Diverse bioactive secondary metabolites from Aspergillus terreus: antimicrobial, anticancer, and anti-SARS-CoV-2 activity studies.

Owing to its high interest as prolific source of diverse bioactive compounds referred in our previous research work, we have scaled-up the fermentation of the marine Aspergillus terreus LGO13 on a liquid culture medium to isolate and identify the very minor/further promising bioactive secondary metabolites and to study their antibacterial, cytotoxic, and antiviral properties. Twenty-three known bioactive metabolites, including the recently discovered microbial natural product N-benzoyl-tryptophan (1), were obtained herein. Their structures were determined using HR-ESI-MS 1D/2D NMR spectroscopy and data from the literature. The biological properties of the microbial extract and the resulting compounds were examined using a set of microorganisms, cervix carcinoma KB-3-1, nonsmall cell lung cancer (NSCLC) A549, and coronavirus (SARS-CoV-2), respectively. Molecular docking (MD) simulations were used to investigate the potential targets of the separated metabolites as anti-SARS-CoV-2 drugs. According to the current study, a viral protein that may be the target of anticovid drugs is a papain-like protease (PLpro), and chaetominine (2) appears to be a viable choice against this protein. We evaluated the antiviral efficacy of chaetominine (2), fumitremorgin C (6), and azaspirofuran A (9) against SARS-CoV-2 based on MD data. Chaetominine (2) and azaspirofuran A (9) displayed intermediate selectivity indices (SI = 6.6 and 3.2, respectively), while fumitremorgin C (6) displayed a high selectivity index (SI = 19.77). These findings show that fumitremorgin C has promising antiviral action against SARS-CoV-2.

ACT5 Electrical Impedance Tomography System.

OBJECTIVE: This article introduces the Adaptive Current Tomograph 5 (ACT5) Electrical Impedance Tomography (EIT) system. ACT5 is a 32 electrode applied-current multiple-source EIT system that can display real-time images of conductivity and susceptivity at 27 frames per second. The adaptive current sources in ACT5 can apply fully programmable current patterns with frequencies varying from 5 kHz to 500 kHz. The system also displays real-time ECG readings during the EIT imaging process. METHODS: The hardware and software design and specifications are presented, including the current source design, FPGA hardware, safety features, calibration, and shunt impedance measurement. RESULTS: Images of conductivity and susceptivity are presented from ACT5 data collected on tank phantoms and a human subject illustrating the system's ability to provide real-time images of pulsatile perfusion and ECG traces. SIGNIFICANCE: The portability, high signal-to-noise ratio, and flexibility of applied currents over a wide range of frequencies enable this instrument to be used to obtain useful human subject data with relative clinical ease.

Chemical Characterization, DNA-Damage Protection, Antiproliferative Activity and in Silico Studies of the Essential Oils from Perralderia coronopifolia Coss.

In this study, for the first time, we analyzed the chemical composition of essential oils (EOs) steam-distilled from the flowers and leaves of Perralderia coronopifolia by GC-FID/MS. The objective was to explore new anticancer and antioxidant bioactive substances and understand their mechanisms of action through the use of plant-derived natural products. The major chemical components characterizing the EOs were cis-chrysanthenyl acetate 1, 6-oxocyclonerolidol 2, cis-8-acetoxychrysanthenyl acetate 3, and 6α-hydroxycyclonerolidol 4, respectively. Furthermore, the EOs inhibited cell proliferation in HeLa (human cervix carcinoma) and PC3 (human prostate cancer) cells and protected plasmid DNA from oxidative damage caused by UV-photolyzed H2 O2 . Employing a molecular docking study, we elucidated the main compounds' inhibition mechanisms. Consequently, the antitumor activity could be related to the inhibitory property of compound 3 against CDC25B phosphatase. The evaluation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the density functional theory (DFT) calculations of the major compounds, especially compound 3, offer potential insights for designing and developing new cancer drug candidates. In conclusion, our study provides a framework for future research and development in the field by establishing a scientific foundation for the use of Perralderia coronopifolia essential oils as a prospective source of antioxidant and anticancer agents.

The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: a Systematic Review.

