Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Background During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy. Methods Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath. Results A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways. Conclusion We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

Metastatic cutaneous squamous cell carcinoma (cSCC) is associated with a high risk of recurrence and poor prognosis. There is limited published data exploring whole genome sequencing (WGS). The aim of this project was to provide the first comprehensive genomic understanding of the state of metastatic cSCC. In this study, we used WGS on matched tumor and blood DNA to detect somatic genetic alterations from 25 patients with regional metastases of head and neck cSCC. Our computational analyses interrogate clinical impacts of these genetic alterations on metastatic cSCC across the cohort for both the coding and non-coding genome. In the non-coding genome, 3UTR regions of EVC (48%), PPP1R1A (48%) and LUM (16%) were significantly functionally altered (Q-value < 0.05). Further, significant functional alterations are observed in the tumor suppressing lncRNA LINC01003 ( 68% of specimens, Q-value: 0.0158). In addition, significant recurrent copy number loss in tumor suppressor genes KANSL1 and PTPRD and gain in CALR, CCND1 and FGF3 was observed for coding regions. SNVs driver analyses predicted TP53, CDKN2A, as potential drivers of the metastasis cSCC (using 3 different tools). Indel signature analysis highlight dominance of ID signature 13 followed by ID8 & ID9. Interestingly, ID 9 has previously been shown to have no association with skin melanoma, unlike ID 13 and 8, suggesting some point of difference between these two skin-based diseases. The overall landscape of variation in metastatic cSCC is dominated by cell cycle and DNA repair disruption.

A 10-MHz FREE-FREE BEAM MICROMECHANICAL RESONATOR FABRICATION PROCESS USING SURFACE-MICROMACHINED TECHNOLOGY

The fabrication process for the designed MEMS resonator using surface-micromachined technology is presented in this paper. A 10-MHz Free-Free beam MEMS resonator is designed to vibrate in the second-mode shape, which is significant improvement compare to the fundamental mode. The design showed a Q value as high as 75,000, which is significant improvement compared to 8,400 VHF F-F beam MEMS resonator by K. Wang; and very low motional resistance (18kΩ). The surface-micromachined technology is used as the standard process for the design. The process is briefly described from the layout design to the experimental fabricated device.

Changes in Rainfall and Climate Classification in South Sulawesi

The study discuss about Changes in Rainfall and Climate Classification in South Sulawesi. The climate of the Earth is determined by the location of the sun in relation to the earth's surface. Geographical location influences the categorization of climate on our planet. The results of the study (1) Rainfall in Bone Regency has been classified as high rainfall intensity for the last 10 years; (2) Determination of climate classification can be done by processing rainfall data obtained from data before weighting, after weighting, ranking, and opportunity; (3) The climate classification according to Schmidt-Ferguson for Bone Regency has a B climate type, which is a humid subtropical climate; and (4) The climate classification according This is based on a comparison of the number of dry months (BK) and wet months (BB), from which the Q value is obtained, which is then used to determine the type of climate according to Schmidt-Ferguson; (4) Oldeman's climate classification for Bone Regency has a C1 climate type, which has the characteristics of planting lowland rice once a year and secondary crops twice a year; (5) Oldeman's climate classification for Bone Regency has a This is based on the number of Wet Months (BB) and Dry Months (BK) in a given year

Potential Contribution of IL-27 and IL-23 Gene Polymorphisms to Multiple Sclerosis Susceptibility: An Association Analysis at Genotype and Haplotype Level

