Transcriptomic meta-analysis to identify potential antifungal targets in Candida albicans.

BACKGROUND: Candida albicans is a fungal pathogen causing human infections. Here we investigated differential gene expression patterns and functional enrichment in C. albicans strains grown under different conditions. METHODS: A systematic GEO database search identified 239 "Candida albicans" datasets, of which 14 were selected after rigorous criteria application. Retrieval of raw sequencing data from the ENA database was accompanied by essential metadata extraction from dataset descriptions and original articles. Pre-processing via the tailored nf-core pipeline for C. albicans involved alignment, gene/transcript quantification, and diverse quality control measures. Quality assessment via PCA and DESeq2 identified significant genes (FDR < = 0.05, log2-fold change > = 1 or <= -1), while topGO conducted GO term enrichment analysis. Exclusions were made based on data quality and strain relevance, resulting in the selection of seven datasets from the SC5314 strain background for in-depth investigation. RESULTS: The meta-analysis of seven selected studies unveiled a substantial number of genes exhibiting significant up-regulation (24,689) and down-regulation (18,074). These differentially expressed genes were further categorized into 2,497 significantly up-regulated and 2,573 significantly down-regulated Gene Ontology (GO) IDs. GO term enrichment analysis clustered these terms into distinct groups, providing insights into the functional implications. Three target gene lists were compiled based on previous studies, focusing on central metabolism, ion homeostasis, and pathogenicity. Frequency analysis revealed genes with higher occurrence within the identified GO clusters, suggesting their potential as antifungal targets. Notably, the genes TPS2, TPS1, RIM21, PRA1, SAP4, and SAP6 exhibited higher frequencies within the clusters. Through frequency analysis within the GO clusters, several key genes emerged as potential targets for antifungal therapies. These include RSP5, GLC7, SOD2, SOD5, SOD1, SOD6, SOD4, SOD3, and RIM101 which exhibited higher occurrence within the identified clusters. CONCLUSION: This comprehensive study significantly advances our understanding of the dynamic nature of gene expression in C. albicans. The identification of genes with enhanced potential as antifungal drug targets underpins their value for future interventions. The highlighted genes, including TPS2, TPS1, RIM21, PRA1, SAP4, SAP6, RSP5, GLC7, SOD2, SOD5, SOD1, SOD6, SOD4, SOD3, and RIM101, hold promise for the development of targeted antifungal therapies.

Effect of dual tasking on postural control in individuals with schizophrenia.

OBJECTIVE: To investigate the effect of dual tasking on postural control in individuals with schizophrenia. METHODS: Fifteen outpatients with schizophrenia and 15 healthy controls were included. Postural control was assessed with postural sway velocity (PSV) using Balance Master System during three different tasks: single task (standing on a force platform), cognitive task (categorical verbal fluency) and motor task (holding a cup of water) in four conditions: on firm surface with eyes open (1) and closed (2), on foam surface with eyes open (3) and closed (4). RESULTS: Individuals with schizophrenia presented higher PSV during single standing on foam surface with eyes open and closed. During the cognitive task, they showed higher PSV on foam surface with eyes closed. During the motor task PSV in schizophrenia group was higher on firm surface with eyes closed and on foam surface with eyes open and closed. Individuals with schizophrenia showed higher PSV during cognitive task on firm surface with eyes closed compared to the single task. CONCLUSIONS: Dual tasking results in a deterioration in postural control in individuals with schizophrenia. A cognitive task specifically alters postural control in the absence of visual information suggesting a possible sensorimotor dysfunction in this population.

Surf Redfish-Based ZnO-NPs and Their Biological Activity with Reference to Their Non-Target Toxicity.

