Miracle-dz/UniFAR-FTUs huggingface dataset:
Prognostic value of E-Cadherin and its tumor suppressor role in Saudi women with advanced epithelial ovarian cancer

ABSTRACT The extracellular matrix (ECM) disruption and cytoskeleton reorganization are crucial events in tumor proliferation and invasion. E-Cadherin (E-CAD) is a member of cell adhesion molecules involved in cell-cell junctions and ECM stability. The loss of E-CAD expression is associated with cancer progression and metastasis. This retrospective study aimed to assess E-CAD protein expression in ovarian cancer (OC) tissues and to evaluate its prognostic value. Patients and Methods: 143 formalin-fixed and paraffin-embedded (FFPE) blocks of primary advanced stages OC were retrieved and used to construct Tissue microarrays. Automated immunohistochemistry technique was performed to evaluate E-CAD protein expression patterns in OC. Results: E-CAD protein expression was significantly correlated with OC histological subtype (p < 0.0001), while borderline significant correlations were observed with both tumor grade (p = 0.06) and stage (p = 0.07). Interestingly, Kaplan-Meier survival analysis showed that OC patients with membranous E-CAD expression survived longer than those with no E-CAD expression mainly those at advanced stages (p < 0.009). Further in silico analysis confirms the key roles of E-CAD in OC molecular functions. Conclusion: we reported a prognosis value of membranous E-CAD in advanced stage OC patients. Further validation using larger cohorts is recommended to extract clinically relevant outcomes towards better OC management and individualized oncology.
Knockdown of the inducible nitric oxide synthase (NOS2) splicing variant S3 promotes autophagic cell death from nitrosative stress in SW480 human colon cancer cells

Low levels of nitric oxide (NO) produced by constitutively expressed inducible NO synthase (NOS2) in tumor cells may be an important factor in their development. NOS2 expression is associated with high mortality rates for various cancers. Alternative splicing of NOS2 down‐regulates its enzymatic activity, resulting in decreased intracellular NO concentrations. Specific probes to detect alternative splicing of NOS2 were used in two isogenic human colon cancer cell lines derived either from the primary tumor (SW480) or from a lymph node metastasis (SW620). Splicing variant of NOS2 S3, lacking exons 9, 10, and 11, was overexpressed in SW480 cells. NOS2 S3 was silenced in SW480 cells. Flow‐cytometry analysis was used to estimate the intracellular NO levels and to analyze the cell cycle of the studied cell lines. Western blot analysis and quantitative real‐time polymerase chain reaction (qRT‐PCR) were used to determine apoptosis and autophagy markers. SW480 and SW620 cells expressed NOS2 S3. Overexpression of the NOS2 S3 in SW480 cells downregulated intracellular NO levels. SW480 cells with knocked down NOS2 S3 (referred to as S3C9 cells) had higher intracellular levels of NO compared to the wild‐type SW480 cells under serum restriction. Higher NO levels resulted in the loss of viability of S3C9 cells, which was associated with autophagy. Induction of autophagy by elevated intracellular NO levels in S3C9 cells under serum restriction, suggests that autophagy operates as a cytotoxic response to nitrosative stress. The expression of NOS2 S3 plays an important role in regulating intracellular NO production and maintaining viability in SW480 cells under serum restriction. These findings may prove significant in the design of NOS2/NO‐based therapies for colon cancer.
Incubation media modify silver nanoparticle toxicity for whitefish (Coregonus lavaretus) and roach (Rutilus rutilus) embryos

ABSTRACT Toxicological studies were performed to examine silver nanoparticle (AgNP, size: 14.4 ± 2.5 nm) transformation within three different test media and consequent effects on embryos of whitefish (Coregonus lavaretus) and roach (Rutilus rutilus). The test media, namely ASTM very hard water, ISO standard dilution medium, and natural lake water differed predominantly in ionic strength. Total silver was determined using inductively coupled plasma mass spectrometry (ICP-MS), while AgNPs were characterized by transmission electron microscopy and single particle ICP-MS. Silver species distributions were estimated via thermodynamic speciation calculations. Data demonstrated that increased AgNP dissolution accompanied by decreasing ionic strength of the test medium did not occur as noted in other studies. Further, other physicochemical parameters including AgNP size and metallic species distribution did not markedly affect AgNP-induced toxicity. Irrespective of the test medium, C. lavaretus were more sensitive to AgNP exposure (median lethal concentration after 8 weeks: 0.51–0.73 mg/L) compared to R. rutilus, where adverse effects were only observed at 5 mg/L in natural lake water. In addition, AgNP-induced toxicity was lower in the two standard test media compared to natural lake water. Currently, there are no apparent studies assessing simultaneously the sensitivity of C. lavaretus and R. rutilus to AgNP exposure. Therefore, the aim of this study was to (1) investigate AgNP-induced toxicity in C. lavaretus and R. rutilus cohabiting in the same aquatic environment and (2) the role played by test media in the observed effects of AgNPs on these aquatic species.
Acute Aerobic Exercise Induces Short-Term Reductions in Ambulatory Blood Pressure in Patients With Hypertension: A Systematic Review and Meta-Analysis

