The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic ...leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
A search for charged Higgs bosons heavier than the top quark and decaying via H± → tb is presented. The data analysed corresponds to 36.1 fb−1 of pp collisions at √ s = 13 TeV and was recorded with ...the ATLAS detector at the LHC in 2015 and 2016. The production of a charged Higgs boson in association with a top quark and a bottom quark, pp → tbH±, is explored in the mass range from mH± = 200 to 2000 GeV using multi-jet final states with one or two electrons or muons. Events are categorised according to the multiplicity of jets and how likely these are to have originated from hadronisation of a bottom quark. Multivariate techniques are used to discriminate between signal and background events. No significant excess above the background-only hypothesis is observed and exclusion limits are derived for the production cross-section times branching ratio of a charged Higgs boson as a function of its mass, which range from 2.9 pb at mH± = 200 GeV to 0.070 pb at mH± = 2000 GeV. The results are interpreted in two benchmark scenarios of the Minimal Supersymmetric Standard Model.
The Roman domination in a graph <inline-formula> <tex-math notation="LaTeX">G </tex-math></inline-formula> is a variant of the classical domination, defined by means of a so-called Roman domination ...function <inline-formula> <tex-math notation="LaTeX">f\colon V(G)\to \{0,1,2\} </tex-math></inline-formula> such that if <inline-formula> <tex-math notation="LaTeX">f(v)=0 </tex-math></inline-formula> then, the vertex <inline-formula> <tex-math notation="LaTeX">v </tex-math></inline-formula> is adjacent to at least one vertex <inline-formula> <tex-math notation="LaTeX">w </tex-math></inline-formula> with <inline-formula> <tex-math notation="LaTeX">f(w)=2 </tex-math></inline-formula>. The weight <inline-formula> <tex-math notation="LaTeX">f(G) </tex-math></inline-formula> of a Roman dominating function of <inline-formula> <tex-math notation="LaTeX">G </tex-math></inline-formula> is the sum of the weights of all vertices of <inline-formula> <tex-math notation="LaTeX">G </tex-math></inline-formula>, that is, <inline-formula> <tex-math notation="LaTeX">f(G)=\sum _{u\in V(G)}f(u) </tex-math></inline-formula>. The Roman domination number <inline-formula> <tex-math notation="LaTeX">\gamma _{R}(G) </tex-math></inline-formula> is the minimum weight of a Roman dominating function of <inline-formula> <tex-math notation="LaTeX">G </tex-math></inline-formula>. In this paper we propose algorithms to compute this parameter involving the <inline-formula> <tex-math notation="LaTeX">(\min,+) </tex-math></inline-formula> powers of large matrices with high computational requirements and the GPU (Graphics Processing Unit) allows us to accelerate such operations. Specific routines have been developed to efficiently compute the <inline-formula> <tex-math notation="LaTeX">(\min,+) </tex-math></inline-formula> product on GPU architecture, taking advantage of its computational power. These algorithms allow us to compute the Roman domination number of cylindrical graphs <inline-formula> <tex-math notation="LaTeX">P_{m}\Box ~C_{n} </tex-math></inline-formula> i.e., the Cartesian product of a path and a cycle, in cases <inline-formula> <tex-math notation="LaTeX">m=7,8 </tex-math></inline-formula>,9 <inline-formula> <tex-math notation="LaTeX">n\geq 3 </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">m\geq </tex-math></inline-formula>10<inline-formula> <tex-math notation="LaTeX">, n\equiv 0\pmod 5 </tex-math></inline-formula>. Moreover, we provide a lower bound for the remaining cases <inline-formula> <tex-math notation="LaTeX">m\geq </tex-math></inline-formula>10<inline-formula> <tex-math notation="LaTeX">, n\not \equiv 0\pmod 5 </tex-math></inline-formula>.
