CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.

An innovative single-cell approach for phenotyping and functional genotyping of CAR NK cells.

BACKGROUND: To accelerate the translation of novel immunotherapeutic treatment approaches, the development of analytic methods to assess their efficacy at early in vitro stages is necessary. Using a droplet-based microfluidic platform, we have established a method for multiparameter quantifiable phenotypic and genomic observations of immunotherapies. Chimeric antigen receptor (CAR) natural killer (NK) cells are of increased interest in the current immunotherapy landscape and thus provide an optimal model for evaluating our novel methodology. METHODS: For this approach, NK cells transduced with a CD19 CAR were compared with non-transduced NK cells in their ability to kill a lymphoma cell line. Using our microfluidic platform, we were able to quantify the increase in cytotoxicity and synaptic contact formation of CAR NK cells over non-transduced NK cells. We then optimized our droplet sorter and successfully used it to separate NK cells based on target cell killing to perform transcriptomic analyses. RESULTS: Our data revealed expected improvement in cytotoxicity with the CD19 CAR but more importantly, provided unique insights into the factors involved in the cytotoxic mechanisms of CAR NK cells. This demonstrates a novel, improved system for accelerating the pre-clinical screening of future immunotherapy treatments. CONCLUSIONS: This study provides a new potential approach for enhanced early screening of immunotherapies to improve their development, with a highly relevant cell model to demonstrate. Additionally, our validation studies provided some potential insights into transcriptomic determinants influencing CAR NK cytotoxicity.

LC-qTOF-MS/MS phytochemical profiling of Tabebuia impetiginosa (Mart. Ex DC.) Standl. leaf and assessment of its neuroprotective potential in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tabebuia impetiginosa (Bignoniaceae) was traditionally used for memory enhancement and central nervous system (CNS) stimulation. AIM OF THE STUDY: This study aims to create a metabolic profile of the ethyl acetate fraction of T. impetiginosa (TEF) and investigate for the first time its neuroprotective potential on cyclophosphamide (CP)-induced chemobrain, validating its traditional use. MATERIALS AND METHODS: Metabolite profiling of TEF was performed using Liquid Chromatography coupled with Quadrupole Time of Flight-Mass/Mass Spectrometry (LC-qTOF-MS/MS). For the in vivo study, CP (200 mg/kg, i.p.) was administered to induce cognitive impairment in rats; TEF (30 mg/kg, p.o.) was administered throughout the 14 days of the experiment to assess its role in mitigating CP-induced neuronal deficits. Behavioral tests including locomotor, Y-maze, and passive avoidance tests were conducted. Additionally, biochemical markers such as reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and caspase-3 immunoexpression were assessed in the hippocampus area. RESULTS: Forty-four phytoconstituents were tentatively identified in TEF, mainly iridoids and organic acids. TEF showed significant memory enhancement as evidenced by the increase in step-through latency in the passive avoidance test by 1.5 folds and the increase in sequence alternation percentage (SAP) in the Y-maze test by 67.3%, as compared to CP-group. Moreover, it showed pronounced antioxidant and anti-inflammatory potentials evidenced by the significant elevation in reduced glutathione (GSH) levels by 80% and a pronounced decline in MDA and TNF-α levels by 24% and 45%, respectively relative to the CP group. TEF treatment restored normal hippocampal histological features and attenuated apoptotic caspase-3 expression by 70% compared to the CP group. CONCLUSIONS: TEF can act as a promising natural scaffold in managing the chemobrain induced by CP in cancer patients.

Cymbopogon proximus and Petroselinum crispum seed ethanolic extract/Gum Arabic nanogel emulsion: Preventing ethylene glycol and ammonium chloride-induced urolithiasis in rats.