Supplemental Digital Content is available in the text. Chronic exercise reduces clinic and ambulatory blood pressure (BP), but the short-term effects of an acute exercise bout on ambulatory BP have not been studied widely. We reviewed the literature regarding the short-term effects of acute exercise on ambulatory BP in patients with hypertension and considered moderating factors (medication status and exercise modality/intensity) on ambulatory BP outcomes. A systematic search was conducted (PubMed, Cochrane Library, and Scopus; since inception to January 1, 2021) for crossover randomized controlled trials assessing the short-term effects of acute exercise on ambulatory BP in hypertensive individuals versus nonexercise control conditions. A meta-analysis was conducted for 24-hour, daytime, and nighttime systolic and diastolic BP. Subanalyses also were performed attending to medication status and exercise modality/intensity. Thirty-seven studies (N=822) met the inclusion criteria. A single acute exercise bout reduces 24-hour (systolic BP, −1.6 mm Hg [95% CI, −2.4 to −0.8] for all exercise modalities combined; diastolic BP, −1.0 mm Hg [95% CI, −1.5 to −0.5]), daytime (−3.1 mm Hg [95% CI, −4.1 to −2.2]; -2.0 mm Hg [95% CI, −2.8 to −1.2]), and nighttime ambulatory BP (−1.8 mm Hg [95% CI, −3.0 to −0.6]; −1.5 mm Hg [95% CI, −2.3 to −0.6]), respectively. The magnitude of the effect appears similar in medicated and nonmedicated patients. In separate analyses for exercise modalities, aerobic exercises reduce all ambulatory BP measures (P<0.001) yet with no significant effects for resistance or combined (aerobic and resistance) exercise for any ambulatory BP measure. Vigorous aerobic exercise tends to produce the largest effects. A single bout of acute aerobic exercise, reduces ambulatory BP over 24 hours in medicated and nonmedicated hypertensive adults.
Phospho-Ku70 induced by DNA damage interacts with RNA Pol II and promotes the formation of phospho-53BP1 foci to ensure optimal cNHEJ

Abstract Canonical non-homologous end-joining (cNHEJ) is the prominent mammalian DNA double-strand breaks (DSBs) repair pathway operative throughout the cell cycle. Phosphorylation of Ku70 at ser27-ser33 (pKu70) is induced by DNA DSBs and has been shown to regulate cNHEJ activity, but the underlying mechanism remained unknown. Here, we established that following DNA damage induction, Ku70 moves from nucleoli to the sites of damage, and once linked to DNA, it is phosphorylated. Notably, the novel emanating functions of pKu70 are evidenced through the recruitment of RNA Pol II and concomitant formation of phospho-53BP1 foci. Phosphorylation is also a prerequisite for the dynamic release of Ku70 from the repair complex through neddylation-dependent ubiquitylation. Although the non-phosphorylable ala-Ku70 form does not compromise the formation of the NHEJ core complex per se, cells expressing this form displayed constitutive and stress-inducible chromosomal instability. Consistently, upon targeted induction of DSBs by the I-SceI meganuclease into an intrachromosomal reporter substrate, cells expressing pKu70, rather than ala-Ku70, are protected against the joining of distal DNA ends. Collectively, our results underpin the essential role of pKu70 in the orchestration of DNA repair execution in living cells and substantiated the way it paves the maintenance of genome stability.
The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity

Abstract The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular, the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first-regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4 and 14 days after axotomy, Jun upregulates 11, 23 and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the downregulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype.
Quantification of soft tissue parameters from spatially resolved diffuse reflectance finite element models