(1) Background: interleukin 23 (IL-23) and interleukin 27 (IL-27) modulate the activity of T helper 17 cells (Th17) with critical roles in autoimmune diseases and multiple sclerosis (MS). The genes responsible for cytokine generation are highly influenced by the presence of single nucleotide polymorphisms (SNP) in main regions such as regulatory sequences or in promoter regions, contributing to disease susceptibility and evolution. The present study analyzed the associations of IL-23 and IL-27 SNPs with susceptibility to multiple sclerosis. (2) Methods: We performed a case-control study including 252 subjects: 157 patients diagnosed with MS and 95 controls. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypes for IL-27 T4730С (rs 181206), IL-27 A964G (rs 153109), and IL-23 receptor gene (IL-23R) G1142A (rs 11209026). (3) Results: The IL27-T4730С gene polymorphism was significantly associated with an increased odds of MS under the dominant genetic model (TC + CC variant genotypes, adjusted odds ratio OR = 4.06, 95% CI: 2.14–7.83, p-value = 0.000007, Q-value = 0.000063). Individuals carrying the IL-27 A924G variant (AG + GG) genotype presented higher odds of MS compared to non-carriers under the dominant model (adjusted OR = 1.93, 95% CI: 1.05–3.51, p-value = 0.0324, Q-value = 0.05832) and the allelic genetic model (unadjusted p-value = 0.015, OR = 1.58, 95% CI: 1.09–2.28), while IL-23-R381Q SNP conferred a decreased odds of MS under a codominant model of inheritance (adjusted OR = 0.26, 95% CI: 0.08–0.92, p-value = 0.0276, Q-value = 0.058) and an allelic model (unadjusted p-value = 0.008, OR = 0.23, 95% CI: 0.07–0.75). In an additive model with adjustment for age group (≤40 years vs. >40 years), sex and smoking, patients carrying the G-C (A964G, T4730C) haplotype had a 3.18 increased risk (95% CI: 1.74–5.81, p < 0.001) to develop multiple sclerosis. (4) Conclusions: The results of the current study showed a significant relationship of IL-27-A964G and IL-27-T4730C polymorphisms with increased risk of MS, and also the protective role of the IL-23-R381Q polymorphism. Moreover, the haplotype-based analysis proposed the mutant G-C (A924G, T4730C) as a significant risk haplotype for the development of MS.

Scale To Measure the Attitude of Perennial Crop Farmers towards Climate Change in Tamil Nadu

The degree of positive or negative affect associated with a psychological object is referred to as attitude. Any symbol, phrase, slogan, person, institution, idea or ideal toward which people could differ in terms of positive or negative influence can be used as a psychological object. Attitude scale provides a quantitative assessment of attitudes, views, or values by summarizing numerical scores assigned by researchers to people's replies to sets of statements investigating different aspects of a central subject. The objective of this research was to construct and standardize the same. A scale measuring the attitude of perennial crop farmers towards climate change in Tamil Nadu is developed. One hundred possible statements were prepared to assess the perennial crop farmers attitude towards climate change using the five-point continuum. The S-value and Q-value of each statement were found. The scale was developed using the equal appearing interval method, which comprises of 10 statements (four positive and six negative).

Metabolomic Profiles Associated With Incident Ischemic Stroke

Background:Women have higher lifetime risk of stroke than men, and metabolic factors seem more strongly associated with stroke for women than men. However, few studies in either men or women have evaluated metabolomic profiles and incident stroke.Methods:We applied liquid chromatography-tandem mass spectrometry to measure 519 plasma metabolites in a discovery set of women in the Nurses’ Health Study ([NHS], 454 incident ischemic stroke cases, 454 controls) with validation in two independent, prospective cohorts: Prevención con Dieta Mediterránea ([PREDIMED], 118 stroke cases, 791 controls), and Nurses’ Health Study 2 ([NHS2], 49 ischemic stroke cases, 49 controls). We applied logistic regression models with stroke as the outcome to adjust for multiple risk factors; the false discovery rate (FDR) was controlled through the q value method.Results:Twenty-three metabolites were significantly associated with incident stroke in NHS after adjustment for traditional risk factors (q value <0.05). Of these, 14 metabolites were available in PREDIMED and 3 were significantly associated with incident stroke: methionine sulfoxide, N6-acetyllysine, and sucrose (q value<0.05). In NHS2, one of the 23 metabolites (glucuronate) was significantly associated with incident stroke (q value <0.05). For all four metabolites, higher levels were associated with increased risk. These four metabolites were used to create a stroke metabolite score (SMS) in the NHS and tested in PREDIMED. Per unit of standard deviation of SMS, the odds ratio for incident stroke was 4.12 (95% CI: 2.26 – 7.51) in PREDIMED, after adjustment for risk factors. In PREDIMED, the area under the ROC curve (AUC) for the model including SMS and traditional risk factors was 0.70 (95% CI: 0.75-0.79) versus the AUC for the model including the traditional risk factors only of 0.65 (95% CI: 0.70-75), corresponding to a 5% improvement in risk prediction with SMS (p < 0.005).Discussion:Metabolites associated with stroke included two amino acids, a carboxylic acid and sucrose. A composite SMS including these metabolites was associated with ischemic stroke and showed improvement in risk prediction beyond traditional risk factors.Classification of Evidence:This study provides Class II evidence that a stroke metabolic score accurately predicts incident ischemic stroke risk.