Urolithiasis is a prevalent urological disorder that contributes significantly to global morbidity. This study aimed to assess the anti-urolithic effects of Cymbopogon proximus (Halfa Bar) and Petroselinum crispum (parsley) seed ethanolic extract /Gum Arabic (GA) emulsion, and its nanogel form against ethylene glycol (EG) and ammonium chloride (AC)-induced experimental urolithiasis in rats. Rats were divided into four groups: group 1 served as the normal control, group 2 received EG with AC in drinking water for 14 days to induce urolithiasis, groups 3 and 4 were orally administered emulsion (600 mg/kg/day) and nanogel emulsion (600 mg/kg/day) for 7 days, followed by co-administration with EG and AC in drinking water for 14 days. Urolithiatic rats exhibited a significant decrease in urinary excreted magnesium, and non-enzymic antioxidant glutathione and catalase activity. Moreover, they showed an increase in oxalate crystal numbers and various urolithiasis promoters, including excreted calcium, oxalate, phosphate, and uric acid. Renal function parameters and lipid peroxidation were intensified. Treatment with either emulsion or nanogel emulsion significantly elevated urolithiasis inhibitors, excreted magnesium, glutathione levels, and catalase activities. Reduced oxalate crystal numbers, urolithiasis promoters' excretion, renal function parameters, and lipid peroxidation while improving histopathological changes. Moreover, it decreased renal crystal deposition score and the expression of Tumer necrosis factor-α (TNF-α) and cleaved caspase-3. Notably, nanogel emulsion showed superior effects compared to the emulsion. Cymbopogon proximus (C. proximus) and Petroselinum crispum (P. crispum) seed ethanolic extracts/GA nanogel emulsion demonstrated protective effects against ethylene glycol induced renal stones by mitigating kidney dysfunction, oxalate crystal formation, and histological alterations.

Allicin and Cancer Hallmarks.

Natural products, particularly medicinal plants, are crucial in combating cancer and aiding in the discovery and development of new therapeutic agents owing to their biologically active compounds. They offer a promising avenue for developing effective anticancer medications because of their low toxicity, diverse chemical structures, and ability to target various cancers. Allicin is one of the main ingredients in garlic (Allium sativum L.). It is a bioactive sulfur compound maintained in various plant sections in a precursor state. Numerous studies have documented the positive health benefits of this natural compound on many chronic conditions, including gastric, hepatic, breast, lung, cervical, prostate, and colon cancer. Moreover, allicin may target several cancer hallmarks or fundamental biological traits and functions that influence cancer development and spread. Cancer hallmarks include sustained proliferation, evasion of growth suppressors, metastasis, replicative immortality, angiogenesis, resistance to cell death, altered cellular energetics, and immune evasion. The findings of this review should provide researchers and medical professionals with a solid basis to support fundamental and clinical investigations of allicin as a prospective anticancer drug. This review outlines the anticancer role of allicin in each hallmark of cancer.

Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND: Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up. RESULTS: The median follow-up was 3.7 years (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

Exploration of antiproliferative potential of modified triazole-benzohydrazone scaffold: Multitarget approach.

A novel series of triazole-benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad-spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME-3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI-38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR-2), mesenchymal epithelial transition factor (c-Met), proto-oncogene B-Raf, mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR-2 and c-Met with IC50 values of 0.055 and 0.042 µM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16- and 9.4-fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug-likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c-Met and VEGFR-2.

Lactoferrin ameliorates carfilzomib-induced renal and pulmonary deficits: Insights to the inflammasome NLRP3/NF-κB and PI3K/Akt/GSK-3ß/MAPK axes.