The marine environment is a rich source of bioactive compounds. Therefore, the sea cucumber was isolated from the Red Sea at the Al-Ain Al-Sokhna coast and it was identified as surf redfish (Actinopyga mauritiana). The aqueous extract of the surf redfish was utilized as an ecofriendly, novel and sustainable approach to fabricate zinc oxide nanoparticles (ZnO-NPs). The biosynthesized ZnO-NPs were physico-chemically characterized and evaluated for their possible antibacterial and insecticidal activities. Additionally, their safety in the non-target organism model (Nile tilapia fish) was also investigated. ZnO-NPs were spherical with an average size of 24.69 ± 11.61 nm and had a peak at 350 nm as shown by TEM and UV-Vis, respectively. XRD analysis indicated a crystalline phase of ZnO-NPs with an average size of 21.7 nm. The FTIR pattern showed biological residues from the surf redfish extract, highlighting their potential role in the biosynthesis process. DLS indicated a negative zeta potential (-19.2 mV) of the ZnO-NPs which is a good preliminary indicator for their stability. ZnO-NPs showed larvicidal activity against mosquito Culex pipiens (LC50 = 15.412 ppm and LC90 = 52.745 ppm) and a potent adulticidal effect to the housefly Musca domestica (LD50 = 21.132 ppm and LD90 = 84.930 ppm). Tested concentrations of ZnO-NPs showed strong activity against the 3rd larval instar. Topical assays revealed dose-dependent adulticidal activity against M. domestica after 24 h of treatment with ZnO-NPs. ZnO-NPs presented a wide antibacterial activity against two fish-pathogen bacteria, Pseudomonas aeruginosa and Aeromonas hydrophila. Histopathological and hematological investigations of the non-target organism, Nile tilapia fish exposed to 75-600 ppm ZnO-NPs provide dose-dependent impacts. Overall, data highlighted the potential applications of surf redfish-mediated ZnO-NPs as an effective and safe way to control mosquitoes, houseflies and fish pathogenic bacteria.

Change management in sustainability transformation: A model for business organizations.

This study zooms in on sustainability transformation processes by deploying Stouten, Rousseau, and Cremer's (SRC) model of ten key evidence-based steps in managing planned organizational change as an anchor to develop a sequential sustainability transformation model (STM) for business organizations. The study highlights phases and steps in sustainability transformation with environmental, social, and governance (ESG) factors. Implementing planned organizational change models in sustainability transformation provides new evidence that the governance (G) factor plays the most significant role among ESG factors. Moreover, the study reveals the importance of developing more robust metrics to gauge governance factors. This study also connects change management with sustainability transformation and addresses future research in this nexus.

Neurosurgical Education Using Cadaver-Free Brain Models and Augmented Reality: First Experiences from a Hands-On Simulation Course for Medical Students.

Background and Objectives: Neurosurgery has been underrepresented in the medical school curriculum. Advances in augmented reality and 3D printing have opened the way for early practical training through simulations. We assessed the usability of the UpSurgeOn simulation-based training model and report first experiences from a hands-on neurosurgery course for medical students. Materials and Methods: We organized a two-day microneurosurgery simulation course tailored to medical students. On day one, three neurosurgeons demonstrated anatomical explorations with the help of life-like physical simulators (BrainBox, UpSurgeOn). The surgical field was projected onto large high-definition screens by a robotic-assisted exoscope (RoboticScope, BHS Technologies). On day two, the students were equipped with microsurgical instruments to explore the surgical anatomy of the pterional, temporal and endoscopic retrosigmoid approaches. With the help of the RoboticScope, they simulated five clipping procedures using the Aneurysm BrainBox. All medical students filled out a digital Likert-scale-based questionnaire to evaluate their experiences. Results: Sixteen medical students participated in the course. No medical students had previous experience with UpSurgeOn. All participants agreed that the app helped develop anatomical orientation. They unanimously agreed that this model should be part of residency training. Fourteen out of sixteen students felt that the course solidified their decision to pursue neurosurgery. The same fourteen students rated their learning experience as totally positive, and the remaining two rated it as rather positive. Conclusions: The UpSurgeOn educational app and cadaver-free models were perceived as usable and effective tools for the hands-on neuroanatomy and neurosurgery teaching of medical students. Comparative studies may help measure the long-term benefits of UpSurgeOn-assisted teaching over conventional resources.

Prognostic factors and scoring systems associated with outcome in pediatric acute liver failure.