Purpose: Immune checkpoint inhibitor (ICI) use can lead to immune-related adverse events (irAEs) that require treatment with immunosuppressive medications in moderate to severe cases. Oncology society guidelines recommend systemic steroids and immunosuppressants such as infliximab and vedolizumab for the treatment of refractory cases. Limited information is available about the safety profile and potential adverse effects of these immunosuppressants. We have investigated the safety profile of multiple immunosuppressants which are used in the treatment of ICI-related irAEs. Methods: We performed a systematic review of studies reporting irAEs, from ICI use, and their medical management with immunosuppressants in adult cancer patients. We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception through September 1, 2022, using the following keywords or their equivalents: ICI, immunosuppressant, and irAE. We extracted observational studies and clinical trials that matched our criteria. A random effects model was used to estimate the overall incidence of infections associated with the treatment of irAEs. Results: Among the 11 studies included in this review (1036 total patients), melanoma (548 patients, 52.9%) was the most common primary cancer, followed by lung cancer (139 patients, 13.4%) and genitourinary cancers (131 patients, 12.6%). PD-1/PD-L1 monotherapy (460 patients, 44.4%) was used most, followed by a combination of PD-1/PD-L1 and CTLA-4 therapy (350 patients, 33.8%) and CTLA-4 monotherapy (226 patients, 22%). A total of 1024 (98.8%) patients had their irAEs treated with systemic steroids with majority having colitis and hepatobiliary irAEs; 335 patients (32.3%) were also treated with infliximab (mainly for colitis). Our review found 22.3% of patients treated for irAEs developed infectious adverse events (95% CI: 15.6%-29.1%, p<0.001). Among the 3 studies reporting the types of infections (41 total patients), bacterial (80.5%), followed by fungal (36.6%), infections were most common. Conclusions: Adverse events from irAE treatment occurred in about one-third of patients that received either steroids or a combination of steroids and other immunosuppressants. Clinicians should be aware of these immunosuppressant-related adverse effects, which can negatively impact cancer treatment and patient outcomes, when treating irAEs and consider shortening treatment duration or using alternative strategies when possible to mitigate these complications, future prospective studies should further investigate the safety of immunosuppressants in treating irAEs.

The Impact of Core Complex Training on Some Basketball-Related Aspects of Physical Strength and Shooting Performance.

Exercises for the core can be categorized as promoting core-stability, core-strength, or functionality, as these are crucial aspects of most sports activities. This study aimed to examine the effects of using core complex training (CCT), complex training (CT), and core exercise (CE) on some aspects of muscle strength and shooting performance in basketball players. The 36 participants were divided into three groups of 12 each, and then the experimental approach was applied to each group. The groups were labeled as follows: the core complex training group (N = 12; age, 18.58 ± 0.67 years; height, 178.08 ± 0.79 cm; weight, 76.42 ± 1.38 kg; training age, 7.42 ± 0.51 years); the complex training group (N = 12; age, 18.50 ± 0.52 years; height, 177.92 ± 1.31 cm; weight, 76.67 ± 1.78 kg; training age, 7.33 ± 0.49 years); and the core exercise group (n = 12; age, 18.42 ± 0.52 years; height, 177.75 ± 1.29 cm; weight, 76.58 ± 1.38 kg; training age, 7.42 ± 0.67 years). For ten weeks, each of the three groups participated in three training sessions every week. This study investigates the impact of core complex training on basketball shooting ability and muscle strength. The eight-week program, consisting of weight training, plyometric exercises, and core exercises, yielded improvements in muscle strength and shooting accuracy. In tests of muscular strength and basketball shooting ability, the CCT group outperformed the CE and CT groups. The F value varied from 3.75 to 58.77, which are function values with a p < 0.05 significance level. The core complex training group exhibited superior muscle strength to that of both the complex training group and the core exercise group, in some areas. This is shown in the results of the javelin quadrathlon medicine ball test, the core muscle strength and stability test, the sit-up abdomen test, the sit-up back test, the standing long jump test, the Sargent jump test, and the shooting test (p < 0.005). Due to the effect of the core complex training program on improving performance efficiency and muscle strength, which affects the results of matches, we have recommended using the proven basic strength training program at other age stages, with the objective of including the concept, importance, and design of compound basic strength training in training programs used by basketball coaches.

Indications, Efficacy, and Complications of Pediatric Bronchoscopy: A Retrospective Study at a Tertiary Center.