Molecular Signatures of Immune Pressure and Immune Escape in Hematological Malignancies

Downmodulation of antigen presentation machinery represents a paradigm of evasion from adaptive immune surveillance. This mechanism underpins the decrease in presentation of immunogenic peptides below the activation threshold of effector T-cells. Large genomic aberrations, fine somatic mutations, epigenetic silencing and transcriptional modifications involving directly the human leukocyte antigen (HLA) region or genes encompassing antigen degradation, transportation and processing have been invoked across large cohorts of solid tumors and hematological disorders, all as a result of a common lynchpin: the established immune pressure. During tumor growth this orchestra of mechanisms shape the oncogenic landscape and facilitate the emergence of clones with lower immunogenic potential. By analyzing genomic profiles extracted from more than 7000 patients and specimens across 25 previously published cohorts encompassing both lymphoid and myeloid diseases (Table 1), we performed a large genomic study aiming to dissect the multifaceted immunoediting processes in hematological malignancies We first analyzed a broad HLA genomic dysfunction in 31 classical and non-classical loci and identified 892 somatic mutations or allelic losses in 337/6694 patients (5%). Among the different subtypes of hematological malignancies, HLA mutations were found in 16% (N=138/831) of acute lymphoblastic leukemia (ALL), 7% (N=1/14) of histiocytic disorders, 7% (N=3/43) of T-cell lymphoma, 6% (N=136/2247) of myeloid disorders, 2% (N=4/205) of multiple myeloma, 1.6% (N=55/3354) of B-cell lymphoma/chronic lymphocytic leukemia (B-LNH/CLL). Most affected loci were classical A, B and DRB1, while non-classical DPB2, F and DOA were the least interested by somatic events. Interestingly, alterations were never found in non-expressed DRB genes (DRB2-4,7-9). Among the immune genes, we focused on those which, if affected by mutations (either loss or gain of function), could possibly be associated with an immune escape signature. We identified such aberrations in 13% of cases, including CREBBP (4.5%, N=450/9875), EP300 (2.5%, N=252/9831), IRF8 (2.1%, N=166/7865), B2M (2%, N=158/7868), CD70 (1.7%, N=127/7253), TNFRSF14 (2.8%, N=221/7868), IRF4 (1.4%, N=110/7869), which were the most frequently altered. The frequency of those mutations was particularly high in B-NHL/CLL (28%) and ALL (23%). These events and HLA hits were not mutually exclusive. When analyzing the pattern of co-mutations in immune aberrant vs. non-aberrant group, we found that both lymphoid and myeloid entities were enriched in genomic abnormalities also in other immune players (e.g., NOTCH4, NFKB1, IL4R, IFNAR2, C3), emphasizing how the genomic dysfunction of the immune response may be a pathophysiological link, beyond the disease ontogenic classification. Of note is that, in MN subset, aberrations in leukemic drivers, such as: NPM1 (3% vs 16%, q=4.69E-11), JAK2 (3% vs 9%, q=1.00E-04), FLT3 (7% vs 14%, q=1.26E-04), SRSF2 (4% vs 10%, q-value=2.20E-04), DNMT3A (13% vs 21%, q=.001), TP53 (6% vs 10%, q=.009), NRAS (7% vs 12%, q=.021) were enriched in the non-immune-altered group. When accounting for the total number of mutational events, we found that this was significantly increased in immune aberrant vs. non-aberrant cases (q-value=10e-10) in both lymphoid and myeloid disorders. These findings are consistent with the hypothesis that HLA and immune defective escaping clones may arise in the context of a strong anti-tumor response, as a negative feedback to the immunoediting responsible for sculpting the tumor clonal burden. While driver hits can easily gain a fitness advantage regardless of the acquisition of immune escape signatures, immune-aberrant clones (especially if lacking more strong leukemogenic hits) would accrue subclonal alterations as a result of evasion from tumor surveillance, promoting growth only when opposing immune response. In analogy with solid cancers, our results show that also in hematological malignancies, the biology underpinning immune escape mechanisms is intimately related to the processes of immunoediting and may shape malignant clonal progression. In this setting, mutations in determinants of immune responsiveness might constitute markers of operative tumor surveillance. Figure 1 Figure 1. Disclosures Maciejewski: Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.

