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To provide some causal evidence concerning the effects of metformin on osteoarthritis (OA) using two metformin targets, namely AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15) as metformin proxies.This is a 2-sample Mendelian randomization design. We constructed 44 AMPK-related variants genetically predicted in HbA1c (%) as instruments for AMPK and five variants strongly predicted GDF-15 as instruments for GDF-15. Summary-level data for three OA phenotypes, including OA at any site, knee OA, and hip OA were obtained from the largest genome-wide meta-analysis across the UK Biobank and arcOGEN with 455,211 Europeans. Main analyses were conducted using the inverse-variance weighted method. Weighted median and MR-Egger were conducted as sensitivity analyses to assess the robustness of our results.Genetically predicted AMPK were negatively associated with OA at any site (OR: 0.60; 95% CI: 0.43-0.83) and hip OA (OR: 0.42; 95% CI: 0.22-0.80), but with not knee OA (OR: 0.85; 95% CI: 0.49-1.50). Higher levels of genetically predicted GDF-15 reduced the risk of hip OA (OR: 0.95; 95% CI: 0.90-0.99), but not OA at any site (OR: 1.00; 95% CI: 0.98-1.02) and knee OA (OR: 1.02; 95% CI: 0.98-1.07).This study indicates that AMPK and GDF-15 can be potential therapeutic targets for OA, especially for hip OA, and metformin would be repurposed for OA therapy which needs to be verified in randomized controlled trials.

Disc displacement without reduction is a common disorder of the temporomandibular joint, causing clinical symptoms and sometimes condylar degeneration. In some cases, bone regeneration is detected following disc-repositioning procedures. Until now, however, systems-wide knowledge of the protein levels for condylar outcome with disc position is still lacking. Here, we performed comprehensive expression profiling of synovial fluid from 109 patients with disc displacement without reduction using high-resolution data-independent acquisition mass spectrometry and characterized differences in 1,714 proteins. Based on magnetic resonance imaging, samples were divided into groups with versus without condylar absorption and subgroups with versus without new bone. For the proteomic analysis, 32 proteins in groups presented with statistical significance (>2-fold, P < 0.05). Pathways such as response to inorganic substances, blood coagulation, and estrogen signaling were significantly expressed in the group with bone absorption as compared with pathways such as regulation of body fluid levels, vesicle-mediated transport, and focal adhesion, which were enriched in the group without bone absorption. In subgroup analysis, 45 proteins of significant importance (>2-fold, P < 0.05) were associated with pathways including would healing, glycolysis and gluconeogenesis, and amino acid metabolism. Combined with clinical examination, molecules such as acetyl-CoA carboxylase beta (ACACB) and transforming growth factor beta 1 (TGFB1) were related to features such as visual analog scale and maximum interincisal opening ( P < 0.05). In addition, 7 proteins were examined by Western blotting, including progesterone immunomodulatory binding factor 1 (PIBF1), histidine-rich glycoprotein (HRG), and protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). In conclusion, this study provides the first proteome analysis of condylar absorption at disc displacement without reduction and postoperative new bone formation after disc reposition. Integrated with clinical data, this analysis provides an important insight into the proteomics of condylar modification at disc position.

Swallow (Family: Hirundinidae) populations in the Canadian Maritimes have declined since the 1980s. Using mark–recapture data from 2012 to 2019, we determined apparent annual adult survival rates for Barn ( Hirundo rustica Linnaeus, 1758), Tree ( Tachycineta bicolor (Vieillot, 1808)), Bank ( Riparia riparia (Linnaeus, 1758)), and Cliff ( Petrochelidon pyrrhonota (Vieillot, 1817)) swallows. For two data-rich species (Barn and Tree swallows), we modelled the relationships between survival and weather (cold snaps, precipitation, temperature, and wind speed), climate (El Niño–Southern Oscillation (ENSO) and North Atlantic Oscillation (NAO)), Enhanced Vegetation Index (EVI) as a measure of primary productivity during the winter, number of active nests as a measure of site quality, and the Breeding Bird Survey (BBS) annual population index as density-dependent processes. Survival rates for all four species were typically higher (Barn and Tree) or similar to (Cliff and Bank) of estimates from populations that have not undergone severe, long-term declines. Across weather and climate variables, conditions that are typically favourable for high insect availability (e.g., higher precipitation, warmer temperatures, and lower wind speeds) resulted in higher survival. For female Barn and Tree swallows, survival was higher when EVI was lower, and for Barn Swallows, survival was also higher when the BBS index was higher. Collectively our results demonstrate that conditions throughout the annual cycle affect survival, and the relationships with weather and climate variables support the importance of high insect availability.