The most frequently reported definition of cystic ovarian disease in cattle is an abnormally persistent follicle (>7 to 10 d) with a diameter >25 mm. Discrimination between luteal and follicular ...ovarian cystic structures has traditionally been conducted by measuring the rim width of luteal tissue. The most common practice used in the field for diagnosis of cystic ovarian disease is examination by rectal palpation with or without the use of a B-mode ultrasound. Color Doppler ultrasound technology allows assessment of blood flow area measurements in the ovary, which has been proposed as a potential indirect measure for plasma progesterone (P4) concentrations. The objective of this study was to compare the diagnostic accuracy of differentiating luteal structures from follicular ovarian cysts using measures collected with B-mode and color Doppler transrectal ultrasonography. The definition of an ovarian cyst was a follicle greater than 20 mm in diameter in the absence of a corpus luteum that persisted for at least 10 d. A 3-mm luteal rim width was used to differentiate follicular and luteal cysts. A total of 36 cows were enrolled in the study during routine herd reproductive examination visits, with 26 and 10 having follicular and luteal cysts, respectively. Cows enrolled in the study were examined using a Mini-ExaPad mini ultrasound with color Doppler capabilities (IMV Imaging Ltd.). Blood samples were collected from each cow to measure P4 serum concentrations. History and signalment of each cow, including days in milk, lactation, times bred, days since last heat, milk composition, and somatic cell counts, were retrieved from an online database (DairyComp 305, Valley Agricultural Software). The accuracy of diagnosing follicular from luteal cysts based on luteal rim thickness was analyzed by receiver operating characteristic (ROC) curve using P4 as the gold standard, where P4 concentrations exceeding 1 ng/mL was defined as luteal, and all other structures with less P4 were considered follicular. Luteal rim and blood flow area were selected for further analysis because they presented the best ROC curves for differentiating cystic ovarian structures, with areas under the curve of 0.80 and 0.76, respectively. Luteal rim width of 3 mm was used as the cutoff standard in the study, resulting in sensitivity and specificity of 50% and 86%, respectively. Blood flow area of 0.19 cm2 was used as the cutoff standard in the study, resulting in sensitivity and specificity of 79% and 86%, respectively. When combining the use of luteal rim width and blood flow area to differentiate cystic ovarian structures, a parallel approach resulted in sensitivity and specificity of 73% and 93%, respectively, whereas an in-series approach resulted in sensitivity and specificity of 35% and 100%, respectively. In conclusion, the use of color Doppler ultrasonography when discriminating between luteal and follicular ovarian cysts in dairy cattle resulted in higher diagnostic accuracy compared with using B-mode ultrasonography alone.
Infectious bovine keratoconjunctivitis (IBK) is a common ocular disease in cattle that causes economic losses to producers and negatively impacts animal welfare. In a 2016 survey of cow-calf ...producers in California, IBK was identified as the disease for which antimicrobials are most frequently used. The presented scoping review examined the available literature for methods to prevent IBK and for alternatives to antimicrobials to treat the disease that can be applied in cow-calf operations. Online databases were searched for publications about IBK in cattle populations that were reported from 1950 to 2020. Citations were systematically evaluated in a multi-stage approach using commercial software and summarized in a scoping review format. For the studies included in the review, most research (n = 50) has focused on the development of vaccines for the prevention of IBK. Although the quality of publications has improved over time, there is a lack of consistent evidence for vaccine efficacy against IBK in post-2000 experimental and conventional vaccine trials. A systematic analysis of vaccine studies is warranted. A limited number (n = 6) of studies evaluated the prevention of IBK through fly control, where most have found efficacy of this control measure. Several treatment options (n = 5) that do not include the use of antimicrobials have been investigated but remain at the preliminary stage of testing. Differences in breed susceptibility has been demonstrated with breeds belonging to the Bos indicus subspecies less frequently affected compared to those belonging to the Bos taurus subspecies. Hereford cattle and those lacking pigmentation around the eyelid margin are more frequently affected than other breeds. At present, there are few evidence-based measures that producers can utilize to reduce the burden of IBK in their herds and more research into the efficacy of fly control measures, non-antimicrobial treatment options, the continued search for a viable vaccine, as well as identifying genetic markers associated with traits that confer resistance to the disease are needed.
