New divisors in the boundary of the instanton moduli space

Let ${\mathcal I}(n)$ denote the moduli space of rank $2$ instanton bundles of charge $n$ on ${\mathbb P}^3$. It is known that ${\mathcal I}(n)$ is an irreducible, nonsingular and affine variety of dimension $8n-3$. Since every rank $2$ instanton bundle on ${\mathbb P}^3$ is stable, we may regard ${\mathcal I}(n)$ as an open subset of the projective Gieseker-Maruyama moduli scheme ${\mathcal M}(n)$ of rank $2$ semistable torsion free sheaves $F$ on ${\mathbb P}^3$ with Chern classes $c_1=c_3=0$ and $c_2=n$, and consider the closure $\overline{{\mathcal I}(n)}$ of ${\mathcal I}(n)$ in ${\mathcal M}(n)$. We construct some of the irreducible components of dimension $8n-4$ of the boundary $\partial{\mathcal I}(n):=\overline{{\mathcal I}(n)}\setminus{\mathcal I}(n)$. These components generically lie in the smooth locus of ${\mathcal M}(n)$ and consist of rank $2$ torsion free instanton sheaves with singularities along rational curves

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds.

Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another non-cytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixed-effects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR]=0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p<0.001), which was most pronounced for the association between immunotherapy combinations and longer survival. Combinations also significantlyincreased the risk of high-grade toxicities (OR=2.42, 95%CI 1.98-2.97) (most notably for immunotherapy and small molecule inhibitors) and mortality at least possibly therapy related (OR: 1.33, 95%CI 1.15-1.53) (both p<0.001) (absolute mortality = 0.90% (single agent) versus 1.31% (combinations)) compared to single agents. In conclusion, combinations of non-cytotoxic drugs versus monotherapy in randomized cancer clinical trials attenuated safety, but increased efficacy, with the balance tilting in favor of combination therapy, based on the prolongation in survival

Irreducible components of the moduli space of rank 2 sheaves of odd determinant on the projective space

We describe new irreducible components of the moduli space of rank $2$ semistable torsion free sheaves on the three-dimensional projective space whose generic point corresponds to non-locally free sheaves whose singular locus is either 0-dimensional or consists of a line plus disjoint points. In particular, we prove that the moduli spaces of semistable sheaves with Chern classes $(c_1,c_2,c_3)=(-1,2n,0)$ and $(c_1,c_2,c_3)=(0,n,0)$ always contain at least one rational irreducible component. As an application, we prove that the number of such components grows as the second Chern class grows, and compute the exact number of irreducible components of the moduli spaces of rank 2 semistable torsion free sheaves with Chern classes $(c_1,c_2,c_3)=(-1,2,m)$ for all possible values for $m$; all components turn out to be rational. Furthermore, we also prove that these moduli spaces are connected, showing that some of sheaves here considered are smoothable

Measurement of the 0.511 MeV gamma ray line from the Galactic Center

The detection of the 0.511 MeV electron positron annihilation line coming from the Galactic Center to provide the means to estimate the rate of positron production and to test some theoretical sources of positrons is addressed. The results of the measurements of the 0.511 MeV line flux made with a gamma ray experiment on board a stratospheric balloon are presented. The detector field of view looked at the galactic longitude range -31 deg l(II) +41 deg. The observed flux is 0.0067 (+ or - 0.0005) photons 1/cm(2)5 which is in very good agreement with the expected flux when assuming that the Galactic Center is a line source emitting uniformly

Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities.

BackgroundThe phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.MethodsConsecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).ResultsAlterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.ConclusionsComprehensive genomic profiling reveals altered PI3K-related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co-occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy