Diabetes, obesity, cardiovascular diseases, and cancer are noncommunicable diseases representing the main global health challenges of the current century ...
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor ...immunity are unclear. In this study, we isolated three bacterial species-
,
, and
species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal
modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A
receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.
The sphenodontian fossil record in South America is well known from Mesozoic and Paleogene deposits of Argentinean Patagonia, mainly represented by opisthodontians, or taxa closely related to the ...modern Sphenodon. In contrast, the Brazilian fossil record is restricted to the Caturrita Formation, Late Triassic of Rio Grande do Sul, represented by several specimens of Clevosauridae, including Clevosaurus brasiliensis Bonaparte and Sues, 2006. Traditionally, Clevosauridae includes several Late Triassic to Early Jurassic taxa, such as Polysphenodon, Brachyrhinodon, and Clevosaurus, the latter well-represented by several species. The detailed description of the specimen MCN-PV 2852 allowed the first systematic revision of most Clevosaurus species. Within Clevosauridae, Polysphenodon is the most basal taxon, and an IterPCR analysis revealed Brachrhynodon as a possible Clevosaurus; C. petilus, C. wangi, and C. mcgilli as possibly distinct taxonomic entities; and the South African Clevosaurus sp. is not closely related to C. brasiliensis. These data indicate the need of a deep phylogenetic review of Clevosauridae, in order to discover synapomorphic characters among the diversity of these Triassic/Jurassic sphenodontians.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper we consider the fractional nonlinear Schrödinger equation
where
,
,
is a nonlinearity satisfying Berestycki–Lions type conditions and
is a positive potential. For
small, we prove the ...existence of at least
positive solutions, where
is a set of local minima in a bounded potential well and
denotes the cup-length of
. By means of a variational approach, we analyze the topological difference between two levels of an indefinite functional in a neighborhood of expected solutions. Since the nonlocality comes in the decomposition of the space directly, we introduce a new fractional center of mass, via a suitable seminorm. Some other delicate aspects arise strictly related to the presence of the nonlocal operator. By using regularity results based on fractional De Giorgi classes, we show that the found solutions decay polynomially and concentrate around some point of
for ε small.
Aim of this study was to compare cancer incidence in populations with and without diabetes by cancer site. Furthermore, we aimed at comparing excess risk of cancer according to diabetes type, ...diabetes duration and treatment, the latter as regards Type 2 diabetes.
By use of the Reggio Emilia diabetes registry we classified the resident population aged 20-84 at December 31
2009 into two groups: with and without diabetes. By linking with the cancer registry we calculated the 2010-2013 cancer incidence in both groups. The incidence rate ratios (IRR) by cancer site, type of diabetes, diabetes duration, and as concerns Type 2 diabetes, by treatment regimen were computed using Poisson regression model and non-diabetic group as reference.
The cohort included 383,799 subjects without diabetes and 23,358 with diabetes. During follow-up, we identified 1464 cancer cases in subjects with diabetes and 9858 in the remaining population. Overall cancer incidence was higher in subjects with diabetes than in those without diabetes (IRR = 1.22, 95%CI 1.15-1.29), with similar results focusing on subjects with at least 2-year diabetes duration. Cancer sites driving overall increased risk were liver, pancreas, Colon rectum, and bladder in both sexes, corpus uteri for females. There was also suggestion of an increased risk for kidney cancer in females and a decreased risk for prostate cancer. Excess risk was found in patients with Type 2 diabetes, more marked among insulin users, especially with combined therapy. We observed an increasing risk for diabetes duration up to 10 years from diagnosis (IRR = 1.44, 95%CI 1.29-1.61) and a subsequent decrease to moderate-higher risk (IRR = 1.15, 95%CI 1.04-1.30).
Our study indicates that the strength of association depends on specific cancer site. Insulin, monotherapy or combined therapy, per se or as an indication of poor blood glucose control, in addition to diabetes duration, may play a role in the association of diabetes and cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper we study the following nonlinear fractional Hartree (or Choquard-Pekar) equation
(*) where
> 0,
∈ (0, 1),
≥ 2,
∈ (0,
),
is the Riesz potential, and
is a general subcritical ...nonlinearity. The goal is to prove existence of multiple (radially symmetric) solutions
, by assuming
odd or even: we consider both the case
> 0 fixed and the case
prescribed. Here we also simplify some arguments developed for
= 1 (S. Cingolani, M. Gallo, and K. Tanaka, “Multiple solutions for the nonlinear Choquard equation with even or odd nonlinearities,”
, vol. 61, no. 68, p. 34, 2022). A key point in the proof is given by the research of suitable multidimensional odd paths, which was done in the local case by Berestycki and Lions (H. Berestycki and P.-L. Lions, “Nonlinear scalar field equations II: existence of infinitely many solutions,”
, vol. 82, no. 4, pp. 347–375, 1983); for (*) the nonlocalities play indeed a special role. In particular, some properties of these paths are needed in the asymptotic study (as
varies) of the mountain pass values of the unconstrained problem, then exploited to describe the geometry of the constrained problem and detect infinitely many normalized solutions for any
> 0. The found solutions satisfy in addition a Pohozaev identity: in this paper we further investigate the validity of this identity for solutions of doubly nonlocal equations under a
-regularity.
Goal of this paper is to study the asymptotic behaviour of the solutions of the following doubly nonlocal equation (−Δ)su+μu=(Iα∗F(u))f(u)onRNwhere s∈(0,1), N≥2, α∈(0,N), μ>0, Iα denotes the Riesz ...potential and F(t)=∫0tf(τ)dτ is a general nonlinearity with a sublinear growth in the origin. The found decay is of polynomial type, with a rate possibly slower than ∼1|x|N+2s. The result is new even for homogeneous functions f(u)=|u|r−2u, r∈N+αN,2), and it complements the decays obtained in the linear and superlinear cases in Cingolani et al. (2022); D’Avenia et al. (2015). Differently from the local case s=1 in Moroz and Van Schaftingen (2013), new phenomena arise connected to a new “s-sublinear” threshold that we detect on the growth of f. To gain the result we in particular prove a Chain Rule type inequality in the fractional setting, suitable for concave powers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We prove the existence of a spherically symmetric solution for a Schrödinger equation with a nonlocal nonlinearity of Choquard type. This term is assumed to be subcritical and satisfy almost optimal ...assumptions. The mass of of the solution, described by its norm in the Lebesgue space, is prescribed in advance. The approach to this constrained problem relies on a Lagrange formulation and new deformation arguments. In addition, we prove that the obtained solution is also a ground state, which means that it realizes minimal energy among all the possible solutions to the problem.
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We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact ...maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including
We demonstrate that this gene is co-expressed with stemness genes in GSCs and that CD276 can be targeted with an antibody-drug conjugate to eliminate self-renewing cells. Our results demonstrate that integrated structural genomics data sets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.
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