Spatially resolved diffuse reflectance spectroscopy (SRDRS) is a non‐invasive optical technique that helps in clinical diagnosis of various tissue microcirculation and skin pigmentation disorders based on collected backscattered light from multi‐layered tissue. The extraction of the optical properties from the reflectance spectrum using analytical solutions is laborious. Model‐based light tissue interaction studies help in quantifying the optical properties. This work presents the use of finite element models of light tissue interaction for this purpose. A bilayer model mimicking human skin was considered and the diffused reflectance spectra at multiple detector points were generated using finite element modelling for varying melanin concentration, epidermal thickness, blood volume fraction, oxygen saturation and scattering components. The reflectance value based on varying optical parameters from multiple detection points lead to the generation of a look‐up table (LUT), which is further used for finding the tissue parameters that contribute to the spatially resolved reflectance values. The tissue parameters estimated after inverse modelling showed a high degree of agreement with the expected tissue parameters for a test dataset different from the training dataset.
Coordinated cellular and humoral immune responses after two‐dose SARS‐CoV2 mRNA vaccination in liver transplant recipients

Limited data are available on risks and benefits of anti‐SARS‐CoV2 vaccination in solid organ transplant recipients, and weaker responses have been described. At the Italian National Institute for Infectious Diseases, 61 liver transplant recipients underwent testing to describe the dynamics of humoral and cell‐mediated immune response after two doses of anti‐SARS‐CoV2 mRNA vaccines and compared with 51 healthy controls. Humoral response was measured by quantifying both anti‐spike and neutralizing antibodies; cell‐mediated response was measured by PBMC proliferation assay with IFN‐γ and IL‐2 production. Liver transplant recipients showed lower response rates compared with controls in both humoral and cellular arms; shorter time since transplantation and multi‐drug immunosuppressive regimen containing mycophenolate mofetil were predictive of reduced response to vaccination. Specific antibody and cytokine production, though reduced, were highly correlated in transplant recipients.
Honey Bee (Hymenoptera: Apidae) Nursing Responses to Cuticular Cues Emanating from Short-term Changes in Larval Rearing Environment

Abstract Honey bee larvae are dependent on the social structure of colony for their provisioning and survival. With thousands of larvae being managed collectively by groups of foragers (collecting food resources) and nurse bees (processing food and provisioning larvae), coordination of colony efforts in rearing brood depends on multiple dynamic cues of larval presence and needs. Much of these cues appear to be chemical, with larvae producing multiple pheromones, major being brood ester pheromone (BEP; nonvolatile blend of fatty acid esters) that elicits both short-term releaser effects and long-term primer effects. While BEP can affect colony food collection and processing with the signaling of larval presence, it is unclear if BEP signals individual larval needs. To understand this aspect, in a series of experiments we manipulated larval feeding environment by depriving larvae from adult bee contact for 4-h period and examined (1) nurse bee interactions with contact-deprived and nondeprived larvae and larval extracts; (2) forager bee responses to contact-deprived and nondeprived larval extracts. We also characterized BEP of contact-deprived and nondeprived larvae. We found that nurse honey bees tend to aggregate more over contact-deprived larvae when compared with nondeprived larvae, but that these effects were not found in response to whole hexane extracts. Our analytical results suggest that BEP components changed in both quantity and quality over short period of contact deprivation. These changes affected foraging behavior, but did not appear to directly affect nursing behavior, suggesting that different chemical cues are involved in regulating nursing effort to individual larvae.
A SWOT analysis of contemporary gaps and a possible diagnostic tool for environmental health in an upper-middle income country: a case study of South Africa

ABSTRACT This study evaluated the state of environmental health in the Republic of South Africa using the strengths, weaknesses, opportunities, and threats (SWOT) analysis framework. The internal and external factor evaluations were conducted by reviewing existing literature searched using a combination of keywords and boolean functions. The weighted score for the strengths and weaknesses was 0.79 and 1.04, respectively. The external factor evaluations findings revealed that environmental health has an equal amount of threats and opportunities, however, the threats outweigh the opportunities. The total weighted score for the internal and external factor evaluations was 1.83 and 2.25, respectively, which were below the average value of 2.5. The internal-external factors matrix indicated that environmental health in the Republic of South Africa needs to be refocused and re-aligned to public health protection. Failure to address the weaknesses and threats and optimise the strengths and opportunities may further weaken the provision of environmental health services.
Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review