AIMS: Carfilzomib, an irreversible proteasome inhibitor, has been increasingly used to treat multiple myeloma worldwide. However, case studies showed its treatment has been associated with cardiac, renal, and pulmonary deleterious effects. Lactoferrin is an iron-binding glycoprotein present in milk. It is a multifunctional protein with antimicrobial activity, antitumor, antioxidant, and anti-inflammatory effects. Thus, this study aimed to assess the protective effects of lactoferrin against carfilzomib-induced nephrotoxicity and pulmonary toxicity, in addition to identifying the possible underlying molecular mechanisms. MAIN METHODS: Mice were treated with lactoferrin (300 mg/kg/day) concomitantly with carfilzomib (4 mg/kg, i.p.) twice weekly for three weeks. Kidney and lung indices, serum creatinine, blood urea nitrogen (BUN), uric acid, kidney injury molecule-1 (KIM-1), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and histological examination were assessed. In addition, biochemical analyses of the inflammasome NLRP3/NF-κB and PI3K/Akt/GSK-3ß/MAPK axes were conducted. KEY FINDINGS: Treatment with lactoferrin decreased serum levels of creatinine, BUN, uric acid, KIM-1, ALP, AST, and LDH and reversed carfilzomib-induced histological changes in both kidney and lung. The inflammatory markers NLRP3, p65 NF-kB, caspases1, interleukin-1ß, and interleukin-18, as well as the MAPK signaling pathway, were significantly reduced in renal and pulmonary tissues of mice following lactoferrin administration. Moreover, lactoferrin significantly counteracted carfilzomib-induced reduced expression of pAkt and pGSK-3ß in both renal and pulmonary tissues. SIGNIFICANCE: The current study suggests lactoferrin might be a promising candidate for ameliorating carfilzomib-induced nephrotoxicity and pulmonary toxicity.

Kinetic and equilibrium study of graphene and copper oxides modified nanocomposites for metal ions adsorption from binary metal aqueous solution.

Presently, the main cause of pollution of natural water resources is heavy metal ions. The removal of metal ions such as nickel (Ni2+) and cadmium (Cd2+) has been given considerable attention due to their health and environmental risks. In this regard, for wastewater treatment containing heavy metal ions, graphene oxide (GO) nanocomposites with metal oxide nanoparticles (NPs) attained significant importance. In this study, graphene oxide stacked with copper oxide nanocomposites (GO/CuO-NCs) were synthesized and characterized by Fourier transform infrared (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), and atomic force microscopy (AFM) analytical procedures. The prepared GO/CuO-NCs were applied for the removal of Ni2+ and Cd2+ ions from a binary metal ion system in batch and continuous experiments. The obtained results revealed that GO/CuO-NCs exhibited the highest removal efficiencies of Ni2+ (89.60% ± 2.12%) and Cd2+ (97.10% ± 1.91%) at the optimum values of pH: 8, dose: 0.25 g, contact time: 60 min, and at 50 ppm initial metal ion concentration in a batch study. However, 4 mL/min flow rate, 50 ppm initial concentration, and 2 cm bed height were proved to be the suitable conditions for metal ion adsorption in the column study. The kinetic adsorption data exhibited the best fitting with the pseudo-second-order model. The adsorption isotherm provided the best-fitting data in the Langmuir isotherm model. This study suggested that the GO/CuO nanocomposites have proved to be efficient adsorbents for Ni2+ and Cd2+ ions from a binary metal system.

The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis.

Natural killer (NK) cells are predominant innate lymphocytes that initiate the early immune response during infection. NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection. Tumor necrosis factor-alpha (TNFα) is a well-known inflammatory cytokine that enhances NK cell function; however, the mechanism underlying NK cell proliferation in response to TNFα is not well established. Here, we demonstrated that upon infection/inflammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity, and effector function. Notably, IL-18 can induce TNFR2 expression in NK cells, augmenting their sensitivity toward TNFα. Mechanistically, TNFα-TNFR2 signaling upregulates the expression of CD25 (IL-2Rα) and nutrient transporters in NK cells, leading to a metabolic switch toward aerobic glycolysis. Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice. Accordingly, our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation, glycolysis, and effector function.

Influencing Factors of Future Specialty Choice for Undergraduate Medical Students: An Updated Experience from the UAE.