BACKGROUND: Pediatric acute liver failure (PALF) is an uncommon, devastating illness with significant mortality. Liver transplantation remains the mainstay of treatment for irreversible PALF. The purpose of this study was to determine the etiology and prognostic factors associated with outcome of PALF in South Africa and to evaluate prognostic scoring systems used. METHODS: Records of 45 pediatric patients younger than 16 years of age who presented with PALF from 1 January 2015 till 31 October 2020 were analysed. Patients were divided into two groups with one group consisting of patients with spontaneous recovery of the liver with supportive treatment (6/45:13.3%) and the second group consisting of patients with poor outcomes who demised (19/45: 42%) or underwent liver transplantation (20/45: 44%). RESULTS: The median age of presentation was 3.3 years (IQR 1.8-6.9) with the 1-5 years age group constituting majority of patients (55.6%). Median time to follow up was 6.1 months (IQR 0.2-28.8). Higher liver injury unit scores were observed in patients who had poorer outcomes (P = 0.008) with a threshold of greater than 246 having a sensitivity of 84% and specificity of 83% (P < 0.001). Higher peak PELD/MELD (P = 0.006) and admission UKELD (P = 0.002) scores, were found in patients with poorer outcomes. Kings College Hospital criteria (KCHC) was useful in predicting which patients would die without liver transplantation (P = 0.002). Liver transplantation was performed in 20/45 (44%) patients with a post transplantation 1 year patient and graft survival of 80%. CONCLUSION: Although, survival of PALF patients was lower than high and other low-middle income countries, outcomes post transplantation were good. Our study demonstrates the utility of dynamic scoring systems in PALF patients, it underscores the need for early referral and clinical monitoring in a tertiary center once the criteria for PALF have been met.

Arthroscopic Wafer Procedure Versus Ulnar Shortening Osteotomy for Treatment of Idiopathic Ulnar Impaction Syndrome: A Randomized Controlled Trial.

PURPOSE: We compared the arthroscopic wafer procedure (AWP) and ulnar shortening osteotomy (USO) for treatment of idiopathic ulnar impaction syndrome in terms of clinical, functional improvement and time of return to work. METHODS: This single-center study was conducted at an academic level 1 referral center between 2014 and 2020. Sixty patients with idiopathic ulnar impaction syndrome were prospectively randomized to treatment with either AWP or USO. At the final follow-up, patients were evaluated by the Disabilities of the Arm, Shoulder, and Hand; the Modified Mayo Wrist Score; the visual analog scale for pain; wrist range of motion; and grip strength. Also, the time of return to work and complications were reported. RESULTS: The mean follow-up periods were 22 ± 5.7 months in the AWP group and 21.1 ± 5.3 months in the USO group. All patients in the USO group achieved union by 12 weeks. At the final follow-up, there were no statistically significant differences in the outcome measures (Disabilities of the Arm, Shoulder, and Hand score; Modified Mayo Wrist Score; visual analog scale score; range of motion; and grip strength) in either group. Fewer complications and an earlier return to work were observed in the AWP group. CONCLUSIONS: Both techniques yielded comparable outcomes, with earlier return to work, a lower incidence of complications, and fewer secondary procedures in the AWP group. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model.

Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor (PD150606) in combination with methylprednisolone sodium succinate (MPSS) as an anti-inflammatory drug. SCI was experimentally induced in sixteen mongrel dogs through an epidural balloon compression technique. The dogs were allocated randomly into four groups: control, MPSS, PD150606, and MPSS+PD150606. Clinical evaluation, serum biochemical, somatosensory evoked potentials, histopathological, and immunoblotting analyses were performed to assess treated dogs during the study. The current findings revealed that the combined administration of MPSS+PD150606 demonstrated considerably lower neuronal loss and microglial cell infiltration than the other groups, with a significant improvement in the locomotor score. The increased levels of inflammatory markers (GFAP and CD11) and calcium-binding proteins (Iba1 and S100) were significantly reduced in the combination group and to a lesser extent in MPSS or PD150606 treatment alone. Interestingly, the combined treatment effectively inhibited the calpain-induced cleavage of p35, limited cdk5 activation, and inhibited tau phosphorylation. These results suggest that early MPSS+PD150606 therapy after acute SCI may prevent subsequent neurodegeneration via calpain inhibition.

Evaluation of Antioxidant Activity and Biotransformation of Opuntia Ficus Fruit: The Effect of In Vitro and Ex Vivo Gut Microbiota Metabolism.