The midpalatal suture (MPS) corresponds to the tissue that joins the two maxillary bones. Understanding the mechanical behavior of this tissue is of particular interest to those patients who require ...orthodontic treatments such as Rapid Maxillary Expansion (RME). The objective of this research was to observe the influence of interdigitation and collagen fibers on the mechanical response of MPS. To this end, a finite element analysis in two-dimensional models of the bone-suture-bone interface was performed considering the characteristics of the MPS. The geometry of the suture was modeled with 4 different levels of interdigitation: null, moderate, scalloped and fractal. The influence of collagen fibers, aligned transversely along the suture, was considered by incorporating linked structures of the bone fronts. According to the results, the factor that has the greatest impact on the magnitude and distribution of stresses is the interdigitation degree. A higher level of interdigitation produces an increase in tissue stiffness and a lower influence of collagen fibers on the mechanical response of the tissue. Therefore, this research contributes to the understanding of the MPS biomechanics by providing information that may be useful to health staff when evaluating the feasibility of procedures such as RME.
Graphical Abstract
A search for decays of the Higgs boson into a pair of new spin-zero particles, H→aa, where the a-bosons decay into a b-quark pair and a muon pair, is presented. The search utilizes 36.1 fb-1 of ...proton–proton collision data at $\sqrt{s}$ = 13 TeV recorded by the ATLAS experiment at the LHC in 2015 and 2016. No significant deviation from the Standard Model prediction is observed. Upper limits at 95% confidence level are placed on the branching ratio (δH/δSM) x $\mathcal{B(H→aa→bbμμ)}$, ranging from 1.2 10-4 to 8.4 x 10-4 in the a-boson mass range of 20–60 GeV. Model-independent limits are set on the visible production cross-section times the branching ratio to the bbμμ final state for new physics, δVIS(X) x $\mathcal{B(X→bbμμ)}$, ranging from 0.1 fb to 0.73 fb for mμμ between 18 and 62 GeV.
Purpose
There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by
BRCA1
and
BRCA2
genes. In this report, next-generation sequencing (NGS) ...techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility.
Methods
Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene
ATM
(c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in
BRCA1/2
(BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for
ATM
mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer.
Results
Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the
ATM
gene revealed 1.78% prevalence of mutations in the
ATM
gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about
ATM
mutations were very limited.
Conclusion
ATM
mutation prevalence in Spanish population highlights the importance of considering
ATM
pathogenic variants linked to breast cancer susceptibility.
Studies of the fragmentation of jets into charged particles in heavy-ion collisions can provide information about the mechanism of jet quenching by the hot and dense QCD matter created in such ...collisions, the quark-gluon plasma. This paper presents a measurement of the angular distribution of charged particles around the jet axis in √sNN=5.02 TeV Pb+Pb and pp collisions, using the ATLAS detector at the LHC. The Pb+Pb and pp data sets have integrated luminosities of 0.49nb−1 and 25pb−1, respectively. The measurement is performed for jets reconstructed with the anti-kt algorithm with radius parameter R=0.4 and is extended to an angular distance of r=0.8 from the jet axis. Results are presented as a function of Pb+Pb collision centrality and distance from the jet axis for charged particles with transverse momenta in the 1- to 63-GeV range, matched to jets with transverse momenta in the 126- to 316-GeV range and an absolute value of jet rapidity of less than 1.7. Modifications to the measured distributions are quantified by taking a ratio to the measurements in pp collisions. Yields of charged particles with transverse momenta below 4 GeV are observed to be increasingly enhanced as a function of angular distance from the jet axis, reaching a maximum at r=0.6. Charged particles with transverse momenta above 4 GeV have an enhanced yield in Pb+Pb collisions in the jet core for angular distances up to r=0.05 from the jet axis, with a suppression at larger distances.
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