Background Medical students' career choices determine the prospects of the future medical workforce, thus influencing the delivery of medical care. This study aims to identify and provide information about factors affecting the selection of future specialties among medical students. Methods A cross-sectional study was conducted on students in both preclerkship and clerkship phases at a single institution in the United Arab Emirates. A self-administered questionnaire included questions about demographic data, most preferred specialties, and influential factors. The influential factors were measured using a Likert scale. Results Surgery and internal medicine were the most desired specialties, respectively. Gender has a significant role in influencing career choice. There was no association between preclerkship and clerkship students' career choices. The most influential factors were seeing good treatment outcomes and having abilities for the specialty. Conclusions Surgery and internal medicine were the most preferred specialties, even though significant gender differences existed in specialty choices among these students.

Anticancer role of mango (Mangifera indica L.) peel and seed kernel extracts against 7,12- dimethylbenz[a]anthracene-induced mammary carcinogenesis in female rats.

Breast cancer is the second leading cause of cancer death among women. The present study is an effort to reveal the antiproliferative and antioxidant actions of mango seed kernel extract (KE), peel extract (PE), and their combination (KEPE) on mammary tumors induced by 7,12 dimethylbenz[a]anthracene (DMBA). Seven groups of adult female Sprague-Dawley rats were prepared, including C: (control), DMBA: (rats were administered with DMBA), (DMBA-KE), (DMBA-PE), and (DMBA-KEPE): rats were administered with DMBA and then treated with KE, PE, and (both KE and PE), respectively, (KE) and (PE): rats were administered with KE and PE, separately. The study focused on the assessment of markers of endocrine derangement [serum 17-ß estradiol (E2)], apoptosis [caspase-3 and deoxyribonucleic acid fragmentation (DNAF)], and oxidative stress [lipid peroxidation and antioxidants (glutathione, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, and superoxide dismutase)]. Histopathological examination and immunohistochemical expression of caspase-3 and estrogen receptor-α (ER-α) in mammary gland tissues (MGTs) were determined, as well as the characterization of mango extracts. The results showed that DMBA administration induced mammary tumors by increasing cell proliferation and evading apoptosis. In addition, DMBA administration caused oxidative stress by the production of reactive oxygen species, which increased lipid peroxidation and decreased cellular antioxidants, allowing cancer to progress. In contrast, treatment with DMBA-KE, DMBA-PE, or DMBA-KEPE diminished mammary tumors induced by DMBA, where they reduced oxidative stress via increased antioxidant parameters including reduced glutathione, superoxide dismutase, total glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Also, different treatments decreased proliferation through the reduction of E2, and ER-α expression levels. However, these treatments increased the apoptosis of unwanted cells as they increased caspase-3 activity and DNAF. All these changes led to the prevention of breast injuries and the reduction of mammary tumors. This demonstrates that the contents of mango extracts, especially phenolics and flavonoids, have an important role in mammary tumor treatment through their potential antioxidant, antiproliferative, proapoptotic, and anti-estrogenic effects. KE and PE administration for 4 weeks had no adverse effects. Conclusion: Each of KE, PE, and KEPE has a therapeutic effect against DMBA-induced mammary tumors via induction of apoptosis and reduction of each of the OS, proliferation, and estrogenic effects. So, they can play an important role in the pharmacological tole.

Predicting left/right lung volumes, thoracic cavity volume, and heart volume from subject demographics to improve lung transplant.

