Elevated Numbers Research Articles

HIF-3α Facilitates the Proliferation and Migration in Pancreatic Cancer by Inhibiting Autophagy Through Downregulating TP53INP2.

Pancreatic cancer is a highly aggressive malignant tumor, often diagnosed late, leading to a poor prognosis and extremely high mortality rates. In recent years, the role of cellular autophagy in tumors has become increasingly prominent, gradually becoming an important target for malignant tumors. HIF-3α is a member of HIF family with potential oncogenic function. However, the role of HIF-3α in pancreatic cancer is not clear. The present study revealed its role in pancreatic cancer by exploring the regulatory mechanism of HIF-3α on autophagy. HIF-3α was found markedly upregulated in pancreatic cancer cell lines. In HIF-3α silenced MiaPaCa-2 cells, largely declined migration distance, reduced number of invaded cells and colonies, increased number of autophagosome, downregulated p62, and upregulated Beclin1, LC3II/I, and ATG7 were observed, accompanied by elevated TP53INP2 expressions. on the contrary, in HIF-3α overexpressed PANC-1 cells, notably increased migration distance, and elevated number of invaded cells and colonies were observed, along with decreased autophagosome, upregulated p62, and downregulated Beclin1, LC3II/I, ATG7, and TP53INP2. Subsequently, HIF-3α overexpressed PANC-1 cells were transfected with TP53INP2 overexpressing vector. The influence of HIF-3α overexpression on the proliferation, migration, invasion, and autophagy was abolished by TP53INP2 overexpressing. Furthermore, HIF-3α overexpression facilitated the in vivo growth of PANC-1 cells, accompanied by the autophagy inhibition in tumor tissues, which were remarkably abolished by TP53INP2 overexpressing. Collectively, HIF-3α facilitated the proliferation and migration in pancreatic cancer by inhibiting autophagy through downregulating TP53INP2.

Titanate coupling agent modified lead sulphide for the manufacture of highly filled flexible neoprene based radiation protection materials

AbstractBased on the principles of photon and matter attenuation, lead sulphide (PbS) has the potential for applications in radiation protection owed to its elevated atomic number and density. Achieving good dispersion stability of PbS powder in highly filled composites remains a challenge due to the inherent nature. Here, we proposed a solution to these issues for highly filled rubber‐based flexible wearable composites. PbS particles were firstly synthesized and subsequently surface‐modified with a titanate coupling agent (NDZ‐201) enhanced the interfacial compatibility with the rubber‐based. Then, highly filled PbS@NDZ‐201/chloroprene rubber (CR) composites were obtained by physical blending. Test results showed that these highly filled composites exhibited even distribution of PbS granule and favorable interface compatibility. All the prepared PbS@NDZ‐201/CR composites exhibit excellent mechanical properties. In comparison to pure CR, the mechanical properties of the 70 wt% filler‐modified powder composites remained at a high level, with a tensile strength of 7.51 MPa and an elongation at break of 670.11%, represented improvements of 155% and 105%, respectively. The mass attenuation coefficient and the γ‐rays shielding coefficients of 70 wt% PbS@NDZ‐201/CR composites reached 34.15% and 36.87%, respectively. In conclusion, this method is feasible for the preparation of highly filled radiation protective rubber‐based flexible wearable materials.Highlights Introduction of PbS in the field of radiation protection. NDZ‐201 improved the interfacial compatibility of PbS with CR. The mechanical properties of the composites were improved after modification by NDZ‐201. Highly filled flexible wearable composites for radiation protection was successfully prepared.

Abstract 4144503: Association of Granular Sleep Health Metrics with Arterial Stiffness in the Community