Although subchondral bone marrow lesions (BMLs) and synovitis have been well acknowledged as important sources of pain in knee osteoarthritis (KOA), it is unclear if synovitis plays the mediating role in the relationship between BMLs and knee pain.We analyzed 600 subjects with magnetic resonance imaging (MRI) in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium (FNIH) cohort at baseline and 24-month. BMLs and synovitis were measured according to the MRI Osteoarthritis Knee Score (MOAKS) scoring system. BMLs were scored in five subregions. A summary synovitis score of effusion and Hoffa-synovitis was calculated. Knee pain was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Linear regression models were applied to analyze the natural direct effect (NDE) of BMLs and synovitis with knee pain, respectively, and natural indirect effect (NIE) mediated by synovitis.590 participants (58.8% females, with a mean age of 61.5) were included in the present analyses. For NDE, knee pain was cross-sectionally associated with medial femorotibial BMLs (β = 0.23, 95% CI: 0.09, 0.38) and synovitis (β = 0.40, 95% CI: 0.20, 0.60). Longitudinal associations retained significant [medial femorotibial BMLs (β = 0.37, 95% CI: 0.21, 0.53); synovitis (β = 0.72, 95% CI: 0.45, 0.99)]. In the NIE analyses, synovitis mediated the association between medial femorotibial BML and knee pain at baseline (β = 0.051, 95% CI: 0.01, 0.09) and over 24 months (β = 0.079, 95% CI: 0.023, 0.15), with the mediating proportion of 17.8% and 22.4%, respectively.Synovitis partially mediates the association between medial femorotibial BMLs and knee pain.

Male-to-female (MtF) transgender individuals are at risk for prostate cancer, although guidelines for screening and management in this population are not well established. We describe a series of 9 MtF transgender patients who underwent prostate tissue sampling and highlight histopathologic features and challenges related to pathologic interpretation of prostate tissue in this patient population. Seven of 9 total patients were diagnosed with prostate cancer and all had elevated prostate-specific antigen at the time of diagnosis. Three of the 7 patients diagnosed with prostate cancer had received different types of hormone therapy for gender affirmation before the diagnosis of prostate cancer, and in all 3 of these patients, there was histologic evidence of hormone therapy effect in both benign prostate tissue and/or the adenocarcinoma. The 2 patients with benign prostate tissue underwent transurethral resection for lower urinary tract symptoms and were previously on hormone therapy for gender affirmation. Both of these specimens showed diffuse glandular atrophy and basal cell hyperplasia, indicative of hormone therapy effect on benign prostatic tissue. In the patients diagnosed with prostate cancer, a spectrum of grades was observed, ranging from Grade Group 1 to Grade Group 5. Four patients underwent radical prostatectomy, with 2 cases showing extraprostatic extension and Grade Group 5 prostatic adenocarcinoma, and 2 showing Grade Group 2 prostatic adenocarcinoma. Three of the 4 patients who underwent radical prostatectomy had received gender-affirming hormone therapy before surgery, and all 3 of these specimens showed hormone therapy effect in non-neoplastic prostate tissue and focal hormone therapy effect in prostatic adenocarcinoma. The presence of areas of viable carcinoma without hormone therapy effect enabled the assignment of a Gleason score and Grade Group in these 3 cases. Hormone therapy administered for gender identity affirmation induces histopathologic changes to both benign prostate tissue (nonkeratinizing squamous metaplasia, diffuse atrophy, basal cell hyperplasia, and stromal dominance with decreased numbers of glands) and prostatic adenocarcinoma (nuclear pyknosis, atrophy, cytoplasmic vacuolization, and architectural patterns that would qualify for Gleason 4 and 5 in the absence of hormone therapy effect) that have been traditionally seen in cis-male prostate cancer patients receiving hormone therapy. In the absence of hormone therapy, the morphology of prostatic adenocarcinoma in transgender patients shows classic morphologic features similar to those seen in cis-male patients not on hormone therapy. Prostate cancer with hormone therapy effect may not only be histologically quite subtle and may be overlooked if not suspected, but also should not be assigned a Gleason score because the Gleason score would substantially overstate its biologic potential. Therefore, similar to cis-male patients who have received androgen deprivation therapy for prostate cancer, transgender patients on hormone therapy for gender affirmation may be at risk for both underrecognition and over-grading of prostate cancer, particularly if the pathologist is not aware of the clinical history.

Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5′ 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as “founder” end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.

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Ovarian cancer is the deadliest gynecologic cancer. Despite recent advances, clinical outcomes remain poor, necessitating novel therapeutic approaches. To investigate metabolic susceptibility, we performed nutrigenetic screens on a panel of clear cell and serous ovarian cancer cells and identified cystine addiction and vulnerability to ferroptosis, a novel form of regulated cell death. Our results may have therapeutic potential, but little is known about the determinants of ferroptosis susceptibility in ovarian cancer. We found that vulnerability to ferroptosis in ovarian cancer cells is enhanced by lower cell confluency. Because the Hippo pathway effectors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are recognized as sensors of cell density, and TAZ is the predominant effector in the tested ovarian cancer cell lines, we investigated the role of TAZ in ferroptosis of ovarian cancer. TAZ removal confers ferroptosis resistance, while TAZS89A overexpression sensitizes cells to ferroptosis. In addition, we found that lower TAZ level in chemo-resistant recurrent ovarian cancer is responsible for reduced ferroptosis susceptibility. The integrative genomic analysis identified ANGPTL4 as a direct TAZ-regulated target gene that sensitizes ferroptosis by activating NOX2. Collectively, cell density–regulated ferroptosis in ovarian cancer is mediated by TAZ through the regulation of the ANGPTL4–NOX2 axis, suggesting therapeutic potentials for ovarian cancers and other TAZ-activated tumors.Implications:This study reveals that TAZ promotes ferroptosis in ovarian cancers by regulating ANGPTL4 and NOX, offering a novel therapeutic potential for ovarian tumors with TAZ activation.

Background Jagged ends of plasma DNA are a recently recognized class of fragmentomic markers for cell-free DNA, reflecting the activity of nucleases. A number of recent studies have also highlighted the importance of jagged ends in the context of pregnancy and oncology. However, knowledge regarding the generation of jagged ends is incomplete. Methods Jaggedness of plasma DNA was analyzed based on Jag-seq, which utilized the differential methylation signals introduced by the DNA end-repair process. We investigated the jagged ends in plasma DNA using mouse models by deleting the deoxyribonuclease 1 (Dnase1), DNA fragmentation factor subunit beta (Dffb), or deoxyribonuclease 1 like 3 (Dnase1l3) gene. Results Aberrations in the profile of plasma DNA jagged ends correlated with the type of nuclease that had been genetically deleted, depending on nucleosomal structures. The deletion of Dnase1l3 led to a significant reduction of jaggedness for those plasma DNA molecules involving more than 1 nucleosome (e.g., size ranges 240-290 bp, 330-380 bp, and 420-470 bp). However, less significant effects of Dnase1 and Dffb deletions were observed regarding different sizes of DNA fragments. Interestingly, the aberration in plasma DNA jagged ends related to multinucleosomes was observed in human subjects with familial systemic lupus erythematosus with Dnase1l3 deficiency and human subjects with sporadic systemic lupus erythematosus. Conclusions Detailed understanding of the relationship between nuclease and plasma DNA jaggedness has opened up avenues for biomarker development.

