This paper improves upon an existing extreme precipitation monitoring system that is based on the Tropical Rainfall Measuring Mission (TRMM)daily product (3B42) using new statistical models. The ...proposed system utilizes a regional modeling approach in which data from similar locations are pooled to increase the quality of the resulting model parameter estimates to compensate for the short data record. The regional analysis is divided into two stages. First, the region defined by the TRMM measurements is partitioned into approximately 28 000 nonoverlapping clusters using a recursive k-means clustering scheme. Next, a statistical model is used characterize the extreme precipitation events occurring in each cluster. Instead of applying the block maxima approach used in the existing system, in which the generalized extreme value probability distribution is fit to the annual precipitation maxima at each site separately, the present work adopts the peak-over-threshold method of classifying points as extreme if they exceed a prespecified threshold. Theoretical considerations motivate using the point process framework for modeling extremes. The fitted parameters are used to estimate trends and to construct simple and intuitive average recurrence interval (ARI) maps that reveal how rare a particular precipitation event is. This information could be used by policy makers for disaster monitoring and prevention. The new method eliminates much of the noise that was produced by the existing models because of a short data record, producing more reasonable ARI maps when compared with NOAA’s long-term Climate Prediction Center ground-based observations. Furthermore, the proposed method can be applied to other extreme climate records.
The Salvador-Warts-Hippo (SWH) pathway was first discovered in Drosophila melanogaster as a potent inhibitor of tissue growth. The SWH pathway is highly conserved between D. melanogaster and mammals, ...both in function and in the mechanism of signal transduction. The mammalian SWH pathway limits tissue growth by inhibiting the nuclear access and expression of the transcriptional co-activator, Yes-associated protein (YAP). Mutation and altered expression of SWH pathway proteins has been observed in several types of human cancer, but the contribution of these events to tumorigenesis has been unclear. Here we show that YAP can enhance the transformed phenotype of ovarian cancer cell lines and that YAP confers resistance to chemotherapeutic agents that are commonly used to treat ovarian cancer. We find that high nuclear YAP expression correlates with poor patient prognosis in a cohort of 268 invasive epithelial ovarian cancer samples. Segregation by histotype shows that the correlation between nuclear YAP and poor survival is predominantly associated with clear cell tumors, independent of stage. Collectively our findings suggest that YAP derepression contributes to the genesis of ovarian clear cell carcinoma and that the SWH pathway is an attractive therapeutic target.
Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye. ...Prevalence of celiac disease is increased in patients with mono- and/or polyglandular autoimmunity and their relatives. We have reviewed the current and pertinent literature that addresses the close association between celiac disease and endocrine autoimmunity. The close relationship between celiac disease and glandular autoimmunity can be largely explained by sharing of a common genetic background. Further, between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5⁻7% of patients with autoimmune thyroid disease, type 1 diabetes, and/or polyglandular autoimmunity are IgA anti-tissue transglutaminase antibody positive. While a gluten free diet does not reverse glandular autoimmunity, its early institution may delay or even prevent its first manifestation. In conclusion, this brief review highlighting the close association between celiac disease and both monoglandular and polyglandular autoimmunity, aims to underline the need for prospective studies to establish whether an early diagnosis of celiac disease and a prompt gluten-free diet may positively impact the evolution and manifestation of glandular autoimmunity.
In September 1999, the perceptions of the use of adenoviral (Ad) vectors for gene therapy were altered when a patient exposed via the hepatic artery to a high dose of adenoviral vector succumbed to ...the toxicity related to vector administration. Appropriately, concerns were raised about continued use of the Ad vector system and, importantly, there were increased efforts to more fully understand the toxicity. Today it is recognized that there is no ideal vector system, and that while Ad vectors are not suitable for all applications, the significant advantages over other vector systems including efficient transduction of a variety of cell types, both quiescent and dividing, make it optimal for certain applications. These include protocols where high levels of short-term expression are sufficient to provide a therapeutic benefit. Potential target applications include therapeutic angiogenesis, administration into immune-privileged sites such as the CNS, or treatments where the adjuvant effect of adenovirus can be of benefit such as cancer vaccines. Broader applicability of Ad vectors will require resolution of toxicity issues. This review will therefore focus on studies conducted over the last 2 years that have advanced our understanding of the toxicity associated with Ad vectors, studies that have employed methods to reduce toxicity and improvements in Ad vectors themselves that will reduce toxicity by one of several mechanisms. These mechanisms include retargeting vector to the tissue of interest, minimizing or eliminating viral gene expression that is thought to result in loss of transduced cells, or by methods that seek to reduce the vector dose required for therapeutic benefit. An area where there remains significant room for improvement is when readministration of vector is required because transgene expression has decreased to background levels.
The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). ...Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.
We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs ...were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza).
To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED.
We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher potency phase dependent on TSHR/IGF1R crosstalk and the lower potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of teprotumumab biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR.
We show: (1) Tepro dose-dependently inhibits stimulation by TED-Igs; (2) Tepro does not bind to TSHRs; (3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and (4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk and prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs.
We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED.
Recent experiments have shown that grain size of metals in graphene/metal nanocomposites has a significant effect on their strength and ductility. As the grain size decreases, the strength tends to ...increase while the ductility tends to decrease. But quantitative assessment of these observations remains a challenge. In this paper, we establish a hierarchical scheme from nano to macro scale to evaluate the dependance of these properties on the grain size and graphene volume concentration. In the nano scale, the elastic properties of graphene nanofiller and metal matrix are evaluated via the density functional theory (DFT). In the micro scale, the plasticity of the ductile metal is described by a dislocation density-based constitutive equation, and its degradation process is accounted for by the generation of micro voids. In the macro scale we consider the system of randomly distributed graphene nanosheets in the degraded metal matrix. The grain-size dependent stress-strain relation of the overall graphene/metal nanocomposites are calculated by a two-scale homogenization method with the assistance of the field-fluctuation approach. In this process, the grain-size dependent thermodynamic driving force for the progressive generation of micro voids and the influence of an ultrathin imperfect interphase surrounding the graphene nanofiller are also considered. It is demonstrated that the predicted results from the developed hierarchical scheme agree well with the experimental data of graphene/aluminum nanocomposites. The developed multiscale theory can provide a useful guideline for the design and applications of graphene/metal nanocomposites through the grain-size controlled process.
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