Background Bronchoscopy is an essential procedure for evaluating, diagnosing, and treating pediatric respiratory diseases. In this study, we demonstrate the indications and contraindications of bronchoscopy done in a tertiary referral hospital, Al Qassimi Woman's and Children's Hospital (AQWCH) in Sharjah, United Arab Emirates (UAE), in order to achieve better service. This study aims to evaluate patients' characteristics, diagnostic and therapeutic indications, and complications of bronchoscopy. Material and method This retrospective chart review included children aged between one day and 13 years, admitted to AQWCH, who underwent bronchoscopy (rigid or flexible) procedures between January 2018 and December 2019. All patients were identified by using a computerized search of hospital discharge diagnosis, which was codified as "pediatric bronchoscopy, flexible, rigid, bronchoalveolar lavage". The main study outcome measure was to evaluate patients' characteristics, diagnostic or therapeutic indications, bronchoalveolar lavage (BAL) analysis, as well as complications of bronchoscopy at AQWCH.  Results There were 72 pediatric bronchoscopies (rigid and flexible) performed in patients aged less than 13 years old; the reason for bronchoscopy procedure was diagnostic in 51% and both diagnostic and therapeutic in 49%. Cough was the most common symptom (n=53; 74%), and chest recession was the most common clinical finding (n=46; 64%). Foreign body aspiration was the main indication (n=23; 32%), followed by stridor (26%). Consolidation was the most common radiological finding. Foreign body was the common finding, seen in 25% of bronchoscopies, followed by tracheomalacia in 17%. The suspected diagnosis was confirmed in 89%, and management change was needed in 54% of patients. The main complication during the procedure was desaturation (26%), and cough was the main post-bronchoscopy complication (14%). BAL was done for 28 (39%) patients, in which BAL culture was positive in 75%. Rigid bronchoscopy was done when foreign body aspiration was suspected based on positive history in 70%, abnormal physical examination in 60%, and chest X-ray abnormalities in 39% of patients. Sensitivity and specificity for patient history, physical examination, and chest X-ray were 80% and 83%, 66% and 60%, and 40% and 66 %, respectively. Conclusion Bronchoscopy is an important tool for evaluating, diagnosing, and treating pediatric respiratory diseases. While it is a safe procedure, it still needs a careful selection of patients as it is invasive.

Radiological-histopathological discordance in patients transplanted for HCC and its impact on post-transplant outcomes.

BACKGROUND AND AIMS: Contrast-enhanced cross-sectional imaging is the cornerstone in the diagnosis, staging, and management of HCC, including eligibility for liver transplantation (LT). Radiological-histopathological discordance may lead to improper staging and may impact patient outcomes. We aimed to assess the radiological-histopathological discordance at the time of LT in HCC patients and its impact on the post-LT outcomes. METHODS: We analyzed further the effect of 6-month waiting policy on the discordance. Using United Network for Organ Sharing-Organ Procurement and Transplantation Network (UNOS-OPTN) database, we examined the discordance between pre-LT imaging and explant histopathology for all adult HCC patients who received liver transplants from deceased donors between April 2012 and December 2017. Kaplan-Meier methods and Cox regression analyses were used to evaluate the impact of discordance on 3-year HCC recurrence and mortality. RESULTS: Of 6842 patients included in the study, 66.7% were within Milan criteria on both imaging and explant histopathology, and 33.3% were within the Milan based on imaging but extended beyond Milan on explant histopathology. Male gender, increasing numbers of tumors, bilobar distribution, larger tumor size, and increasing AFP are associated with increased discordance. Post-LT HCC recurrence and death were significantly higher in patients who were discordant, with histopathology beyond Milan (adj HR 1.86, 95% CI 1.32-2.63 for mortality and 1.32, 95% CI 1.03-1.70 for recurrence). Graft allocation policy with 6-month waiting time led to increased discordance (OR 1.19, CI 1.01-1.41), although it did not impact post-LT outcome. CONCLUSION: Current practice for staging of HCC based on radiological imaging features alone results in underestimation of HCC burden in one out of three patients with HCC. This discordance is associated with a higher risk of post-LT HCC recurrence and mortality. These patients will need enhanced surveillance to optimize patient selection and aggressive LRT to reduce post-LT recurrence and increase survival.

Current Status of Biomarkers and Molecular Diagnostic Tools for Rejection in Liver Transplantation: Light at the End of the Tunnel?

Strategies to minimize immune-suppressive medications after liver transplantation are limited by allograft rejection. Biopsy of liver is the current standard of care in diagnosing rejection. However, it adds to physical and economic burden to the patient and has diagnostic limitations. In this review, we aim to highlight the different biomarkers to predict and diagnose acute rejection. We also aim to explore recent advances in molecular diagnostics to improve the diagnostic yield of liver biopsies.