Abstract Background Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development. Methods Our systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response. Results Based on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45–89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48–64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23–54%], ganglioglioma (GG): 40% [33–46%], and anaplastic ganglioglioma (aGG): 46% [18–76%]. Prevalence in astroblastoma was 24% [8–43%], desmoplastic infantile astrocytoma (DIA): 16% [0–57%], subependymal giant cell astrocytoma (SEGA): 8% [0–37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0–11%], diffuse astrocytoma (DA): 3% [0–9%], and pilocytic astrocytoma (PA): 3% [2–5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively. Conclusions BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.
Prediction of radiation pneumonitis with machine learning using 4D-CT based dose-function features

Abstract In this article, we highlight the fundamental importance of the simultaneous use of dose-volume histogram (DVH) and dose-function histogram (DFH) features based on functional images calculated from 4-dimensional computed tomography (4D-CT) and deformable image registration (DIR) in developing a multivariate radiation pneumonitis (RP) prediction model. The patient characteristics, DVH features and DFH features were calculated from functional images by Hounsfield unit (HU) and Jacobian metrics, for an RP grade ≥ 2 multivariate prediction models were computed from 85 non-small cell lung cancer patients. The prediction model is developed using machine learning via a kernel-based support vector machine (SVM) machine. In the patient cohort, 21 of the 85 patients (24.7%) presented with RP grade ≥ 2. The median area under curve (AUC) was 0.58 for the generated 50 prediction models with patient clinical features and DVH features. When HU metric and Jacobian metric DFH features were added, the AUC improved to 0.73 and 0.68, respectively. We conclude that predictive RP models that incorporate DFH features were successfully developed via kernel-based SVM. These results demonstrate that effectiveness of the simultaneous use of DVH features and DFH features calculated from 4D-CT and DIR on functional image-guided radiotherapy.
Histology and ultrastructure of the gastrointestinal tract in four temperate marine herbivorous fishes

While alimentary tract anatomy in many terrestrial herbivorous vertebrates is well documented, the digestive systems of marine herbivorous fishes are poorly characterised. The gastrointestinal tract (GIT) of four species of marine herbivorous fishes from northeastern New Zealand, butterfish Odax pullus (Labridae), marblefish Aplodactylus arctidens (Aplodactylidae), notch‐head marblefish A. etheridgii (Aplodactylidae) and silver drummer Kyphosus sydneyanus (Kyphosidae), were examined using histology and transmission electron microscopy (TEM) to provide a detailed histological and ultrastructural description of gut anatomy. Gastric glands were distributed over rugae in the stomach of A. arctidens, A. etheridgii and K. sydneyanus. The luminal surface of the stomach of these three species was lined by columnar mucous cells, and oxynticopeptic cells lined the glands in the stomach. Villi were present along the length of the intestine in all four species. The anterior intestine had thin musculature, and was lined by absorptive cells with long microvilli and numerous small vesicles in the apical cytoplasm. The posterior intestine was lined by absorptive columnar cells with long microvilli, invaginations between microvilli with electron‐dense membranes, and pinocytotic vesicles. Surface area generally decreased from the anterior to posterior intestine. Histological and ultrastructural results were consistent with lipid absorption occurring in the anterior GIT and protein absorption in the posterior GIT. The results of this study indicate clear differences in GIT structure among the study species, and digestion models based on chemical reactor theory were developed to characterise these differences.
Formation and persistence of polyglutamine aggregates in mistranslating cells

Abstract In neurodegenerative diseases, including pathologies with well-known causative alleles, genetic factors that modify severity or age of onset are not entirely understood. We recently documented the unexpected prevalence of transfer RNA (tRNA) mutants in the human population, including variants that cause amino acid mis-incorporation. We hypothesized that a mistranslating tRNA will exacerbate toxicity and modify the molecular pathology of Huntington's disease-causing alleles. We characterized a tRNAPro mutant that mistranslates proline codons with alanine, and tRNASer mutants, including a tRNASerAGA G35A variant with a phenylalanine anticodon (tRNASerAAA) found in ∼2% of the population. The tRNAPro mutant caused synthetic toxicity with a deleterious huntingtin poly-glutamine (polyQ) allele in neuronal cells. The tRNASerAAA variant showed synthetic toxicity with proteasome inhibition but did not enhance toxicity of the huntingtin allele. Cells mistranslating phenylalanine or proline codons with serine had significantly reduced rates of protein synthesis. Mistranslating cells were slow but effective in forming insoluble polyQ aggregates, defective in protein and aggregate degradation, and resistant to the neuroprotective integrated stress response inhibitor (ISRIB). Our findings identify mistranslating tRNA variants as genetic factors that slow protein aggregation kinetics, inhibit aggregate clearance, and increase drug resistance in cellular models of neurodegenerative disease.