To describe the associations between osteoarthritis (OA)-related biochemical markers (COMP, MMP-3, HA) and MRI-based imaging biomarkers in middle-aged adults over 10-13 years.Blood serum samples collected during the Childhood Determinants of Adult Health (CDAH)-1 study (year:2004-06; n = 156) and 10-13 year follow-up at CDAH-3 (n = 167) were analysed for COMP, MMP-3, and HA using non-isotopic ELISA. Knee MRI scans obtained during the CDAH-knee study (year:2008-10; n = 313) were assessed for cartilage volume and thickness, subchondral bone area, cartilage defects, and BML.In a multivariable linear regression model describing the association of baseline biochemical markers with MRI-markers (assessed after 4-years), we found a significant negative association of standardised COMP with medial femorotibial compartment cartilage thickness (β:-0.070; 95%CI:-0.138,-0.001), and standardised MMP-3 with patellar cartilage volume (β:-141.548; 95%CI:-254.917,-28.179) and total bone area (β:-0.729; 95%CI:-1.340,-0.118). In multivariable Tobit regression model, there was a significant association of MRI-markers with biochemical markers (assessed after 6-9 years); a significant negative association of patellar cartilage volume (β:-0.001; 95%CI:-0.002,-0.00004), and total bone area (β:-0.158; 95%CI-0.307,-0.010) with MMP-3, and total cartilage volume (β:-0.001; 95%CI:-0.001,-0.0001) and total bone area (β:-0.373; 95%CI:-0.636,-0.111) with COMP. No significant associations were observed between MRI-based imaging biomarkers and HA.COMP and MMP-3 levels were negatively associated with knee cartilage thickness and volume assessed 4-years later, respectively. Knee cartilage volume and bone area were negatively associated with COMP and MMP-3 levels assessed 6-9 years later. These results suggest that OA-related biochemical markers and MRI-markers are interrelated in early OA.

Background The emergence and spread of Plasmodium falciparum parasites that lack HRP2/3 proteins and the resulting decreased utility of HRP2-based malaria rapid diagnostic tests (RDTs) prompted the World Health Organization and other global health stakeholders to prioritize the discovery of novel diagnostic biomarkers for malaria. Methods To address this pressing need, we adopted a dual, systematic approach by conducting a systematic review of the literature for publications on diagnostic biomarkers for uncomplicated malaria and a systematic in silico analysis of P. falciparum proteomics data for Plasmodium proteins with favorable diagnostic features. Results Our complementary analyses led us to 2 novel malaria diagnostic biomarkers compatible for use in an RDT format: glyceraldehyde 3-phosphate dehydrogenase and dihydrofolate reductase-thymidylate synthase. Conclusions Overall, our results pave the way for the development of next-generation malaria RDTs based on new antigens by identifying 2 lead candidates with favorable diagnostic features and partially de-risked product development prospects., The World Health Organization called for the identification of novel biomarkers that can fill the diagnostic gap in settings where hrp2/3 deletions are common. By adopting a dual approach, we identified 2 candidates, glyceraldehyde 3-phosphate dehydrogenase and dihydrofolate reductase-thymidylate synthase, with favorable diagnostic features.

SARS-CoV-2 has infected more than 600 million people worldwide and caused more than 6 million deaths. The emerging novel variants have made the epidemic rebound in many places. Meteorological factors can affect the epidemic spread by changing virus activity, transmission dynamic parameters and host susceptibility. This paper systematically analyzed the currently available laboratory and epidemiological studies on the association between the meteorological factors and COVID-19 incidence, in order to provide scientific evidence for future epidemic control and prevention, as well as developing early warning system.新型冠状病毒已在全球范围内感染超过6亿人，并造成超过600万人死亡，不断出现的新型变异株使得新型冠状病毒肺炎疫情态势在多地出现反弹。气象因素可通过改变病毒活性、传播动力学条件和宿主易感性等，影响疫情传播，本文通过系统梳理和分析气象因素对疫情影响的实验室和流行病学研究结果，分析了气象因素与疾病传播之间的关联，以期为未来疫情防控及开发早期预警系统提供科学参考。.