Introduction: Poor sleep is a risk factor for cardiovascular disease and all-cause mortality; however, the mechanisms underlying this relationship remain poorly understood. Since sleep health is a complex construct extending beyond mere sleep duration, we aimed to examine the relationship between granular sleep health indicators and arterial stiffness. Methods: We analyzed Framingham Offspring cohort (Exam 9) and OMNI cohort 1 (Exam 4) participants with sleep study and applanation tonometry data (n= 847, 56.6% females). Participants wore an M1 device to obtain ECG-derived sleep spectrograms to assess sleep quality and the Nonin WristOx device for oximetry data over two consecutive nights. Sleep variables of interest included total sleep time, duration of stable and unstable NREM, duration of elevated low-frequency coupling (e-LFC), and duration and number of nocturnal hypoxia events. Measures of aortic stiffness and pressure pulsatility included carotid-femoral pulse wave velocity (PWV), and central pulse pressure (CPP). Results: Characteristics of the sample are presented in Table 1. Several sleep measures were associated with PWV in univariable analysis, but significance attenuated after age/sex adjustment (Table 2). After adjusting for cardiovascular risk factors and sociodemographics, duration of e-LFCnb remained associated with CPP (β = 0.036, p = 0.02) Conclusion: Sleep measures associated with aortic stiffness are closely tied to age and sex. Longer duration of e-LFCnb, a hallmark of carotid body-driven elevated sympathetic tone and periodic breathing, is associated with greater pressure pulsatility. Longitudinal studies are needed to fully elucidate the role of e-LFCnb in vascular health

TMIC-39. SPATIAL MULTIOMICS PROFILING REVEALS HETEROGENEITY OF B:T CELL INTERACTIONS AND PLASMA CELL FORMATION IN TERTIARY LYMPHOID STRUCTURES IN HUMAN GLIOMAS

Abstract Adult-type diffuse gliomas, the most common primary brain tumours, remain a clinical challenge in oncology with limited treatment options, restricted anti-tumour immune response and a dismal patient prognosis. Despite their immunosuppressive microenvironment, the formation of lymphoid aggregates containing adaptive immune cells has been reported in gliomas. However, the cellular compositions, immunological function, and relevance of lymphoid aggregates for adaptive anti-tumour immunity is not well understood. Therefore, we performed a comprehensive, unbiased analysis of lymphoid aggregation in 642 adult-type diffuse gliomas using a multi-modal approach, combining DNA methylation and RNA sequencing with spatial transcriptome and proteome profiling. Overall, B cell aggregates and tertiary lymphoid structures (TLS) were observed in 15% of tumours, with the highest prevalence in primary glioma localised to the temporoparietal lobe. The presence of TLS was associated with an improved overall survival. Gliomas containing TLS displayed a remodelled perivascular space, characterised by transcriptional upregulation and spatial redistribution of collagens associated with barrier functions. Spatial transcriptome and proteome profiling revealed heterogenous B:T cell interactions that were associated with elevated CD8 T-cell numbers and differences in IgA and IgG plasma cell forming capacity, suggestive of dynamic adaptive immune response.

EPCO-23. LONGITUDINAL TRACKING AND LONG-READ CHROMATIN FIBER SEQUENCING OF HUMAN ASTROCYTES WITH TELOMERE DYSFUNCTION REVEALED ALTERED CHROMATIN ACCESSIBILITY AND INCREASED STRUCTURAL VARIATION

Abstract Glioma is an aggressive cancer of the central nervous system that is genetically characterized by aneuploidy and frequent structural variation (SV). We sought to investigate the role of telomere dysfunction (TD) in shaping the SV landscape in glioma. Normal human astrocytes (NHA) were engineered to express viral E6E7 oncoproteins which are known to spontaneously trigger TD by suppressing p53/pRb. We hypothesized that NHA-E6E7 cells gradually accumulate SVs and aneuploidy over time because of progressive TD. We therefore longitudinally tracked bulk and single-cell clones of NHA-E6E7 cells for a period of over 6 months since viral infection. Overall, NHA-E6E7 cells demonstrate a growth benefit over primary NHA cells. We obtained Illumina short-read sequencing for NHA-E6E7 cells at multiple time points. Three time points were additionally selected for both Oxford Nanopore and PacBio HiFi long-read sequencing using the single-molecule chromatin fiber sequencing (fiber-seq) protocol. Copy number variation (CNV) analysis of short-read data showed deletion events in chromosome 13 as early as population doubling level (PDL) 48. K-mer based CNV analysis using the long-read data confirmed this finding and also detected deletion events in chromosome 7 at PDL 50. From the long-read data, we found an elevated number of SVs in NHA-E6E7 cells compared to the primary NHA cells. In particular, we detected telomere junctions and found that telomere-associated SVs were more prevalent in NHA-E6E7 cells compared to primary cells. Next, chromatin accessibility and regulatory elements were predicted from fiber-seq data with exogenous N6-methyladenosine (m6A) stencils. We observed large-scale chromatin actuation changes in various regulatory elements across the genome that intensified in later passages of NHA-E6E7 cells. For example, we found a decrease in the accessibility in FBXO7 which is a gene that maintains chromosome stability. Our preliminary results indicated that TD is an important mediator of structural variation in glioma.