Purpose: Lung transplantation is the standard treatment for end-stage lung diseases. A crucial factor affecting its success is size matching between the donor's lungs and the recipient's thorax. Computed tomography (CT) scans can accurately determine recipient's lung size, but donor's lung size is often unknown due to the absence of medical images. We aim to predict donor's right/left/total lung volume, thoracic cavity, and heart volume from only subject demographics to improve the accuracy of size matching. Approach: A cohort of 4610 subjects with chest CT scans and basic demographics (i.e., age, gender, race, smoking status, smoking history, weight, and height) was used in this study. The right and left lungs, thoracic cavity, and heart depicted on chest CT scans were automatically segmented using U-Net, and their volumes were computed. Eight machine learning models [i.e., random forest, multivariate linear regression, support vector machine, extreme gradient boosting (XGBoost), multilayer perceptron (MLP), decision tree, k -nearest neighbors, and Bayesian regression) were developed and used to predict the volume measures from subject demographics. The 10-fold cross-validation method was used to evaluate the performances of the prediction models. R -squared ( R 2 ), mean absolute error (MAE), and mean absolute percentage error (MAPE) were used as performance metrics. Results: The MLP model demonstrated the best performance for predicting the thoracic cavity volume ( R 2 : 0.628, MAE: 0.736 L, MAPE: 10.9%), right lung volume ( R 2 : 0.501, MAE: 0.383 L, MAPE: 13.9%), and left lung volume ( R 2 : 0.507, MAE: 0.365 L, MAPE: 15.2%), and the XGBoost model demonstrated the best performance for predicting the total lung volume ( R 2 : 0.514, MAE: 0.728 L, MAPE: 14.0%) and heart volume ( R 2 : 0.430, MAE: 0.075 L, MAPE: 13.9%). Conclusions: Our results demonstrate the feasibility of predicting lung, heart, and thoracic cavity volumes from subject demographics with superior performance compared with available studies in predicting lung volumes.

The influence of self-inflating soft tissue expander on the outcomes of horizontal alveolar ridge augmentation: A randomized controlled clinical and histological study.

OBJECTIVE: The present study was conducted to evaluate the effect of soft tissue augmentation using a self-inflating soft tissue expander when performed before horizontal alveolar ridge augmentation on the outcomes of the bone augmentation procedure. The primary outcome is the bucco-palatal radiographical changes in alveolar ridge width, while the secondary outcome is the quality of the augmented bone assessed histomorphometrically. MATERIALS AND METHODS: Sixteen patients underwent horizontal alveolar ridge augmentation using autogenous bone. For the test group, soft tissue expanders were used in a separate surgery before bone grafting surgery. For the control group, patients received treatment including single surgery of bone grafting associated with periosteal releasing incision. Implants were placed in both groups 6 months after bone augmentation. Bucco-palatal changes in alveolar ridge width were evaluated via cone-beam computed tomography. Augmented bone quality was assessed histomorphometrically. RESULTS: After 6 months, regarding radiographic bone width, there was no statistically significant difference between the two groups, as mean bone width in group I and group II were 8.57 mm and 8.75 mm, respectively. Regarding histomorphometric analysis, Group I showed significantly higher mean bone surface area fraction, higher median mature collagen area fraction, and higher median blood vessel count than Group II (p-value = .012), (p-value = .004), and (p-value = .014), respectively. CONCLUSION: Within the limitations of the present study, soft tissue expander has no influence on bone width gain after horizontal alveolar ridge augmentation with an autogenous bone block but may have a positive effect on the quality of augmented bone.

Toxicity and efficacy of CAR T-cell therapy in primary and secondary CNS lymphoma: a meta-analysis of 128 patients.

Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Anti-CD19 chimeric antigen receptor (CAR) T cells, effective in systemic large B-cell lymphoma (LBCL), have shown responses in PCNSL and SCNSL in early reports, but with limited sample size. We, therefore, performed a comprehensive systematic review and meta-analysis of all published data describing CAR T-cell use in PCNSL and SCNSL. This identified 128 patients with PCNSL (30) and SCNSL (98). Our primary objectives were to evaluate CAR T-cell specific toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS]) as well as response rates in these 2 populations. Seventy percent of patients with PCNSL had CRS of any grade (13% grade 3-4) and 53% had ICANS of any grade (18% grade 3-4). Comparatively, 72% of the SCNSL cohort experienced CRS of any grade (11% grade 3-4) and 48% had ICANS of any grade (26% grade 3-4). Of the patients with PCNSL, 56% achieved a complete remission (CR) with 37% remaining in remission at 6 months. Similarly, 47% of patients with SCNSL had a CR, with 37% in remission at 6 months. In a large meta-analysis of central nervous system (CNS) lymphomas, toxicity of anti-CD19-CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.