Opuntia ficus-indica biological effects are attributed to several bioactive metabolites. However, these actions could be altered in vivo by biotransformation reactions mainly via gut microbiota. This study assessed gut microbiota effect on the biotransformation of O. ficus-indica metabolites both in vitro and ex vivo. Two-time aliquots (0.5 and 24 h) from the in vitro assay were harvested post incubation of O. ficus-indica methanol extract with microbial consortium, while untreated and treated samples with fecal bacterial culture from the ex vivo assay were prepared. Metabolites were analyzed using UHPLC-QTOF-MS, with flavonoid glycosides completely hydrolyzed in vitro at 24 h being converted to two major metabolites, 3-(4-hydroxyphenyl)propanoic acid and phloroglucinol, concurrent with an increase in the gallic acid level. In case of the ex vivo assay, detected flavonoid glycosides in untreated sample were completely absent from treated counterpart with few flavonoid aglycones and 3-(4-hydroxyphenyl)propanoic acid in parallel to an increase in piscidic acid. In both assays, fatty and organic acids were completely hydrolyzed being used as energy units for bacterial growth. Chemometric tools were employed revealing malic and (iso)citric acids as the main discriminating metabolites in vitro showing an increased abundance at 0.5 h, whereas in ex vivo assay, (iso)citric, aconitic and mesaconic acids showed an increase at untreated sample. Piscidic acid was a significant marker for the ex vivo treated sample. DPPH, ORAC and FRAP assays were further employed to determine whether these changes could be associated with changes in antioxidant activity, and all assays showed a decline in antioxidant potential post biotransformation.

Basal cisternostomy for traumatic brain injury: A case report of unexpected good recovery.

In subarachnoid hemorrhage following traumatic brain injury (TBI), the high intracisternal pressure drives the cerebrospinal fluid into the brain parenchyma, causing cerebral edema. Basal cisternostomy involves opening the basal cisterns to atmospheric pressure and draining cerebrospinal fluid in an attempt to reverse the edema. We describe a case of basal cisternostomy combined with decompressive craniectomy. A 35-year-old man with severe TBI following a road vehicle accident presented with acute subdural hematoma, Glasgow coma scale score of 6, fixed pupils and no corneal response. Opening of the basal cisterns and placement of a temporary cisternal drain led to immediate relaxation of the brain. The patient had a Glasgow coma scale score of 15 on postoperative day 6 and was discharged on day 10. We think basal cisternostomy is a feasible and effective procedure that should be considered in the management of TBI.

Synergistic Toll-like Receptor 3/9 Signaling Affects Properties and Impairs Glioma-Promoting Activity of Microglia.

In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/TLR9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon ß release and phagocytic tumor clearance. Combined TLR3/TLR9 stimulation also augmented several functional features of microglia, such as the release of proinflammatory factors, motility, and phagocytosis activity. TLR3/TLR9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the coactivation of TLR3/TLR9 also augments the impairment of glioma growth in vivo Our results show that combined activation of TLR3/TLR9 in microglia/macrophages results in a more efficient glioma suppression, which may provide a potential strategy for glioma treatment.SIGNIFICANCE STATEMENT Glioma-associated microglia/macrophages (GAMs) are the predominant immune cells in glioma growth and are recently considered as antitumor targets. TLRs are involved in glioma growth, but the TLR3 or TLR9 ligands were not successful in clinical trials in treating glioma. We therefore combined TLR3 and TLR9 activation of GAMs, resulting in a strong synergistic effect of tumor clearance in vitro, ex vivo, and in vivo Mechanisms of this GAM-glioma interaction involve IFNß signaling and increased tumor clearance by GAMs. Interfering with CD47 signaling had an additional impact on tumor clearance. We propose that these signaling pathways could be exploited as anti-glioma targets.

Antimicrobial and antibiofilm potentials of cinnamon oil and silver nanoparticles against Streptococcus agalactiae isolated from bovine mastitis: new avenues for countering resistance.