EPA and DHA inhibit LDL-induced upregulation of human adipose tissue NLRP3 inflammasome/IL-1β pathway and its association with diabetes risk factors

Elevated numbers of atherogenic lipoproteins (apoB) predict the incidence of type 2 diabetes (T2D). We reported that this may be mediated via the activation of the NLRP3 inflammasome, as low-density lipoproteins (LDL) induce interleukin-1 beta (IL-1β) secretion from human white adipose tissue (WAT) and macrophages. However, mitigating nutritional approaches remained unknown. We tested whether omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA) treat LDL-induced upregulation of WAT IL-1β-secretion and its relation to T2D risk factors. Twelve-week intervention with EPA and DHA (2.7 g/day, Webber Naturals) abolished baseline group-differences in WAT IL-1β-secretion between subjects with high-apoB (N = 17) and low-apoB (N = 16) separated around median plasma apoB. Post-intervention LDL failed to trigger IL-1β-secretion and inhibited it in lipopolysaccharide-stimulated WAT. Omega-3 supplementation also improved β-cell function and postprandial fat metabolism in association with higher blood EPA and mostly DHA. It also blunted the association of WAT NLRP3 and IL1B expression and IL-1β-secretion with multiple cardiometabolic risk factors including adiposity. Ex vivo, EPA and DHA inhibited WAT IL-1β-secretion in a dose-dependent manner. In conclusion, EPA and DHA treat LDL-induced upregulation of WAT NLRP3 inflammasome/IL-1β pathway and related T2D risk factors. This may aid in the prevention of T2D and related morbidities in subjects with high-apoB.Clinical Trail Registration ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects with High Number of Particles That Carry “Bad Cholesterol” in the Blood – Full Text View - ClinicalTrials.gov.

Prickly postglacial pioneers: freshwater plankton community composition influences fatty acid desaturase (FADS2) copy number in southern Greenland threespine sticklebacks

The adaptation of marine fish to freshwater environments includes prodigious examples of rapid evolution.Given the scarcity of ω‐3 long‐chain polyunsaturated fatty acids (LC‐PUFA) in freshwater, we expect selection to be strong on fish transitioning to freshwater habitats and yet the underlying ecological causes of genomic and phenotypic differentiation are poorly understood for traits associated with lipid content and composition. Threespine stickleback Gasterosteus aculeatus have repeatedly colonized, and adapted to, freshwater habitats across the Northern Hemisphere. These freshwater populations often show elevated copy number of the fatty acid desaturase 2 gene (FADS2), which increases the biosynthetic capacity of LC‐PUFA. The starkly lower content of LC‐PUFA in freshwater compared to marine prey, especially docosahexaenoic acid (DHA), likely imposes strong positive selection on freshwater fish for either increased biosynthesis or greater dietary acquisition of LC‐PUFA. The recently colonized and relatively undisturbed threespine stickleback populations in postglacial coastal lakes of southern Greenland offer an exceptional opportunity to study how variation in the copy number of FADS2 is related to abiotic and biotic conditions of lakes and their morphometry. As expected, given its position on the stickleback X chromosome, we found strong sexual dimorphism in FADS2 copy number in all populations (19 freshwater, 1 marine and 1 brackish), and an increased dimorphism in some freshwater populations. We also found that FADS2 copy number was negatively correlated, for both males and females, with the abundance of copepods, which are a DHA‐rich food source in the zooplankton community. Overall, our results suggest that the prey community context of lakes might influence the process of metabolic adaptation of marine fish colonizing freshwater ecosystems.

Hyperresponsiveness of Corticoid-Resistant Th17/Tc-17 Cells to TLR-2 and TLR-4 Ligands is a Feature of Multiple Sclerosis Patients at Higher Risk of Therapy Failure.