Purpose Papillary thyroid carcinoma (PTC) represents the most common subtype of thyroid cancer (TC). This study was set out to explore the potential effect of CHD1L on PTC and type 2 diabetes mellitus (T2DM). Methods We searched for T2DM susceptibility genes through the GWAS database and obtained T2DM-related differentially expressed gene from the GEO database. The expression and clinical data of TC and normal samples were collated from the TCGA database. Receiver operating characteristic (ROC) curve analysis was subsequently applied to assess the sensitivity and specificity of the CHD1L for the diagnosis of PTC. The MCP-counter package in R language was then utilized to generate immune cell score to evaluate the relationship between CHD1L expression and immune cells. Then, we performed functional enrichment analysis of co-expressed genes and DEGs to determine significantly enriched GO terms and KEGG to predict the potential functions of CHD1L in PTC samples and T2DM adipose tissue. Results From two genes (ABCB9, CHD1L) were identified to be DEGs (p 1, p

International audience; In this work, we use the finite element method to study the acoustic properties of single and coupled Helmholtz resonators (HRs). Each HR consists of a sphere drilled with one or several small openings. For a single HR, we show that the total pressure computed at the opening's edge as a function of frequency reveals the presence of a local dip in addition to the well-known resonance peak. In the case of coupled resonators, we highlight two resonance peaks at low frequencies, arising from excitation of a monopolar breathing mode, for which the twin resonators are in phase ( S- peak), and a dipolar mode, where the two spheres resonate out of phase ( AS- peak). In the near field, we study the influence of the number of apertures, the distance between spheres and their orientation on the frequencies, and quality factors of the two resonances. In the far field, we show that the propagation of the scattered wave is quasi-isotropic for the S- peak, while it leads to a dipolar-type pressure distribution for the AS- peak, with a directionality depending on the relative orientation of the openings in adjacent HRs. By increasing the number of coupled HRs from two to four units, we investigate the effect of additional mode coupling. Accordingly, the present study aims to manipulate the sound at targeted frequencies, by varying the distance or orientation between twin resonators, and to discuss the effect of dissipation. The demonstration of the coupling between sub-wavelength units opens the way to multi-frequency functionalities of acoustic metasurfaces.

Background Immunoassay platforms that simultaneously detect malaria antigens including histidine-rich protein 2 (HRP2)/HRP3 and Plasmodium lactate dehydrogenase (pLDH), are useful epidemiological tools for rapid diagnostic test evaluation. This study presents the comparative evaluation of two multiplex platforms in identifying Plasmodium falciparum with presence or absence of HRP2/HRP3 expression as being indicative of hrp2/hrp3 deletions and other Plasmodium species. Moreover, correlation between the malaria antigen measurements performed at these platforms is assessed after calibrating with either assay standards or international standards and the cross-reactivity among Plasmodium species is examined. Methods A 77-member panel of specimens composed of the World Health Organization (WHO) international Plasmodium antigen standards, cultured parasites for P. falciparum and Plasmodium knowlesi, and clinical specimens with mono-infections for P. falciparum, Plasmodium vivax, and Plasmodium malariae was generated as both whole blood and dried blood spot (DBS) specimens. Assays for HRP2, P. falciparum–specific pLDH (PfLDH), P. vivax–specific pLDH (PvLDH), and all human Plasmodium species Pan malaria pLDH (PanLDH) on the Human Malaria Array Q-Plex and the xMAP platforms were evaluated with these panels. Results The xMAP showed a higher percent positive agreement for identification of hrp2-deleted P. falciparum and Plasmodium species in whole blood and DBS than the Q-Plex. For whole blood samples, there was a highly positive correlation between the two platforms for PfLDH (Pearson r = 0.9926) and PvLDH (r = 0. 9792), moderate positive correlation for HRP2 (r = 0.7432), and poor correlation for PanLDH (r = 0.6139). In Pearson correlation analysis between the two platforms on the DBS, the same assays were r = 0.9828, r = 0.7679, r = 0.6432, and r = 0.8957, respectively. The xMAP HRP2 assay appeared to cross-react with HRP3, while the Q-Plex did not. The Q-Plex PfLDH assay cross-reacted with P. malariae, while the xMAP did not. For both platforms, P. knowlesi was detected on the PvLDH assay. The WHO international standards allowed normalization across both platforms on their HRP2, PfLDH, and PvLDH assays in whole blood and DBS. Conclusions Q-Plex and xMAP show good agreement for identification of P. falciparum mutants with hrp2/hrp3 deletions, and other Plasmodium species. Quantitative results from both platforms, normalized into international units for HRP2, PfLDH, and PvLDH, showed good agreement and should allow comparison and analysis of results generated by either platform.

