino gas. We also note the implications of Dirac vs. Majorana relics, and briefly consider unconventional neutrino histories. We ask what kinds of external information would enhance the potential of cosmic-neutrino absorption spectroscopy, and estimate the sensitivity required to make the technique a reality.Comment: 25 pages, 26 figures (in 46 files), uses RevTe

Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities

Despite improvements in our understanding of the molecular basis of acute myeloid leukemia (AML), the association between genetic mutations with morphological dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow (BM) specimens from 168 patients with de novo AML; none of these patients had cytogenetic abnormalities according to the 2016 World Health Organization Classification. We then performed targeted sequencing of diagnostic BM aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations [q (FDR-adjusted P)=0.046] were associated with a higher degree of megakaryocytic dysplasia and STAG2 mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with STAG2 mutations (q=0.010), as well as NPM1 mutations (q=0.022 when considering the presence of any vs. no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and FLT3-ITD (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, NPM1 mutations were associated with longer event-free survival (EFS) (P=0.042), while RUNX1 (P=0.042), NF1 (P=0.040), frequent micromegakaryocytes (P=0.018) and presence of a subclone (P=0.002) were associated with shorter EFS. In multivariable modeling, NPM1 was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS

Back to Business and (Re)employing Workers? Labor Market Activity During State COVID-19 Reopenings

We study the effect of state reopening policies on a large set of labor market indicators through May 2020 to: (1) understand the recent increase in employment using longitudinal as well as cross-sectional data, (2) assess the likely trajectory of reemployment going forward, and (3) investigate the strength of job matches that were disrupted by COVID-19. Estimates from event studies and difference-in-difference regressions suggest that some of the recent increases in employment activity, as measured by cellphone data on work-related mobility, internet searches related to employment, and new and continuing unemployment insurance claims, were likely related to state reopenings, often predating actual reopening dates somewhat. We provide suggestive evidence that increases in employment stem from people returning to their prior jobs: reopenings are only weakly related to job postings, and longitudinal CPS data show that large shares of the unemployed-on-layoff and employed-but-absent in April who transitioned to employment in May remain in the same industry or occupation. Longitudinal CPS estimates further show declines in reemployment probabilities with time away from work. Taken together, these estimates suggest that employment relationships are durable in the short run, but raise concerns that employment gains requiring new employment matches may not be as rapid.Weinberg gratefully acknowledges support from UL1 TR002733 and R24 HD058484

Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells

Loss of the Y chromosome (LOY) is one of the most common somatic genomic alterations in hematopoietic cells in men. However, due to the high prevalence of LOY as the sole cytogenetic finding in the healthy older population, differentiating isolated LOY associated with clonal hematologic processes from aging-associated mosaicism can be difficult in the absence of definitive morphological features of disease. In the past, various investigators have proposed that a high percentage of metaphases with LOY is more likely to represent expansion of a clonal myeloid disease-associated population. It is unknown whether the proportion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations. To address this question, we identified marrow samples with LOY as isolated cytogenetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with median age of 75 years (range 29-90), the percentage of metaphases with LOY was <25% in 23 patients, 25-49% in 10, 50-74% in 8 and ≥75% in 32. A threshold of ≥75% LOY was significantly associated with morphologic diagnosis of myeloid neoplasm (p = 0.004). Further, ≥75% LOY was associated with a higher lifetime incidence of diagnosis of myelodysplastic syndromes (MDS; p < 0.0001), and in multivariate analysis ≥75% LOY was a statistically significant independent predictor of myeloid neoplasia [OR 6.17; 95% CI = 2.15-17.68; p = 0.0007]. Higher LOY percentage (≥75%) was associated with greater likelihood of having somatic mutations (p = 0.0009) and a higher number of these mutations (p = 0.0002). Our findings indicate that ≥75% LOY in marrow is associated with increased likelihood of molecular alterations in genes commonly seen in myeloid neoplasia and with morphologic features of MDS. These observations suggest that ≥75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration