Automated reporting of cervical biopsies using artificial intelligence.

When detected at an early stage, the 5-year survival rate for people with invasive cervical cancer is 92%. Being aware of signs and symptoms of cervical cancer and early detection greatly improve the chances of successful treatment. We have developed an Artificial Intelligence (AI) algorithm, trained and evaluated on cervical biopsies for automated reporting of digital diagnostics. The aim is to increase overall efficiency of pathological diagnosis and to have the performance tuned to high sensitivity for malignant cases. Having a tool for triage/identifying cancer and high grade lesions may potentially reduce reporting time by identifying areas of interest in a slide for the pathologist and therefore improving efficiency. We trained and validated our algorithm on 1738 cervical WSIs with one WSI per patient. On the independent test set of 811 WSIs, we achieved 93.4% malignant sensitivity for classifying slides. Recognising a WSI, with our algorithm, takes approximately 1.5 minutes on the NVIDIA Tesla V100 GPU. Whole slide images of different formats (TIFF, iSyntax, and CZI) can be processed using this code, and it is easily extendable to other formats.

Biological Evaluation of Anti-Cholinesterase Activity, in Silico Molecular Docking Studies, and DFT Calculations of Green Synthesized Thiadiazolo[3,2-a]pyrimidine Derivatives.

A series of [1,3,4] thiadiazolo[3,2-a]pyrimidine-6-carboxylate derivatives 4(a-n) have been designed and synthesized as inhibitors of acetylcholinesterase (AChE). Synthesizing of thiadiazolo[3,2-a] pyrimidines was carried out in a single step, one-pot reaction using aromatic aldehydes, ethyl acetoacetate and different derivatives of 1,3,4-thiadiazoles (with molar ratio of 1 : 2 : 1, respectively) in conjunction with the catalyst, anhydrous iron(III) chloride by a grinding method under solvent-free conditions at room temperature. The in-vitro studies exhibited good potency for inhibiting AChE comparable with donepezil as the reference drug. The best results were obtained by Ethyl 2-(4-nitroophenyl)-7-methyl-5-(pyridin-3-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate 4n with IC50 value of 0.082±0.001 µM which was comparable with AChE inhibitory effects of donepezil (IC50 =0.079 µM).

The possible role of Helicobacter pylori in liver diseases.

According to previous studies, Helicobacter pylori infection is associated with liver disease. In order to better understand the risk of acquiring various liver diseases, we reviewed current knowledge on the impact of H. pylori on the onset, intensification, and progression of various liver diseases caused by the infection of H. pylori. It has been estimated that between 50 and 90% of people worldwide have been infected with H. pylori. The bacterium is mostly responsible for inflamed gastric mucosa, ulcers, and cancers associated with the gastric mucosa. Through the active antioxidant system in H. pylori, the bacteria can neutralize free radicals by synthesizing VacA, a toxin that causes cell damage and apoptosis. Furthermore, there is a possibility that CagA genes may play a role in cancer development. People who have been infected with H. pylori are likely to develop lesions in the skin, the circulation system, and the pancreas. Moreover, transferring blood from the stomach may allow H. pylori to colonize the liver. The bacterium worsened liver function during autoimmune inflammation, toxic injury, chronic HCV infection, chronic HBV infection, and liver cirrhosis. Increasing portal pressure, hyperammonemia, and esophageal varices may be associated with H pylori infection. As a result, it is crucial to diagnose and treat this infection in patients with H. pylori.

Detection of malignancy in whole slide images of endometrial cancer biopsies using artificial intelligence.

In this study we use artificial intelligence (AI) to categorise endometrial biopsy whole slide images (WSI) from digital pathology as either "malignant", "other or benign" or "insufficient". An endometrial biopsy is a key step in diagnosis of endometrial cancer, biopsies are viewed and diagnosed by pathologists. Pathology is increasingly digitised, with slides viewed as images on screens rather than through the lens of a microscope. The availability of these images is driving automation via the application of AI. A model that classifies slides in the manner proposed would allow prioritisation of these slides for pathologist review and hence reduce time to diagnosis for patients with cancer. Previous studies using AI on endometrial biopsies have examined slightly different tasks, for example using images alongside genomic data to differentiate between cancer subtypes. We took 2909 slides with "malignant" and "other or benign" areas annotated by pathologists. A fully supervised convolutional neural network (CNN) model was trained to calculate the probability of a patch from the slide being "malignant" or "other or benign". Heatmaps of all the patches on each slide were then produced to show malignant areas. These heatmaps were used to train a slide classification model to give the final slide categorisation as either "malignant", "other or benign" or "insufficient". The final model was able to accurately classify 90% of all slides correctly and 97% of slides in the malignant class; this accuracy is good enough to allow prioritisation of pathologists' workload.

Weakly supervised learning and interpretability for endometrial whole slide image diagnosis.

Fully supervised learning for whole slide image-based diagnostic tasks in histopathology is problematic due to the requirement for costly and time-consuming manual annotation by experts. Weakly supervised learning that utilizes only slide-level labels during training is becoming more widespread as it relieves this burden, but has not yet been applied to endometrial whole slide images, in iSyntax format. In this work, we apply a weakly supervised learning algorithm to a real-world dataset of this type for the first time, with over 85% validation accuracy and over 87% test accuracy. We then employ interpretability methods including attention heatmapping, feature visualization, and a novel end-to-end saliency-mapping approach to identify distinct morphologies learned by the model and build an understanding of its behavior. These interpretability methods, alongside consultation with expert pathologists, allow us to make comparisons between machine-learned knowledge and consensus in the field. This work contributes to the state of the art by demonstrating a robust practical application of weakly supervised learning on a real-world digital pathology dataset and shows the importance of fine-grained interpretability to support understanding and evaluation of model performance in this high-stakes use case.

Reproducibility of deep learning in digital pathology whole slide image analysis.

For a method to be widely adopted in medical research or clinical practice, it needs to be reproducible so that clinicians and regulators can have confidence in its use. Machine learning and deep learning have a particular set of challenges around reproducibility. Small differences in the settings or the data used for training a model can lead to large differences in the outcomes of experiments. In this work, three top-performing algorithms from the Camelyon grand challenges are reproduced using only information presented in the associated papers and the results are then compared to those reported. Seemingly minor details were found to be critical to performance and yet their importance is difficult to appreciate until the actual reproduction is attempted. We observed that authors generally describe the key technical aspects of their models well but fail to maintain the same reporting standards when it comes to data preprocessing which is essential to reproducibility. As an important contribution of the present study and its findings, we introduce a reproducibility checklist that tabulates information that needs to be reported in histopathology ML-based work in order to make it reproducible.

Evaluation of the FAS and FASL Gene changes in women with premature ovarian failure: A case-control study.

Background: Premature ovarian failure (POF), is menopause occurring before the age of 40, affecting 1-3% of women worldwide. The risk of POF increases with altered immunological parameters such as FAS and FASL genes, which play a fundamental role in embryogenesis and cellular homeostasis. Objective: The study aimed to investigate the potential role of FAS and FASL genes in POF pathogenesis. Materials and Methods: In this case-control study, the polymorphisms of FAS-670A/G and FASLIVS2nt_124A/G apoptotic genes were analyzed in 51 Iranian women suffering from POF, and 61 healthy controls. Isolation of DNA was done using the salting-out method, and genotypic analysis was performed for all the subjects using the polymerase chain reaction-restriction fragment length polymorphism method. Results: Our results revealed that homozygous FAS-670A/A and G/G, and heterozygous FAS-670A/G are not significantly different between cases and controls (p = 0.99). Also, in different genotyping models of FASIVS2nt_124, polymorphisms were not related to POF risk (p = 0.23). Conclusion: There is no statistical association between these polymorphisms and POF risk in women referred to genetic counseling clinics.

MicroRNA-365 promotes apoptosis in human melanoma cell A375 treated with hydatid cyst fluid of Echinococcus granulosus sensu stricto.

Hydatid cyst fluid (HCF)-based therapeutics has experimentally targeted approaches for treating human cancer cell lines. MicroRNA-365 (miR-365) has been reported to be an important tumor suppressor miRNA in cancers. However, it remains unknown, how miR-365 plays a pivotal role in inducing apoptosis in HCF-treated cancer cells in vitro. The fertile/infertile HCF was aspirated from liver of infected sheep and in terms of molecular taxonomy was identified as G1 genotype of Echinococcus granulosus sensu stricto. A375 human melanoma cancer cells were cultured into two groups: fertile and infertile HCF-treated A375 cells. To assess the cytotoxicity of various concentrations of HCF on melanoma cells, cell viability was determined by using MTT assay. The IC50 value of HCF on A375 cells was determined 85 µg/mL. Caspase-3 enzymatic activity was evaluated by fluorometric assay in the HCF-treated melanoma cells. In addition, the mRNA expression of Bax, Bcl-2, Caspase-9 and miR-365 were determined by qRT-PCR. Findings of MTT assay showed that concentrations 85 µg/mL to 100 µg/mL of fertile HCF have the highest mortality (50%-52%) on A375 cells during 24 h. The fold change of Bax/Bcl-2 ratio, Caspase-9, miR-365 and Caspase-3 activity was higher in the fertile HCF-treated melanoma cells compared to infertile fluid treated A375 cells and human normal epithelial cell (as control cell). In conclusion, we over-expressed the miR-365 in melanoma A375 cells, via treatment of fertile HCF. Our findings suggested that inducing high expression of miR-365 might be a negative regulator of melanoma growth through activation of pro-apoptotic Bax, Caspase-9 and Caspase-3 that are essential to intrinsic apoptotic pathway. These findings provide new insights into the use of Echinococcus HCF-derived metabolites in the design of drug therapies and in vivo tumor cell vaccine to combat melanoma progression.

Magnetite Fe3O4 surface as an effective drug delivery system for cancer treatment drugs: density functional theory study.

In this paper, the magnetite Fe3O4 surface was studied as a drug delivery system for the two commercially famous cancer treatment drugs, including Cisplatin and Mercaptopurine, using the density functional theory (DFT) computations. Adsorption properties, magnetic and electronic properties were calculated. Results indicate that the adsorptions are thermodynamically favorable and binding energies were decreased by increasing the concentration of the ligands adsorption on the Fe3O4 surface. Our spin-polarized calculations determine that the magnetization of all systems is greater than the pristine magnetite Fe3O4 surface witch is vital for drug delivery and magnetic hyperthermia. This study provides a deep understanding of the interaction mechanism at the atomistic scale and proposed that magnetite Fe3O4 could be employed as an efficient drug carrier.Communicated by Ramaswamy H. Sarma.

Helicobacter heilmannii Colonization Is Associated with High Risk for Gastritis.

INTRODUCTION: We aimed to study potential associations between colonization by four common non-pylori Helicobacter species and gastroduodenal diseases by comparing samples from patients infected with H. pylori with samples from non-infected subjects. MATERIALS AND METHODS: Patients (n = 190) who were subjected to upper gastrointestinal endoscopy because of gastroduodenal conditions were enrolled in this cross-sectional study. Antral biopsy samples were taken from patients in two major hospitals (Mehrad and Imam-Hossein) in Tehran, Iran, during 2017-2018. DNA was isolated from the biopsy specimens, and PCR amplification was used to identify the Helicobacter species by using their corresponding specific primer sets. RESULTS: Out of 120 cases positive for H. pylori, 46 (38%) were patients with gastritis, 23 (19%) with duodenal ulcer, 11 (9%) with gastric cancer, and 40 (33.3%) with gastric ulcer. Overall, 70 (36%) patients were negative for H. pylori. H. pylori cases were uninfected by any of the other tested Helicobacter species. Among the 70 patients without H. pylori, 34 had gastritis-31 (94%) of these were positive also for H. heilmannii (p = 0.001, Odds Ratio: 51.6; 95% Confidence Intervals: 11.8-225.6). We did not find any patient carrying mixed Helicobacter infections with any non-pylori Helicobacter species in this cohort. CONCLUSIONS: Given our evidence about the possibility of involvement of H. heilmannii in patients suffering from gastritis and nonexistence of mixed non-pylori Helicobacter infections, bacteriological testing of subjects negative for H. pylori becomes clinically relevant and important.

Fe@(Au/Ag)n (n=1,12,54) core-shell nanoparticles as effective drug delivery vehicles for anti-cancer drugs: The computational study.

In this paper, we study magnetic and structural properties of silver and gold-coated iron nanoparticle as novel drug delivery systems for the two commercially famous cancer treatment drugs, using the density functional theory (DFT) computations. Our calculations show that silver and gold-coated iron nanoparticle have magnetization and the magnetic moment of the Fe atom in the Fe@(Ag/Au)n core-shells saturated to a value of about 3 µB. Thus the Fe@(Ag/Au)n core-shells are very promising to be functionalized for targeted drug delivery. Drug adsorption on the Gold coated iron show higher adsorption energy than Fe@Ag12 core-shell, Also, Mercaptopurine molecules showed higher adsorption energy than the Cisplatin. The Fe@Ag12 core-shells can deliver the drug into the cells while their properties are not significantly changed in the delivering process. Simulation results also have shown that in the low pH of tissue of a malignant tumor, the drug can be separated from the carrier which indicating the potential delivery vehicle of iron core-shells. Results of the calculations for core-shell structure of iron nanoparticle are very promising in biomedical applications and will contribute to the discovery of its novel applications in nanomedicine.