Bioactive secondary metabolites from Trichoderma viride MM21: structure elucidation, molecular docking and biological activity.

Four bioactive metabolites; ergosterol (1), peroxy ergosterol (2), α-cyclopiazonic acid (3) and kojic acid (4), were isolated from the fungal sp. Trichoderma viride MM21. Their structures were assigned by cumulative analysis of NMR and mass spectra, and comparison with literature. The antimicrobial activity of the fungus supernatant, mycelial cake, cumulative crude extract and compounds 1-4 was broadly studied against 11 diverse pathogens, revealing auspicious activity results. Based on the molecular docking, ergosterol (1) and peroxy ergosterol (2) were picked up to be computationally tested against topoisomerase IV of Staphylococcus aureus. The nominated enzyme is a possible target for the antibacterial activity of triterpenoidal/steroidal compounds. Compounds 1, 2 showed a deep inserting inside the enzyme groove recording a good binding affinity of -8.1 and -8.4 kcal/mol, respectively. Noteworthy that the antibacterial activity of ergosterol was higher (14-17 mm) than peroxy ergosterol (11-14 mm), although ergosterol formed only one hydrogen bond with the target, while peroxy ergosterol formed three hydrogen bonds. Such higher antibacterial activity of ergosterol may be attributed to its interference with other proteins included in this inhibition. The cytotoxic activity was tested against brine shrimp, revealing 100% mortality for the supernatant, crude extract and whole isolated compounds. Such strong cytotoxicity is attributed most likely to the abundant productivity/concentration of α-cyclopiazonic acid and kojic acid.

A case of a giant thoracic schwannoma.

Background: Giant solitary schwannomas are rare, benign, and typically slow-growing tumors reaching up to 20 cm in size. Case Description: A 43-year-old male presented with shortness of breath and chest pain. The thoracic MRI showed a giant mass 15 cm in diameter filling the left chest cavity. The lesion was resected utilizing intrathoracic approach and required a multilevel approach. Vertebrectomy with instrumented fusion was performed. The pathological diagnosis was benign schwannoma without nuclear atypia. Postoperatively, the patient fully recovered without sequelae. Conclusion: A 43-year-old male presented with a 15 cm diameter chest mass that proved to be a schwannoma that was resected without long-term sequelae.

A Comprehensive Overview of the Developments of Cdc25 Phosphatase Inhibitors.

Cdc25 phosphatases have been considered promising targets for anticancer development due to the correlation of their overexpression with a wide variety of cancers. In the last two decades, the interest in this subject has considerably increased and many publications have been launched concerning this issue. An overview is constructed based on data analysis of the results of the previous publications covering the years from 1992 to 2021. Thus, the main objective of the current review is to report the chemical structures of Cdc25s inhibitors and answer the question, how to design an inhibitor with better efficacy and lower toxicity?

Insight on Mercapto-Coumarins: Synthesis and Reactivity.

Mercapto (or sulfanyl)-coumarins are heterocycles of great interest in the development of valuable active structures in material and biological domains. They represent a highly exploitable class of compounds that open many possibilities for further chemical transformations. The present review aims to draw focus toward the synthetic applicability of various forms of mercapto-coumarins and their representations in pharmaceuticals and industries. This work covers the literature issued from 1970 to 2021.

A Modified Howland Current Source Design for Simultaneous EIT/ECG Data Acquisition.

The current source is one of the most critical circuits in electrical impedance tomography (EIT) hardware systems. The simplicity and excellent performance of the Howland current source makes it a prime candidate for this role in EIT systems. Although the Howland source and its family may be the best option for the high-frequency EIT operation, its low frequency noise may also limit the implementation of a system to simultaneously collect electrocardiogram (ECG) and EIT signals from the electrodes. This paper proposes modifications to the conventional Howland source to make is suitable for simultaneous EIT and ECG. The preliminary experimental results of this modified Howland show significant improvement in the collected ECG signal quality in the presence of the EIT signal.

Monascin and monascinol, azaphilonoid pigments from Mortierella polycephala AM1: in silico and in vitro targeting of the angiogenic VEGFR2 kinase.

