CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase.

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Genetic Components Derived Parameters and Heterosis in Okra under Saudi Arabia Conditions.

Four parental genotypes of okra were crossed in complete diallel design to study the direction and extent of relative heterosis and heterobeltiosis for yield and its associated traits for utilization of existing genetic diversity to develop heterotic F1 hybrids in okra. The additive genetic component (D) was significant in all studied traits except average pod weight. Nonadditive (H1 and H2) components were found to be significant in all studied traits. However, the values of the dominant effect (H1) were smaller than the D components for no. of nodes/plant, no. of pods/plant, weight of medium pods, weight of large pods, and total fresh pod yield. The maximum significant MP heterosis in the desirable direction (149.9%) was recorded for the weight of large pods/plot. The maximum significant heterobeltiosis in the desirable direction (120.1%) was recorded for the weight of small pods/plot followed by total fresh pod yield (107.4%), the weight of large pods/plot (104.9%), weight of medium pods/plot (92.1%), average pod weight (51.8%), number of pods/plant (38.4%), and plant height (34.3%). It could be concluded that plant height, average pod weight, and the number of branches could be considered for the development of elite hybrids (heterosis breeding) or inbred lines (pure line selection) in succeeding generations. Therefore, these parameters can be considered for selecting genotypes to improve the pod yield of okra. The superior crosses identified through heterosis analysis were Egyptian Balady × Line 4.1.18 (30.8 ton/ha), Line 4.1.18 × Egyptian Balady (29.8 ton/ha), Dwarf Green Long Pod × Line 4.1.18 (28.3 ton/ha), and Egyptian Balady × Dwarf Green Long Pod (27.6 ton/ha) as these crosses had high performance as well as significant and higher estimates of heterobeltiosis for fruit yield per plant and yield attributing other characters.

Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

Medullary colorectal carcinoma revisited: a clinical and pathological study of 102 cases.

AIM: Medullary carcinoma is a recently described subtype of mismatch repair deficient (MMRd) colorectal carcinoma (CRC) which, despite being poorly differentiated by traditional morphological criteria, has been reported to have a good prognosis. We investigated the pathological and clinical features of medullary CRC in an unselected cohort of CRCs undergoing surgical resection. METHODS: All CRCs resected within a single health district database from 1998 to 2012 were categorized prospectively and underwent retrospective review to identify 91 medullary CRCs, with 11 additional cases from 2013 to 2014. Strict criteria were employed to diagnose medullary carcinoma requiring both MMRd and greater than 90 % of the tumor to demonstrate typical morphology, including solid growth. The demographic and pathological features, as well as all-cause survival, were compared with other CRCs, and specifically to other MMRd CRCs. RESULTS: From 1998 to 2012, 91 of 3,295 CRCs (2.8 %) were of the medullary type. Medullary CRC was more likely to arise in females than males (3.3:1; p < 0.0001), the elderly (mean age 77 vs. 71 years; p < 0.001), and the right colon (86 %; p < 0.0001). All medullary CRCs demonstrated MMR deficiency (considered an inclusion criteria) and 86 % were BRAFV600E-mutated (p < 0.0001). Thirty-day mortality after resection was higher in medullary CRC (4.6 vs. 1.7 %; p = 0.049). On univariate analysis, survival was not better than well-differentiated or other MMRd tumors. However, using a multivariate model, a medullary phenotype was protective (hazard ratio of death 0.54, 95 % CI 0.30-0.96; p = 0.037). CONCLUSIONS: Medullary CRC is more common than previously reported, frequently presents with locally advanced disease, and may be associated with higher mortality at 30 days after resection. Despite this, when strict criteria are used for diagnosis, the overall survival is favorable when compared with CRCs with equivalent demographic and pathological characteristics.

Utilization of Foamed Glass as an Effective Adsorbent for Methylene Blue: Insights into Physicochemical Properties and Theoretical Treatment.

This study reports a potential approach for the valorization of glass waste (GW) that is mainly composed of amorphous silica to prepare lightweight foamed glass (FG). The preparation of FG was achieved by mixing sodium hydroxide with GW powder followed by sintering at a temperature of 800 °C. As-synthesized FG was characterized and applied as an effective adsorbent for the removal of hazardous organic water contaminants, in particular, methylene blue (MB) dye. FG exhibited porosity of 91%, bulk density of 0.65 g/cm3, compressive strength of 4 MPa, and thermal conductivity of 0.27 W/m·K. Theoretical treatment indicated that a monolayer model with one energy site was the best in fitting the removal of MB molecules. The number of MB molecules per active site (n) ranged from 2.20 to 1.70, suggesting vertical orientation and a multi-molecular adsorption mechanism. The density of FG receptor sites (DM) increased with the temperature, and this parameter played a vital role in the adsorption process. The adsorption capacity (Qsat) increased from 255.11 to 305.58 mg/g, which signifies endothermic interactions. MB adsorption on FG was controlled by physical forces such as electrostatic interactions (i.e., the adsorption energies were <20 kJ/mol). The results of this study prove the feasibility of glass waste as an effective and low-cost adsorbent for water remediation.

Correction to: "Synthesis of Chitosan/Diatomite Composite as an Advanced Delivery System for Ibuprofen Drug; Equilibrium Studies and the Release Profile".

[This corrects the article DOI: 10.1021/acsomega.1c01514.].

Synthesis of Chitosan/Diatomite Composite as an Advanced Delivery System for Ibuprofen Drug; Equilibrium Studies and the Release Profile.

Chitosan/diatomite nanocomposite (CS/D) was synthesized as a low-cost and highly porous structure of enhanced physicochemical properties to be applied as advanced carriers for ibuprofen drug (IB). The loading properties of CS/D were studied in comparison to diatomite as a separated phase and achieved a loading capacity of 562.6 mg/g. The loading reactions of IB into CS/D show pseudo-second-order kinetic behavior and Langmuir isotherm properties. This demonstrates homogeneous loading processes in monolayer forms and controlled essentially by physical mechanisms. This was confirmed by the calculated Gaussian energy (7.7 kJ/mol (D) and 7.9 kJ/mol (CS/D)) in addition to the thermodynamic parameters. The thermodynamic behavior for the IB loading process is related to spontaneous, favorable, and exothermic reactions. The CS/D composite is of promising IB release profile that extended to about 200 h with a maximum release of 91.5% at the gastric fluid (pH 1.2) and 97.3% in the intestinal fluid (pH 7.4). The IB release rate from CS/D can be controlled based on the ratio of the integrated chitosan in the composite. The IB release reactions from CS/D follow the assumption of Korsmeyer-Peppas kinetics with determined values for the diffusion exponent reflects complex diffusion and erosion as the affected mechanisms during the IB release process.

Evaluation of different forms of Egyptian diatomite for the removal of ammonium ions from Lake Qarun: A realistic study to avoid eutrophication.

Three types of diatomite-based adsorbents-diatomaceous earth (DE), purified diatomite (PD), and diatomite@MgO/CaO (D@MgO) were used for adsorption decontamination of ammonium from Lake Qarun water (28.7 mg/L). The adsorption properties of the three diatomite-based adsorbents were evaluated by both batch and fixed-bed column adsorption studies. The kinetic results demonstrated removal percentages of 97.2%, 69.5%, and 100% using DE, PD, and D@MgO, respectively, at a 1 g/L adsorbent dosage. The adsorption results using DE and D@MgO showed the best fitness with pseudo-first-order kinetic and Langmuir isotherm models, while the obtained results using PD demonstrate better fitness with the Freunlidich model. The recognised fitting results with the pseudo-first-order model and estimated adsorption energies demonstrated physical uptake of ammonium by DE (5.93 kJ/mol), PD (4.05 kJ/mol), and D@MgO (7.81 kJ/mol). The theoretical maximum ammonium uptake capacity of DE, PD, and D@MgO were 63.16 mg/g, 59.5 mg/g, and 78.3 mg/g, respectively. Using synthetic adsorbents in a fixed-bed column system for treating ammonium ions in Lake Qarun water resulted in removal percentages of 57.4%, 53.3%, and 62.6% using a DE bed, PD bed, and D@MgO bed, respectively, after treating approximately 7.2 L of Lake Qarun water using a bed thickness of 3 cm, a flow rate of 5 mL/min, pH 8, and the determined ammonium concentration in Lake Qarun water (28.7 mg/L). The curves demonstrated breakthrough times of 900 min, 900 min, and 960 min for the DE bed, PD bed, and D@MgO bed, respectively, with 1440 min as the saturation time. The columns' performances also were studied based on the Thomas model, the Adams-Bohart model, and the Yoon-Nelson model.

Small Bowel Evisceration through the Vaginal Vault: A Rare Surgical Emergency.

Small bowel evisceration through the vagina is a rare surgical emergency that requires urgent surgical intervention because of the risk of developing acute small bowel ischemia. We present a case of a 91 year old female presenting with acute small bowel evisceration with majority of her small bowel visible outside the vagina. The bowel wall was edematous requiring emergent laparotomy and reduction of bowel with repair of the vaginal vault. The patient did not require bowel resection. Transvaginal small bowel evisceration is uncommonly described in the literature. Rare cases are reported in elderly, post-menopausal women who have undergone hysterectomy. Multiple approaches to surgical management including laparoscopic, open abdominal, transvaginal as well as combined approaches have been described. Perineal herniation must be kept in the differential in elderly post-hysterectomy patients with sudden onset of abdominal pain with urgent surgical intervention advised.