The presence of T cells expressing TLR-2 and TLR-4 has been associated with relapsing-remitting multiple sclerosis (RRMS) pathogenesis. Here, we evaluated whether the effectiveness of DMT in controlling clinical activity of the disease would be associated with modulation of proportion of TLRs+ T cells. Whole peripheral blood mononuclear cells, purified CD4+ and CD8+ T cells from RRMS patients were cultured with different stimuli. The frequency of IL-17-secreting CD4+ and CD8+ T cells positive for TLR-2 and TLR-4 was determined by flow cytometry. The cytokine profile of these T cells following TLR-2 and TLR-4 stimulation was determined by Multiplex. Some of these T cell cultures were treated with hydrocortisone. The levels of LPS-binding protein (LBP) were dosed by ELISA. Clinical (occurrence of relapses) and radiological (number of active brain lesions) activity were evaluated during the 1-year follow-up. Despite DMT, high intensity of TLR-2 and TLR-4 expression on (CD4+ and CD8+) T-cells, as well as the frequency of IL-17-secreting (CD4+ and CD8+) T-cells, are predictive of future RRMS relapses. Moreover, higher cytokine production related to Th17/Tc-17 phenotypes in response to TLR-2 and TLR-4 agonists was observed in DMT-treated patients and displayed an elevated number of brain lesions. The hyperresponsiveness of MS-derived T-cells to TLR-2 and TLR-4 ligands, with high levels of IL-1β, IL-6, IL-17, IFN-γ and GM-CSF in response to both TLR agonists, positively correlated with plasma LBP levels. Interestingly, corticoid was less efficient in reducing Th17 and Tc-17 cytokine production induced by TLR-2 and TLR-4 ligands in DMT-treated patients who relapsed during follow-up. Collectively, the data suggested that persistence of circulating Th17 and Tc17 cells expressing elevated levels of functional TLR-2 and TLR-4 could indicate high disease activity and lower therapeutic efficacy in RRMS patients.

Gut microbiota in very early systemic sclerosis: the first case-control taxonomic and functional characterisation highlighting an altered butyric acid profile

ObjectivesIn systemic sclerosis (SSc), gastrointestinal involvement is one of the earliest events. We compared the gut microbiota (GM), its short-chain fatty acids (SCFAs) and host-derived free fatty acids (FFAs) in...

Assessing Preclinical Diabetic Retinopathy: The Role of Optical Coherence Tomography Angiography.

Objective The present study aimed to investigate the variations in retinal microvascular parameters among diabetic patients without diabetic retinopathy (No DR), those with nonproliferative diabetic retinopathy (NPDR), and healthy controls using spectral domain optical coherence tomography angiography (SD-OCTA). Methods An observational cross-sectional case-control study was conducted involving 68 eyes classified into three groups: 32 eyes with No DR, 16 eyes with NPDR, and 20 controls. The study assessed parameters such as perfused capillary vessel density, foveal avascular zone (FAZ) area, mean vessel diameter, number of capillary dropouts, and flow void areas. OCTA images were obtained using the SD-OCT system (Spectralis HRA, Heidelberg Engineering, Germany)and analyzed with custom MATLAB software. Statistical analysis was performed using SPSS Statistics (IBM Corp., Armonk, NY), with significance set at p<0.05. Results Significant differences were observed across the groups for perfused capillary density, FAZ area, number of capillary dropouts, and number of flow void areas. Specifically, NPDR patients exhibited a significantly lower perfused capillary density (36.50%) and No DR patients demonstrated a considerably higher perfused capillary density (43.98%) when compared with controls (42.71%; p<0.001). The FAZ area was significantly larger in NPDR patients (0.5981 mm²) compared to the No DR (0.3581 mm²) and controls (0.3550 mm2; p<0.001). The number of capillary dropouts and flow void areas were significantly higher in NPDR patientsbut were also detected in the No DR group (p<0.001). No significant differences were found in mean vessel diameter among the groups (p=0.061). Conclusions The study confirms that NPDR is associated with distinct changes in retinal microvascular parameters compared to both No DR and control groups. These changes include reduced perfused capillary density, increased FAZ area, and elevated numbers of capillary dropouts and flow void areas. It also confirms that No DR can be associated with increased capillary vessel density as well as with capillary dropouts and void areas. OCTA proves to be a valuable instrument for evaluating retinal microvascular changes and could aid in the early detection and treatment of diabetic retinopathy (DR).