Electronic, optical and thermoelectric properties of Fe2ZrP compound determined via first-principles calculations.

In this study, based on the density functional theory and semi-classical Boltzmann transport theory, we investigated the structural, thermoelectric, optical and phononic properties of the Fe2ZrP compound. The results of the electronic band structure analysis indicate that Fe2ZrP is an indirect band gap semiconductor in the spin-down state with the band gap of 0.48 eV. Thermoelectric properties in the temperature range of 300-800 K were calculated. Fe2ZrP exhibits the high Seebeck coefficient of 512 µV K-1 at room temperature along with the huge power factor of 19.21 × 1011 W m-1 K-2 s-1 at 800 K, suggesting Fe2ZrP as a potential thermoelectric material. The Seebeck coefficient decreased with an increase in temperature, and the highest value was obtained for p-type doped Fe2ZrP when the optimum carrier concentration was 0.22 × 1023 cm-3; the n-type doped Fe2ZrP had high electrical conductivity than the p-type doped Fe2ZrP. Thermal conductivity increased with an increase in chemical potential. Optical calculations illustrated that there was a threshold in the imaginary dielectric function for the spin-down channel. Spin-dependent optical calculations showed that the intraband contributions affected only the spin-up optical spectra due to the free-electron effects. Generally, the results confirmed that the intraband contribution had the main role in the optical spectra in the low energy infra-red and visible ranges of light. We also presented the phononic properties and found that these materials were dynamically stable.

Biological and physiological characteristics of human cumulus cells in adherent culture condition.

BACKGROUND: Cumulus cells, as oocyte nurse cells, provide a suitable microenvironment with growth factors and cellular interactions required for oocyte maturation. Thus, these cells may serve as a natural niche for in vitro studies of female germ cell development. Cumulus cells may help attain a better understanding of the causes of infertility in women and eventually improve the outcomes of cases that respond poorly to standard infertility treatment. OBJECTIVE: The aim of this study was to isolate, culture, and investigate the biological characteristics of human cumulus cells. MATERIALS AND METHODS: In this experimental study, cumulus cells were isolated, cultured, and characterized using reverse transcription-polymerase chain reaction analyses of specific genes including FOXL2, CYP19A1, FSHR, AMHR, and LHR. The presence of vimentin, a structural protein, was examined via immunofluorescent staining. Moreover, levels of anti-mullerian hormone (AMH) and progesterone secretion by cumulus cells were measured with ELISA after 2, 4, 12, 24, and 48 hr of culture. RESULTS: In adherent culture, human cumulus cells expressed specific genes and markers as well as secreted AMH and progesterone into the medium. CONCLUSION: Cumulus cells secrete AMH and progesterone in an adherent culture and might be applicable for in vitro maturation (IVM) and in vitro gametogenesis (IVG) studies.

Structural, electronic, and magnetic properties of the Fe-doped GaP nanotubes.

In this work we aimed to study the structural, electronic, and magnetic properties of the Fe-doped GaP nanotubes (GaPNTs). The method, utilized in this work is based on first-principle calculations that are applied to the case studies; (5,5) armchair, (8,0) zigzag GaPNTs, and Fe-doped GaPNTs. The results of simulation show that there is distortion around Fe impurity with respect to the pristine GaPNTs for Fe-doped (5,5) and (8,0) GaPNTs. The total density of states (DOS) indicates that Fe-doped GaPNTs show the metal behavior. Furthermore, it is perceived that both Fe-doped (5,5) and (8,0) GaPNTs are magnetic systems while pristine GaPNTs do not show magnetic behavior. The study suggests that such Fe-doped nanotubes may be useful in nanomagnets and spintronics.

A familial occurrence of lip anomaly.

Lip pits are among the rarest congenital deformities recorded. Initially reported in 1845, its familial occurrence has been reported just once. These developmental anomalies occur either as an isolated defect or in association with other developmental deformities, including cleft lip, cleft palate, or both. They may be located at the commissures of the lips or at the midline of the lower lip. Lip pits are often inherited as an autosomal dominant trait with variable penetrance. Our report of a family in which all of the 3 children (2 girls and 1 boy) and their father were involved is in concert with the latter statement.