BACKGROUND: The protocol for optimal antiplatelet therapy to prevent thromboembolic and hemorrhagic complications in patients with cerebral aneurysms using an endovascular approach is not clear. PURPOSE: Our study analyzed the safety and efficacy of prophylactic tirofiban administration compared with oral antiplatelet drug therapy. DATA SOURCES: We used the PubMed, EMBASE, MEDLINE, and Cochrane library data bases. STUDY SELECTION: Our study consisted of all case series with >5 patients that reported treatment-related outcomes of patients undergoing endovascular procedures pretreated with tirofiban or oral antiplatelet drug therapy. DATA ANALYSIS: Random effects or fixed effects meta-analysis was used to pool the cumulative rate of complications, perioperative mortality, and good clinical outcomes. DATA SYNTHESIS: Fifteen studies with 1981 patients were registered. Thromboembolic complications were significantly lower in the tirofiban group (3.6%; 95% CI, 1.9%–5.8%) compared with the dual-antiplatelet therapy group (8.5%, 95% CI, 4.5%–13%; P = .04). Pretreatment with tirofiban did not remarkably increase the rate of hemorrhagic complications (3.5%; 95% CI, 1.8%–5.6%) compared with dual-antiplatelet therapy (5.1%; 95% CI, 2.6%–8.5%; P = .371). There was a trend toward lower perioperative mortality with tirofiban (0.8%; 95% CI, 0.2%–1.6%) compared with dual-antiplatelet therapy (1.2%; 95% CI, 0.7%–2.0%; P = .412). There was no significant difference in the safety and efficacy between the tirofiban bolus plus drip and drip alone. LIMITATIONS: The limitations are selection and publication biases. CONCLUSIONS: Prophylactic therapy with tirofiban resulted in significantly lower rates of thromboembolic complications with no increase in hemorrhagic events or mortality than the prophylactic use of dual-antiplatelet therapy.

Neuroendocrine tumors (NETs) harbor neuroendocrine differentiation (ND) with specific markers including protein gene product 9.5 (PGP9.5) and Chromogranin A (CgA). In prostate cancers (PC), ND is induced by BRN2/SOX2 transcription factors. NET-like cells with low or absent androgen receptor (AR) signaling cause hormone therapy resistance and poor prognosis in PC. Small cell lung carcinoma (SCLC), a high-grade NET, presents with metastasis early and has poor survival. ONC201/TIC10 is a small molecule inducer of TRAIL signaling in clinical trials. ONC201 antagonizes dopamine D2 or D3 receptors (DRD2/DRD3) and is an agonist of mitochondrial caseinolytic protease P (ClpP) resulting in activation of DR5/TRAIL-dependent apoptosis involving the integrated stress response (ISR). ONC201 is active in various malignancies including H3K27M-mutated glioma and NETs expressing high levels of DRD2. We hypothesized that altered BRN2/SOX2 may impact NET apoptosis by ONC201 through the ISR and TRAIL/DR5. We analyzed the expression of neuroendocrine markers PGP9.5, CgA, SOX2, and BRN2, as well as markers of TRAIL signaling pathway markers ATF4, DR5, ClpP, ClpX, and DRD2/DRD3 in PC and SCLC cell lines (N=6) ± treatment with ONC201. Specifically, we compared pre-treatment protein expression levels with the IC50. Our results reveal that DU145 (IC50=3.11μM), PC3 (IC50=3.02μM), and LNCaP (IC50=1.33μM) are ONC201 sensitive. H1417 SCLC expresses CgA, unlike PC3 and DU145. PGP9.5 is expressed in these lines. PGP9.5 is expressed in PC3, DU145, H1417, and H1048 but not in LNCaP and 22RV1. BRN2 is expressed in PC3, H1417, and H1048 but not DU145, LNCaP, or 22RV1. ClpX is expressed in all 6 lines but at lower levels in SCLC. ClpP is expressed in the 6 lines. DR5 is expressed at higher levels in PC3, DU145, LNCaP, and 22RV1 PC versus H1417 and H1048 SCLC. SOX2 is expressed at high levels in H1417 cells. These results are establishing the landscape of ND in PC and SCLC lines for further experimentation and testing of our hypothesis. To characterize the association of BRN2 dysregulation with ONC201 sensitivity, we are performing BRN2/SOX2 knockdown experiments using siRNA and evaluating effects towards ONC201 sensitivity. Our results provide insights into molecular mechanisms of ND in PC and SCLC sensitivity to ONC201. We are also currently working to overexpress BRN2 and SOX2 in cell lines to analyze the impact on neuroendocrine differentiation and ONC201 sensitivity. Citation Format: Elizabeth C. Ding, Wafik S. El-Deiry. Neuroendocrine differentiation (ND) in sensitivity of neuroendocrine tumor (NET) cells to ONC201/TIC10 cancer therapeutic. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3734.