Experimental and numerical investigation of heat transfer characteristics of radiator using Graphene Amine-based nano coolant

This work presents experimental and numerical investigations on enhancing the heat transfer performance of automobile radiators with nano-coolant flowing with different mass flow rate and at different inlet temperatures conditions. Thermal management is critical as it dictates a system's overall power output, performance, efficiency and energy utilisation. Radiators and Thermal management systems for batteries are vital in keeping automobiles operating under optimal conditions. Conventional coolants lack the ability to keep up with the increasing performance requirements of thermal management systems. Nanocoolants represent a cutting-edge advancement in heat transfer fluid, boosting conductivity without compromising essential fluid dynamics of the cooling solutions. Several investigators have worked on various nanocoolants, but less work is done on radiators. In view of this, experimental and numerical investigations were done on radiator heat transfer performance using Graphene Amine based nanocoolant with varied coolant temperatures (50 °C–80 °C) and flow rates (3 l/min to 9 l/min). Thermophysical properties of nanocoolants, such as density, thermal conductivity, viscosity, specific heat, and Prandtl number, were determined by experimental and mathematical modelling techniques and were comparable with an average deviation of 5 %. Compared to the base fluids of De-ionised water and ethylene glycol combinations, Graphene Amine based nanocoolant has exhibited advancements in heat transfer properties, showing elevated Nusselt numbers, heat transfer coefficients and heat transfer rates. The investigation into the thermal transfer properties of nanocoolants utilizing theoretical and real-world experiments shows consistency with an average deviation of 20 %. Maximum heat transfer enhancement of 154.3 % and maximum heat transfer coefficient of 3209.52 W/m2K was found for Graphene Amine at 80 °C with coolant flowing at 9 l/min, which is 83.1 % higher when compared to De-ionised Water.

Cardiomyocyte proliferation is promoted by intracellular Gas6-mediated Yap activity during neonatal heart regeneration

Abstract Purpose The adult mammalian heart has limited regenerative capacity after injury, mostly attributable to postnatal cardiomyocyte (CM) cell cycle arrest. The key to unlocking the regenerative potential of the adult hearts may lie within the developmental transitions occurring during neonatal life. Gas6, a secretory protein, stimulates the proliferation of various type cells through binding to TAM receptor family, such as endothelial progenitor cells, tumor cells, and hair follicle stem-cell. However, no study to date has studied the role of Gas6 during the proliferation of CMs. Herein, our study uncovers that Gas6 is transiently expressed during early postnatal heart and regenerative heart, and functions through intracellular pathway by regulating Yap activity to promote CM proliferation. Methods CM isolation was conducted to assess the change of Gas6 expression in both postnatal development and regenerated stages using the CM-specific Tdtomato mice. Cardiac deletion of Gas6 gene mice was used to evaluate the impaired heart regeneration. CM-specific Gas6 overexpression mice were generated using adeno-associated virus system to evaluate Gas6 pro-proliferate and protect effect after ischemic injury. Secreted signal peptide truncation (ΔSP-Gas6) and predicted functional region truncation (ΔCC-Gas6) were generated to identify the intracellular mechanism of Gas6 via Sav1/p-mst1/p-lats1/ p-yap axis. Results We found that Gas6 expression is enriched in CM4 and the expression profile correlates with the expression of the CM4 marker Acta2, as well as cell-cycle genes Mki67 and Aurora B, in individual CM. Gas6 was highly expressed in the neonatal heart and continued to increase during the neonatal heart regenerative process, but was nearly absent in the adult heart under physiological and ischemia conditions. CM-specific Gas6 deletion resulted in significantly reduced CM proliferation rate and increased CM size in P0 hearts, and congestive heart failure in P28 hearts. Conversely, sustained CM-specific overexpression of Gas6 in postnatal hearts increased CM division, elevated CM numbers, and reduced CM size; and reduced infarct scar area and enhanced cardiac function after ischemia injury. Pre-overexpression of Gas6 in adult CMs protected adult cardiac function against ischemia injury, indicated by the activation of mitosis, angiogenesis and reduced oxidative phosphorylation. In primary neonatal CMs, both Gas6 and ΔSP-Gas6promoted CM proliferation with sarcomere disassembly. Mechanistically, Gas6 interacted with Sav1to inhibit Mst1recruitment and Mst1/Lats1/Yap phosphorylation cascade, therefore, promoted Yap translocation into nucleus. Conclusions We demonstrate that Gas6 is an important intrinsic regulator of neonatal heart regeneration, which acts as a promoter of Yap transcriptional activity to enhance CM proliferation. Supplementing Gas6 in the adult heart represents a potential therapeutic approach for cardiac repair.