Posterior Corneal Asphericity Effect on Postoperative Astigmatism after EDOF Intraocular Lens Implantation in Cataract Patients

Aim. To assess the impact of posterior corneal asphericity on postoperative astigmatism. Methods. We included retrospectively 70 eyes of 70 patients that underwent cataract surgery. We included data of the Q value, Kmax, K1, K2, astigmatism AL, and ACD. We performed a vectorial analysis to calculate the astigmatic vectors. Results. Seventy eyes were evaluated. 40 eyes were of females (58%) and 30 of males (42%). The average cohort age was 73 ± 8.9 years. Axial length (AL) was 23.5 ± 0.9, anterior chamber depth (ACD) was 3.13 ± 0.3, and the average posterior Q value was −0.35 ± 0.2. The only significant predictive variable for the correction index (CI) was the posterior Q value (r = 0.24, p < 0.05) and for the surgically induced astigmatism (SIA) (β = 0.34, r = 0.58, p < 0.05). Conclusion. Posterior corneal surface asphericity significantly influences the surgically induced astigmatism and the overcorrection for cataract patients after Lucidis EDOF IOL implantation.

Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer

BackgroundImmune checkpoint blockade (ICB) induces durable response in approximately 20% of patients with advanced bladder urothelial cancer (aUC). Over 50% of aUCs harbor genomic alterations along the phosphoinositide 3-kinase (PI3K) pathway. The goal of this project was to determine the synergistic effects and mechanisms of action of PI3K inhibition and ICB combination in aUC.MethodsAlterations affecting the PI3K pathway were examined in The Cancer Genome Atlas (TCGA) and the Cancer Dependency Map databases. Human and mouse cells with Pten deletion were used for in vitro studies. C57BL/6 mice carrying syngeneic tumors were used to determine in vivo activity, mechanisms of action and secondary resistance of pan-PI3K inhibition, ICB and combination.ResultsAlterations along the PI3K pathway occurred in 57% of aUCs in TCGA. CRISPR (clustered regularly interspaced short palindromic repeats) knockout of PIK3CA induced pronounced inhibition of cell proliferation (p=0.0046). PI3K inhibition suppressed cancer cell growth, migration and colony formation in vitro. Pan-PI3K inhibition, antiprogrammed death 1 (aPD1) therapy and combination improved the overall survival (OS) of syngeneic mice with PTEN-deleted tumors from 27 days of the control to 48, 37, and 65 days, respectively. In mice with tumors not containing a PI3K pathway alteration, OS was prolonged by the combination but not single treatments. Pan-PI3K inhibition significantly upregulated CD80, CD86, MHC-I, and MHC-II in dendritic cells, and downregulated the transforming growth factor beta pathway with a false discovery rate-adjusted q value of 0.001. Interferon alpha response was significantly upregulated with aPD1 therapy (q value: <0.001) and combination (q value: 0.027). Compared with the control, combination treatment increased CD8+ T-cell infiltration (p=0.005), decreased Treg-cell infiltration (p=0.036), and upregulated the expression of multiple immunostimulatory cytokines and granzyme B (p<0.01). Secondary resistance was associated with upregulation of the mammalian target of rapamycin (mTOR) pathway and multiple Sprr family genes.ConclusionsThe combination Pan-PI3K inhibition and ICB has significant antitumor effects in aUC with or without activated PI3K pathway and warrants further clinical investigation. This combination creates an immunostimulatory tumor milieu. Secondary resistance is associated with upregulation of the mTOR pathway and Sprr family genes.