Genetic diversity analysis of some Egyptian Origanum and Thymus species using AFLP markers.

BACKGROUND: In the present investigation, two genera of family Labiatae (genus Origanum and genus Thymus including their available species in Egypt) were analyzed genetically on DNA level using amplified fragment length polymorphism (AFLP) markers. Four selective primer combinations (E-AGC/M-CAA, E-AGC/M-CAC, E-AGG/M-CTC, and E-ACC/M-CAT) were used to detect genetic variations (polymorphisms) within and between the studied plant species of each genus and with their cultivated relatives. RESULTS: A total of 193 amplified fragments were obtained overall primer combinations with a disparity in the number of bands for each primer combination. The primer combination E-AGG/M-CTC exhibited a large number of amplicons (67) compared to the other primers with polymorphism percentage 69%. The polymorphism information content (PIC) was calculated for the four primer combinations showing a very high values ranging between 0.98 and 0.99. On the other hand, Thymus species (Thymus vulgaris, Thymus capitatus L., and Thymus decassatus Benth.) exhibited a total number of 171 amplicons for all primer combinations with an average of 42 bands. The primer combination E-AGG/M-CTC produced the largest number of bands (62 bands) with polymorphism percentage 35%, even though the primer combination AGC/M-CAA was more efficient to give high polymorphisms within Thymus species where it resulted in a total of 35 bands with polymorphism percentage 63%. The PIC values were calculated ranging from 0.96 to 0.99. CONCLUSION: One can conclude that AFLP technique was informative and efficient technique to give a good coverage of Origanum and Thymus genomes. Furthermore, it was helpful to elucidate the genetic variations and phylogenetic relationships within the studied species as a basis for further studies on these genera and related species.

Shotgun metagenomic sequencing reveals freshwater beach sands as reservoir of bacterial pathogens.

Recreational waters and adjacent beach sands harbor complex microbial communities which may contain human pathogens that cannot be detected by conventional methods. Here, we investigate the diversity of bacterial populations inhabiting four freshwater beaches of the Great Lakes region using shotgun metagenomic sequencing approach. Our analysis suggests that average taxonomic richness and alpha diversity are significantly higher (P < 0.001) in beach sands compared to the corresponding water environments. Compared to the water environments, beach sands harbored taxa from a more diverse range of phyla, including a higher proportion of sequences from unclassified phyla. Unique phyla were also identified in sand which included species from Aquificae, Candidatus Microgenomates, Latescibacteria, and Candidatus Aminicenantes. Sequences originating from pathogens were detected in both sand and water, with some pathogens enriched in both environments. Both lakes exhibited similar community composition suggesting that geographic location did not appear to have any major impact on bacterial diversity. These findings reveal the diversity of bacterial communities of freshwater beaches and highlight the importance of monitoring pathogens in recreational beaches, especially in the sand environment of these beaches.

Potential environmental influence of amino acids on the behavior of ZnO nanoparticles.

The fate of nanomaterials when they enter the environment is an issue of increasing concern and thus it is important to know how they interact with natural organic molecules since this may have a significant impact on the particles' behavior. Because of our poor knowledge in this regard, the interaction of ZnO nanoparticles with amino acids of contrasting surface charge, including Histidine (HIS), Glycine (GLY), Aspartic acid (ASP) and Glutamic acid (GLU) which occur commonly in natural habitats, such as the plant root zone, was investigated over a range of pH conditions and concentrations. The addition of the individual amino acid led to significant changes in nanoparticle colloidal zeta potential stability, particle size distribution and the extent of agglomeration. Variations in pH resulted in considerable changes in nanoparticle surface charge and hydrodynamic size. In general, the particle size distribution decreased as the amino acid concentration increased, with more acidic conditions exacerbating this effect. In addition, increased concentrations of amino acids resulted in more stable nanoparticles in aqueous suspensions. Histidine had the greatest effect on colloidal stability, followed by Glycine, Aspartic acid and finally Glutamic acid. This study illustrates how nanoparticle behavior may change in the presence of naturally occurring amino acids, an important consideration when assessing the fate of nanoparticles in the environment. Additionally, utilization of amino acids in industrial processes could reduce particle agglomeration and it could lead to a way of employing more sustainable reagents.