Galectin-3 zebrafish model: identification and pharmacological modulation of arrhythmogenic cardiomyopathy-related phenotypes

Abstract Background Arrhythmogenic Cardiomyopathy (ACM) is rare hereditary cardiac condition characterized by the substitution of ventricular myocardium with fibro-fatty tissue leading to high risk of life-threatening arrhythmias and sudden cardiac death, particularly among young individuals and athletes. Based on genotype-phenotype correlation, the spectrum of the ACM phenotype was shown to be broader than previously believed. Approximately 40% of ACM patients carry one or more putative pathogenic variants in genes encoding desmosomal proteins. Recently LGALS3 gene involvement in ACM early pathogenesis has been advocated. Aim To achieve a comprehensive understanding of LGALS3 role in the pathogenesis of AC. Methods This stable mutant line was generated by CRISPR/Cas9 strategy and then deeply characterized. Phenotyping included heart activity characterization using a recently published software specific for zebrafish, the pyHeart4Fish. Gene expression analysis was carried out by using RNAseq, Real Time PCR and signaling pathway reporter zebrafish lines. Immunofluorescence analysis were performed using and antibody against L-plastin, a leukocyte marker for the detection of inflammatory cells and Acridine Orange/Ethidium Bromide staining to check the possible presence of apoptotic and necrotic events. Results Morphological investigation revealed notable structural abnormalities such as pericardial effusion and/or hemopericardium. The heart activity analysis detected a diminished ventricle contractility and ejection fraction, with bradycardia and occurrence of arrhythmia events. Rna analysis highlighted the dysregulation of Wnt/β-catenin signaling pathway. Moreover, the L-plastin inflammatory marker revealed a significant infiltration of inflammatory cells in the heart as well as an elevated number of apoptotic and necrotic cells (figure 1). The pharmacological treatment, partially rescued a subset of AC-related cardiac phenotypes observed, including heart contractility, bradycardia and arrhythmia. Conclusion Our findings strongly validate our lgals3a zebrafish mutant as an effective model to elucidate its role in ACM related phenotype. This model accurately replicates the cardiac abnormalities and dysregulation in cell signaling that are characteristic of ACM. Further, observed cell death and inflammation and the partial recovery of cardiac phenotypes through pharmacological intervention, underscores the potential of targeting the Wnt/β-catenin signaling pathway as future perspective for ACM.Figure 1

Overdiagnosis of lung cancer in Chinese populations

Abstract Background Low-dose computed tomography (LDCT) has been widely-used in employee health examinations in China since 2011. This study was designed based on the Cancer Surveillance data to quantify the overdiagnosis of lung cancer due to the introduction of LDCT in Chinese populations. Methods This registry-based cohort study included 46,978 incident cases and 34,475 deaths of lung cancer from Pudong New Area of Shanghai, China, during 2002-2020. We calculated the age-standardized rates (ASR) and average annual changes (AAC) of mortality and overall, stage-specific and histological type-specific incidence by sex to evaluate the potential overdiagnosis of lung cancer. We further estimated the numbers and proportions of lung cancer cases attributable to overdiagnosis by sex and period based on the comparison between the shape of the age-specific curves with that prior to the introduction of LDCT in the populations. Results The ASR of incidence of lung cancer increased rapidly since 2011 in both men (AAC: 1.90%; 95%CI: 0.87, 2.92) and women (AAC: 4.40%; 95%CI: 3.19, 5.62), whereas the ASR of mortality declined persistently, with AAC of -0.12% (-0.64, 0.39) in men and -0.19% (-0.47, 0.09) in women. The upward trends in incidence were mainly observed in women, for early-stage cancer and for lung adenocarcinoma. Overall, the overdiagnosis rate of lung cancer grew from 22% in 2011-2015 to 50% in 2016-2020 in women. Further analysis demonstrated elevated numbers (proportions) of lung adenocarcinoma cases attributable to overdiagnosis, which increased from 182 (8%) in 2011-2015 to 827(22%) in 2016-2020 in men, and from 1,842 (85%) to 4,171 (89%) in women. Conclusions This registry-based cohort study observed considerable and increasing overdiagnosis of lung adenocarcinoma in Chinese men and women. Guideline is urgently needed to maximize the benefits of LDCT screening and reduce the potential overdiagnosis of lung cancer in the populations. Key messages • The secular trends in incidence and mortality of lung cancer in Chinese populations demonstrated the overdiagnosis since 2011, when the LDCT was used as a part of staff health examination in China. • Overdiagnosis of lung cancer in Chinese populations increased incrementally over time and was mainly observed among women.

Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor.

KAT6A and KAT6B genes are two closely related lysine acetyltransferases that transfer an acetyl group from acetyl coenzyme A (AcCoA) to lysine residues of target histone substrates, hence playing a key role in chromatin regulation. KAT6A and KAT6B genes are frequently amplified in various cancer types. In breast cancer, the 8p11-p12 amplicon occurs in 12-15% of cases, resulting in elevated copy numbers and expression levels of chromatin modifiers like KAT6A. Here, we report the discovery of a new acylsulfonamide-benzofuran series as a novel structural class for KAT6A/B inhibition. These compounds were identified through high-throughput screening and subsequently optimized using molecular modeling and cocrystal structure determination. The final tool compound, BAY-184 (29), was successfully validated in an in vivo proof-of-concept study.

Tuning the Nucleophilicity of Anion in Lithium Salt to Enable an Anion‐Rich Solvation Sheath for Stable Lithium Metal Batteries

AbstractTraditional lithium salts typically adhere to the designing principles of enhancing cation‐anion dissociation degree to obtain a high electrolyte conductivity. This promotes the invention of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI), where the symmetric electron‐withdrawing trifluoromethanesulfonyl groups significantly delocalize the negative charge density around the nitrogen atom, thereby weakening the electrostatic interaction between Li+ and the anion. Herein, deviating from the general principle, lithium (methanesulfonyl)(trifluoromethanesulfonyl) imide (LiMTFSI) is deliberately designed by substituting a unilateral electron‐withdrawing trifluoromethyl (─CF3) group of LiTFSI with an electron‐donating methyl (─CH3) group, to tune the nucleophilicity of the anion. This modification enhances Li‐anion interaction, causing the anion to replace the solvent molecules in the Li+ solvation shell. Additionally, the MTFSI− anion exhibits an elevated donor number to facilitate the solubility of LiNO3 in carbonate‐based electrolytes. The synergistic effect of these changes suppresses the decomposition of solvent and helps construct a stable solid electrolyte interphase (SEI) enriched with multiple inorganic lithium salts (e.g., Li2S, Li3N, and LiNxOy) on the Li metal anode, which enables the 500 mAh Li||LiNi0.5Co0.2Mn0.3O2 pouch cell to operate steadily for 150 cycles. It is believed this work would provide new insights and another dimension for designing functional anions beyond their role as charge carriers.

The female reproductive tract microbiome and obesity

High-throughput 16S rRNA sequencing has allowed us to identify novel microorganisms and their relationships in the female reproductive tract. However, in obese patients, the female reproductive tract microbiome, unlike the intestinal microbiome, has been understudied. Here, the literature review analyzes and describes microbiome features in the external genitalia, vagina, cervical canal, uterus, and ovaries in overweight and obese nonpregnant and pregnant females. The microbiome of the lower female reproductive tract in obese patients is characterized by increased bacterial diversity, pH, decreased Lactobacillus abundance, and increased abundance of obligate anaerobes and yeasts of the genus Candida. The endometrial microbiome in overweight and obese patients has been studied only in postmenopause and is characterized by higher Proteobacteria abundance. No data on the characteristics of the ovarian microbiome in obese patients are available. The mechanisms accounting for microbiome changes in obese patients are likely to due to the ability of adipose tissue-derived leptin and estrone to inhibit production of pituitary gonadotropic hormones resulting in blocked ovulation and lowered estradiol production in patients of reproductive age. Consequently, a decline in glycogen synthesis in the vaginal epithelium, decreased Lactobacillus abundance followed by elevated vaginal mucus pH value and number of obligate anaerobes, including those associated with bacterial vaginosis are observed. Weight loss can have a beneficial effect on the state of the vaginal microbiome, restoring normal Lactobacillus abundance.