BackgroundDouble-stranded DNA in plasma is known to carry single-stranded ends, called jagged ends. Plasma DNA jagged ends are biomarkers for pathophysiologic states such as pregnancy and cancer. It remains unknown whether urinary cell-free DNA (cfDNA) molecules have jagged ends.MethodsJagged ends of cfDNA were detected by incorporating unmethylated cytosines during a DNA end-repair process, followed by bisulfite sequencing. Incorporation of unmethylated cytosines during the repair of the jagged ends lowered the apparent methylation levels measured by bisulfite sequencing and were used to calculate a jagged end index. This approach is called jagged end analysis by sequencing.ResultsThe jagged end index of urinary cfDNA was higher than that of plasma DNA. The jagged end index profile of plasma DNA displayed several strongly oscillating major peaks at intervals of approximately 165 bp (i.e., nucleosome size) and weakly oscillating minor peaks with periodicities of approximately 10 bp. In contrast, the urinary DNA jagged end index profile showed weakly oscillating major peaks but strongly oscillating minor peaks. The jagged end index was generally higher in nucleosomal linker DNA regions. Patients with bladder cancer (n = 46) had lower jagged end indexed of urinary DNA than participants without bladder cancer (n = 39). The area under the curve for differentiating between patients with and without bladder cancer was 0.83.ConclusionsJagged ends represent a property of urinary cfDNA. The generation of jagged ends might be related to nucleosomal structures, with enrichment in linker DNA regions. Jagged ends of urinary DNA could potentially serve as a new biomarker for bladder cancer detection.

To develop and validate a nomogram to detect improved knee pain in osteoarthritis (OA) by integrating magnetic resonance imaging (MRI) radiomics signature of subchondral bone and clinical characteristics.Participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. The primary outcome was 20% improvement of knee pain score over 2 years in participants administrated either vitamin D or placebo. Radiomics features of subchondral bone and clinical characteristics from 216 participants were extracted and analyzed. The participants were randomly split into the training and validation cohorts at a ratio of 8:2. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate radiomics signatures. The optimal radiomics signature and clinical indicators were fitted into a nomogram using multivariable logistic regression model.The nomogram showed favorable discrimination performance [AUCThe radiomics-based nomogram comprising the MR radiomics signature and clinical variables achieves a favorable predictive efficacy and accuracy in differentiating improvement in knee pain among OA patients. This proof-of-concept study provides a promising way to predict clinically meaningful outcomes.

Cell-free DNA (cfDNA) in bodily fluids has rapidly transformed the development of noninvasive prenatal testing, cancer liquid biopsy, and transplantation monitoring. Plasma cfDNA consists of a mixture of molecules originating from various bodily tissues. The study of the fragmentation patterns of cfDNA, also referred to as ‘fragmentomics’, is now an actively pursued area of biomarker research. Clues that cfDNA fragmentation patterns might carry information concerning the tissue of origin of cfDNA molecules have come from works demonstrating that circulating fetal, tumor-derived, and transplanted liver-derived cfDNA molecules have a shorter size distribution than the background mainly of hematopoietic origin. More recently, an improved understanding of cfDNA fragmentation has provided many emerging fragmentomic markers, including fragment sizes, preferred ends, end motifs, single-stranded jagged ends, and nucleosomal footprints. The intrinsic biological link between activities of various DNA nucleases and characteristic fragmentations has been demonstrated. In this review, we focus on the biological properties of cell-free DNA unveiled recently and their potential clinical applications.