The fungus, Mortierella polycephala is one of the most productive sources of anticancer bioactive compounds namely those of pigment nature. During our investigation of the produced bioactive metabolites by the terrestrial M. polycephala AM1 isolated from Egyptian poultry feather waste, two main azaphilonoid pigments, monascin (1) and monascinol (2) were obtained as major products; their structures were identified by 1D (1H&13C) and 2D (1H-1H COSY, HMBC) NMR and HRESI-MS spectroscopic data. Biologically, cytotoxic activities of these compounds were broadly studied compared with the fungal extract. To predict the biological target for the presumed antitumor activity, an in silico study was run toward three proteins, topoisomerase IIα, topoisomerase IIß, and VEGFR2 kinase. Monascinol (2) was expected to be moderately active against VEGFR2 kinase without any anticipated inhibition toward topo II isoforms. The in vitro study confirmed the docked investigation consistently and introduced monascinol (2) rather than its counterpart (1) as a potent inhibitor to the tested VEGFR2 kinase. Taxonomically, the fungus was identified using morphological and genetic assessments.

Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer.

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.

Practical Implementation of a Novel Output Impedance Measurement Technique for EIT System While Attached to a Load.

A novel method for measuring the output impedance of current sources in an EIT system is implemented and tested. The paper shows that the proposed method can be used at the time of operation while the load is attached to the EIT system. the results also show that performance of the system improves when the shunt impedance values from the proposed technique are used to set the adaptive sources as opposed to the shunt impedance values acquired through open circuit measurements.

De Novo Hepatocellular Carcinoma in Hepatitis C-Related Cirrhosis: Are Advanced Glycation End Products a Key Driver?

Background and Purpose: The advanced glycation end products (AGEs) have been implicated in different diseases' pathogenesis, but their role in hepatocellular carcinoma (HCC) is still a matter of debate. This study aims to investigate the association of AGEs with HCC development in patients with hepatitis C-related cirrhosis. Methods: Only 153 of the 181 non-diabetic patients with cirrhosis were consecutively involved in this pilot cohort prospective study, along with 34 healthy control participants. Demographic characteristics, biochemical parameters, clinical data, and AGEs levels in all subjects at the starting point and every year after that for two years were assessed. Multivariable Cox regression analysis was used to settle variables that could predict HCC development within this period. Results: HCC developed in 13 (8.5%) patients. Univariate Cox regression analysis reported that body mass index (P=0.013), homeostatic model assessment-insulin resistance (P=0.006), alpha-fetoprotein (P <0.001), and AGEs levels (P <0.001) were related to HCC development. After adjusting multiple confounders, the multivariable Cox regression model has revealed that AFP and AGEs were the powerful parameters related to the HCC occurrence (all P<0.05). AGEs at a cutoff value of more than 79.6 ng/ml had 100% sensitivity, 96.4% specificity, and 0.999 area under the curve (all P<0.001), using the receiver operating characteristic curve, for prediction of HCC development. Conclusion: This work suggests that AGEs are associated with an increased incidence of HCC, particularly in cirrhosis, which is encouraging in decreasing the risk of HCC in these patients.

Collagenase and Tyrosinase Inhibitory Effect of Isolated Constituents from the Moss Polytrichum formosum.

Mosses from the genus Polytrichum have been shown to contain rare benzonaphthoxanthenones compounds, and many of these have been reported to have important biological activities. In this study, extracts from Polytrichum formosum were analyzed in vitro for their inhibitory properties on collagenase and tyrosinase activity, two important cosmetic target enzymes involved respectively in skin aging and pigmentation. The 70% ethanol extract showed a dose-dependent inhibitory effect against collagenase (IC50 = 4.65 mg/mL). The methanol extract showed a mild inhibitory effect of 44% against tyrosinase at 5.33 mg/mL. Both extracts were investigated to find the constituents having a specific affinity to the enzyme targets collagenase and tyrosinase. The known compounds ohioensin A (1), ohioensin C (3), and communin B (4), together with nor-ohioensin D (2), a new benzonaphthoxanthenone, were isolated from P. formosum. Their structures were determined by mass spectrometry and NMR spectroscopy. Compounds 1 (IC50 = 71.99 µM) and 2 (IC50 = 167.33 µM) showed inhibitory activity against collagenase. Compound 1 also exhibited inhibition of 30% against tyrosinase activity at 200 µM. The binding mode of the active compounds was theoretically generated by an in-silico approach against the 3D structures of collagenase and tyrosinase. These current results present the potential application from the moss P. formosum as a new natural source of collagenase and tyrosinase inhibitors.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms.

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom.

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin (benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.