Internal validation of the Precision ID GlobalFiler NGS STR panel v2 kit with locus-specific analytical threshold, and with special regard to mixtures and low template DNA detection

We performed an internal laboratory validation of the Precision ID GlobalFiler NGS STR panel v2 kit to assist the introduction of the technology into the routine forensic casework practice. The study was designed and evaluated based not only on the key validation standards like sensitivity, stability, reproducibility, repeatability, mixture, and concordance, but we also tested the effect of reduced input DNA, we measured and applied locus-specific analytical threshold values, tested two different PCR cycle conditions, sequence artifacts and stutters were also analysed. During the study we also tested the new method on real casework samples. The sensitivity study confirmed that adding 500 pg template DNA for library preparation can be optimal at base PCR cycle number (that was 24), because the measured average heterozygote balance was not lower than 0.82, and each allele was detected above the analytical threshold. However, contrary to previous communications, increasing the PCR cycle numbers up to 28 has not resulted the significant elevation of the heterozygote imbalance. According to our results, raised PCR cycle condition (i.e. 28) is appropriate at or below 150 pg total input DNA. For most loci, the calculated AT was lower than the manufacturer’s recommended. Applying the newly established ATs with raised PCR cycle conditions the allele detection sensitivity and reliability increased. We observed allele dropouts only at the 15 pg template DNA experiments with 5 % frequency, that is better to previously published studies. This result indicates that this low amount of DNA (i.e. 15 pg) could be a minimum limit of template input for a potentially successful analysis. In the mixture study the minor contributor could be detected up to 1:19 mixture ratio. We detected minor alleles in all measurements and concentrations above the threshold if the template DNA were fixed and only SNP differences were observed between the same alleles of the contributors. To test concordance between the new method and traditional STR genotyping we analysed 58 Hungarian individual samples in parallel. Nearby the detected 248 different length-based alleles on the 31 loci in the sample pool we revealed additional 75 sequence variant alleles, that represent an approximately 23 % increase in the total number of observed alleles. The casework study confirmed that the Precision ID GlobalFiler NGS STR panel v2 kit is effective even in genotyping degraded samples with extremely low levels of DNA, if we apply elevated cycle number for library preparation and use locus-specific analytical thresholds.

A rare case of PDGFRA-positive chronic eosinophilic leukemia.

Chronic eosinophilic leukemia (CEL) is a clonal proliferation of eosinophilic precursors resulting in a persistently elevated number of eosinophils in blood, bone marrow, and peripheral tissues. The vaguely overlapping clinicopathological picture of CEL with idiopathic hypereosinophilic syndrome (IHES) often adds to the diagnostic dilemma. Here, we report a rare case of 49-year-old male who presented with multiorgan damage. Peripheral blood smear revealed predominantly eosinophils with dysplastic changes, shift to left in eosinophilic series, and 2% blasts. The bone marrow showed 5% blasts and many eosinophils, precursors of eosinophils, and myeloid and megakaryocytic proliferation. Till date, CEL is a very rare entity. Its presentation with cardiac and neurological manifestations is still rare.

Clinical and pathological features of cerebrospinal meningitis caused by Pantoea agglomerans : a case report

BackgroundPantoea agglomerans (P. agglomerans) is a gram-negative bacterium that is commonly isolated from plant surfaces, seeds, and the environment. As an opportunistic pathogen, it can cause blood, urinary and soft tissue infections in immunocompromised patients. In central nervous system, P. agglomerans infection has been report in children and immune-compromised patients, however, infection by such bacterium in nontraumatized immune competent adults has not been reported. Here, we report a case of P. agglomerans cerebrospinal meningitis accompanied by positive anti-myeloperoxidase (MPO) antibody in a 49-year-old female who has a history of black fungus planting.Case presentationThe patient manifested with repeated fever, headache, generalized muscle pain, and neurological defects. Cerebrospinal fluid (CSF) tests revealed a moderately elevated number of polymorphonuclear leukocytes (50–193 × 106/L), low glucose levels (0.54–2.44 mmo1/L), and extremely high protein content (2.42–25.42 g/L). Blood tests showed positive anti-myeloperoxidase antibodies lasting for 1.5 year before turning negative. Spine MRI showed thickening and enhancement of the whole spinal meninges. CSF metagenomic next-generation sequencing (mNGS) revealed 75,189 specific DNA reads of P. agglomerans. The patient underwent spinal laminectomy due to meningeal adhesions. Pathological results revealed fibrous tissue proliferation, inflammatory infiltration with focal necrosis and calcification in the dura mater. The patient was successfully treated with sufficient antibiotics at 1-year follow-up.ConclusionsPeople should be alert to CNS infections caused by P. agglomerans which presented with relatively mild clinical symptoms at onset, especially for those who contucts relevant agricultural and forestry work. The CSF characterization of P. agglomerans meningitis is elevated multiple nuclei white blood cells, significantly reduced glucose content, and markedly increased protein level which may be related to the secondary spinal membrane adhesions.