BACKGROUND: Streptococcus agalactiae (S. agalactiae) is a contagious pathogen of bovine mastitis. It has financial implications for the dairy cattle industry in certain areas of the world. Since antimicrobial resistance increases in dairy farms, natural antimicrobials from herbal origins and nanoparticles have been given more attention as an alternative therapy. Hence, this study reported the antimicrobial and antibiofilm potentials of cinnamon oil, silver nanoparticles (AgNPs), and their combination against multidrug-resistant (MDR) S. agalactiae recovered from clinical bovine mastitis in Egypt. RESULTS: Our findings revealed that 73% (146/200) of the examined milk samples collected from dairy cows with clinical mastitis were infected with Streptococci species. Of these, 9.59% (14/146) were identified as S. agalactiae and categorized as MDR. S. agalactiae isolates expressed four virulence genes (Hyl, cylE, scpB, and lmb) and demonstrated an ability to produce biofilms. Cinnamon oil showed high antimicrobial (MICs ≤0.063 µg /mL) and antibiofilm (MBIC50 = 4 µg/mL) potentials against planktonic and biofilms of S. agalactiae isolates, respectively. However, AgNPs showed reasonable antimicrobial (MICs ≤16 µg/mL) and relatively low antibiofilm (MBIC50 = 64 µg/mL) activities against screened isolates. Synergistic antimicrobial or additive antibiofilm interactions of cinnamon oil combined with AgNPs were reported for the first time. Scanning electron microscope (SEM) analysis revealed that biofilms of S. agalactiae isolates treated with cinnamon oil were more seriously damaged than observed in AgNPs cinnamon oil combination. Moreover, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) showed that cinnamon oil exerted a remarkable down-regulation of pili biosynthesis genes (pilA and pilB) and their regulator (rogB) against S. agalactiae biofilms, meanwhile the AgNPs cinnamon oil combination demonstrated a lower efficacy. CONCLUSIONS: This is an in vitro preliminary approach that documented the antibiofilm potential of cinnamon oil and the inhibitory activity of cinnamon oil and its combination with AgNPs against MDR S. agalactiae recovered from clinical mastitis. Further in vivo studies should be carried out in animal models to provide evidence of concept for implementing these alternative candidates in the treatment of dairy farms infected by streptococcal mastitis in the future.

In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid.

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

Levels of PAHs, PCBs, and toxic metals in Ruditapes philippinarum and Donax trunculus in Marmara Sea, Turkey.

BACKGROUND: The manila clam Ruditapes philippinarum and the wedge clam Donax trunculus are economic bivalve species which constitute an important part of the natural bivalve beds in the Marmara Sea, Turkey. Toxic chemicals such as, dioxins, dioxin-like polychlorinated biphenyls (PCBs), polycyclic hydrocarbons (PAHs), and toxic metals are recognized as important health risk factors that threaten public health via food or directly in the environment. In the present study, we aimed to determine and monitor levels of these toxic chemicals in both clam species, R. philippinarum and D. trunculus, between 2013 and 2017. RESULTS: According to the results, maximum levels of dioxins, PAHs, and toxic metals (lead, cadmium, mercury) during the period were determined as 0.18 pg g-1 , 2.43 mg kg-1 , and 0.44-0.53-0.1 mg kg-1 , respectively. The level of contaminants in both clam species were determined to be below the threshold or tolerable daily intake values established by the European Commission, European Food Safety Authority (EFSA), and Food and Agriculture Organization/World Health Organization (FAO/WHO). Seasonal fluctuations were observed to be similar in both species and also in seasons, but elevated levels of PCBs and PAHs were detected in warmer months during the period. CONCLUSION: As a consequence, toxic chemicals in both clam species were found at low concentrations in this study from the point of view of public health concerns; however, the contaminants should be closely monitored in the future due to their elevated levels in samples. © 2020 Society of Chemical Industry.

Ecological risk assessment of heavy metal pollution in sediments of Nile River, Egypt.

The Nile River is the soul of Egypt, providing more than 95% of its freshwater demand. However, it receives different pollutants discharged into the water body along its stretch from Aswan (downstream of the High Dam) to Cairo, which is approximately 950 km. Alternatively, sediments play an important role in the dynamics of the entire aquatic environment and act as a sink or a source of pollution in the overlying water under various conditions. This study assessed sediment quality and its heavy metal levels. Several indices and human health risks were determined to assess the potential ecological risk of the Nile River sediment. On the basis of the index results, Cd registered the highest pollution ranking, whereas Fe, Mn, Zn, Cu, and Ni had the lowest effect. In another context, southern sites represented the lowest ecological risk relative to the central and northern sectors. The results of the noncarcinogenic hazard indices, hazard quotient, and hazard index in addition to the lifetime cancer risk were below the acceptable international limits, confirming that there are no adverse effects on the exposed population due to the Nile sediment.

Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.

Biochemical study on modifying role of variants of leptin gene and its receptor on serum leptin levels in breast cancer.

The leptin is discharged from breast adipose tissue and is overexpressed in breast cancer (BC). Conflicting relation of leptin with BC was reported. We investigated this association and its impact on leptin level and disease characteristics. The study included 70 females (40 women with pathological proof of invasive BC patients and 30 controls). LEP and LEPR polymorphisms were evaluated by real-time PCR. Serum leptin was estimated by ELISA. Both LEPR and LEP disturbances increase the danger of BC where GG genotype and G allele frequencies of LEPR were higher in patients vs. control. GG genotype increases BC risk with OR (9.1) while G allele predisposes to disease with OR (3.8). Furthermore, LEP A allele was uniquely elevated in patients than healthy ones with OR (2.06). Precise relation of circulating leptin and its polymorphisms with predicting BC may authorize its utilization in early screening.

Discovery of potent inhibitors for SARS-CoV-2's main protease by ligand-based/structure-based virtual screening, MD simulations, and binding energy calculations.

COVID-19 has caused lockdowns all over the world in early 2020, as a global pandemic. Both theoretical and experimental efforts are seeking to find an effective treatment to suppress the virus. In silico drug design can play a vital role in identifying promising drug candidates against COVID-19. Herein, we focused on the main protease of SARS-CoV-2 that has crucial biological functions in the virus. We performed a ligand-based virtual screening followed by a docking screening for testing approved drugs and bioactive compounds listed in the DrugBank and ChEMBL databases. The top 8 docking results were advanced to all-atom MD simulations to study the relative stability of the protein-ligand interactions. MD simulations support that the catalytic residue, His41, has a neutral side chain with a protonated delta position. An absolute binding energy (ΔG) of -42 kJ mol-1 for the protein-ligand (Mpro-N3) complex has been calculated using the potential-of-mean-force (geometrical) approach. Furthermore, the relative binding energies were computed for the top docking results. Our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 Mpro as follows: a bioactive compound, ChEMBL275592, which has the best MM/GBSA binding energy; the second-best compound, montelukast, is an approved drug used in the treatment of asthma and allergic rhinitis; the third-best compound, ChEMBL288347, is a bioactive compound. Bromocriptine and saquinavir are other approved drugs that also demonstrate stability in the active site of Mpro, albeit their relative binding energies are low compared to the N3 inhibitor. This study provides useful insights into de novo protein design and novel inhibitor development, which could reduce the cost and time required for the discovery of a potent drug to combat SARS-CoV-2.

Adsorption of 4-n-Nonylphenol, Carvacrol, and Ethanol onto Iron Oxide from Nonaqueous Hydrocarbon Solvents.

The adsorption of 4-n-nonylphenol (4NP), carvacrol, and ethanol onto the surface of iron oxide from nonaqueous solutions is presented. It is found that adsorption of 4NP from alkanes is strong and proceeds to monolayer formation, where the molecules are essentially "upright". However, at high relative concentrations, ethanol successfully out-competes 4NP for the iron oxide surface. Estimates of the enthalpy and entropy of binding of 4NP were found to be exothermic and entropically disfavored. Sum frequency generation vibrational spectroscopy data indicate some evidence of binding through a phenolate anion, despite the nonpolar, nonaqueous solvent. Carvacrol is also found to adsorb as a monolayer where the molecules are lying "flat". The adsorption of ethanol onto iron oxide from dodecane was investigated through the use of quantitative NMR, which is a convenient analytical technique for measuring adsorption isotherms. It was concluded that ethanol does not form adsorbed monolayers on the surface. Instead, it partitions onto the surface as a surface-enhanced local phase separation related to its poor solubility in alkane solvents.

Correction: Barrier kinetics of adsorption-desorption of alcohol monolayers on water under constant surface tension.

Correction for 'Barrier kinetics of adsorption-desorption of alcohol monolayers on water under constant surface tension' by Ivan L. Minkov et al., Soft Matter, 2019, DOI: 10.1039/c8sm02076k.