Plasmodium vivax is co-endemic with Plasmodium falciparum in Peru, and optimum management requires distinguishing these two species in the blood of patients. For the differential identification of P. vivax and other Plasmodium spp., the LoopampTM Malaria Pan Detection Kit in combination with the Loopamp Malaria Pv Detection Kit (Eiken Chemical Co. Ltd., Tokyo, Japan) was used to evaluate 559 whole blood samples collected in 2017 from febrile patients with suspected malaria attending different health facilities in the Loreto region. The Loopamp Malaria Pan Detection Kit showed a sensitivity of 87.7% (95% CI: 83.5-91.9) and a specificity of 94.4% (95% CI: 91.9-96.9) and good agreement with PCR (Cohen's kappa 0.8266, 95% CI: 0.7792-0.874). By comparison, the Loopamp Malaria Pv Detection Kit showed a similar sensitivity (84.4%, 95% CI: 79.0-89.7) and specificity (92.4%, 95% CI: 89.7-95.0) and substantial agreement with PCR (Cohen's kappa: 0.7661, 95% CI: 0.7088-0.8234).

Nano-α-Fe2O3 prepared using acid pickling waste as precursor was found to be an effective catalyst for benzylation aniline with benzyl chloride. However, the formation of a green solution was observed during the solvent-free benzylation. A yellow-green single crystal as a byproduct was recovered from the green reaction mixture and characterized by X-ray single crystal diffraction, 1H NMR, FT-IR and elemental analysis. The results showed that this single crystal was a composite structural complex constructed by [(C6H6–CH2)2NH–C6H6]FeCl4 and [(C6H6–CH2)2NH–C6H6]Cl in equimolar ratio. The formation of the complex led to the deactivation and non-reusability of α-Fe2O3 catalyst for catalyzing solvent-free N-benzylation of aniline with benzyl chloride. The forming mechanism of the crystal was also discussed.

Background In low transmission settings early diagnosis is the main strategy to reduce adverse outcomes of malaria in pregnancy; however, microscopy and rapid diagnostic tests (RDTs) are inadequate for detecting low-density infections. We studied the performance of the highly sensitive-RDT (hsRDT) and the loop mediated isothermal DNA amplification (LAMP) for the detection of P. falciparum in pregnant women. Methods A cross-sectional study was conducted in two malaria-endemic municipalities in Colombia. We screened pregnant women in the context of an antenatal care program in health facilities and evaluated five tests (microscopy, conventional RDT, hsRDT, LAMP and nested polymerase chain reaction-PCR) for the detection of P. falciparum in peripheral blood, using a quantitative reverse transcription PCR (qRT-PCR) as the reference standard. Diagnostic performance of hsRDT and LAMP were compared with routine testing. Results The prevalence of P. falciparum was 4.5% by qRT-PCR, half of those infections were subpatent. The sensitivity of the hsRDT (64.1%) was slightly better compared to microscopy and cRDT (59 and 53.8% respectively). LAMP had the highest sensitivity (89.7%) for detecting P. falciparum and the ability to detect very low-density infections (minimum parasite density detected 0.08 p/μL). Conclusions There is an underestimation of Plasmodium spp. infections by tests routinely used in pregnant women attending antenatal care visits. LAMP methodology can be successfully implemented at local hospitals in malaria-endemic areas. The relevance of detecting and treating this sub-patent P. falciparum infections in pregnant women should be evaluated. Trial registration ClinicalTrials.gov, Identifier: NCT03172221, Date of registration: May 29, 2017.

A widely accepted theory is that life originated from the hydrothermal environment in the primordial ocean. Nevertheless, the low desorption temperature from inorganic substrates and the fragileness of hydrogen-bonded nucleobases do not support the required thermal stability in such an environment. Herein, we report the super-robust complexes of xanthine, one of the precursors for the primitive nucleic acids, with Na. We demonstrate that the well-defined xanthine–Na complexes can only form when the temperature is ≥430 K, and the complexes keep adsorbed even at ≈720 K, presenting as the most thermally stable organic polymer ever reported on Au(111). This work not only justifies the necessity of high-temperature, Na-rich environment for the prebiotic biosynthesis but also reveals the robustness of the xanthine–Na complexes upon the harsh environment. Moreover, the complexes can induce significant electron transfer with the metal as inert as Au and hence lift the Au atoms up.