Phycosynthesis of Silver Nanoparticles Using Cladophora Glomerata and Evaluation of Their Ability to Inhibit the Proliferation of MCF-7 and L20B Cell Lines.

BACKGROUND: Nanotechnology is receiving greater attention these days as a result of its applications in numerous industrial, medical, and environmental fields. OBJECTIVE: To synthesize silver nanoparticles with a green alga, Cladophora glomerata, and determine their inhibitory activity against tumor cell (MCF-7) and transgenic mouse cell (L20B) lines. MATERIALS AND METHODS: Methanol extract was prepared from Cladophora glomerata and used as a safe factory for the synthesis of silver nanoparticles (AgNPs). UV-visible spectrophotometer, X-ray diffraction, scanning electron microscopy, and EDX analyses were used to characterize the biosynthesized AgNPs. The anti-tumor activity of the phycosynthesized AgNPs was tested against the MCF-7 and L20B cell lines. Furthermore, the bioactive compounds in the algal extract were determined by gas chromatography-mass spectroscopy (GC-MS). RESULTS: The phycosynthesis produced clusters of spherical and polydispersed cuboidal pure AgNPs with an average size of 32 nm. The phycosynthesized AgNPs possess anti-cancer and anti-tumor activities on the MCF-7 and L20B cell lines, with significant anti-proliferation percentages of 52.8 and 65.8%, respectively, after 48 hours of treatment with 100 µg/ml AgNPs. Both treated cell lines showed a significant change in cellular shape and tissue detachment. The GC-MS analysis revealed the presence of a high proportion of octadecanoic acid (47.59%) and hexadecanoic acid (14.97%). CONCLUSION: Cladophora glomerata contains chemicals that improve the stabilization and reduction properties of the nanoparticles. It can be used as a safe, local, and natural source for the synthesis of AgNPs and can also be used as a benign factory for many other metal nanoparticles. The phycosynthesized AgNPs have anti-cancer and anti-tumor activities on the test cell lines and provide an insight into the potential for using them as a trend in cancer nanotherapy.
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An experimental vignette study to assess stigmatized attitudes towards tobacco smokers in Kuwait.

INTRODUCTION: Smoking is the most common method to consume tobacco. Although the prevalence of smoking is on the increase among females, it is still shown to be lower when compared with males, as there is a buildup of stigma towards tobacco smokers, with structural discrimination beginning to emerge. This study explored the effect of gender on stigmatizing attitude and behavior towards tobacco smokers. METHODS: An experimental vignette study design was used to explore the effect of gender on stigmatizing attitudes towards tobacco smokers of 151 students of both genders from Kuwait University. Students were divided into control and experimental groups and were provided with describing vignettes of male (control) and female (experimental) tobacco smokers along with the standard stigmatization questionnaire 1 (SSQ1). Data were analyzed using independent samples t-test, a p-value <0.05 was considered as statistically significant. RESULTS: Female smokers were more stigmatized than male smokers (p=0.007). In social self-interest, more students think that it is socially acceptable for men to smoke than it is for women (p<0.001). In evolutionary self-interest, there was a significant difference between the participants in accepting to marry or to have a relative who is a smoker (p<0.001), indicating disapproval for female smokers. In psychological self-interest, female tobacco smokers were not considered as good parents compared to male tobacco smokers (p=0.003). CONCLUSIONS: The findings of the study indicate the presence of stigmatizing attitudes towards female tobacco smokers in contrast to male tobacco smokers.

Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes.

Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.

Benzimidazole-based protein kinase inhibitors: Current perspectives in targeted cancer therapy.

Targeted therapy has emerged to be the cornerstone of advanced cancer treatment, allowing for more selectivity and avoiding the common drug toxicity and resistance. Identification of potential targets having vital role in growth and survival of cancer cells got much easier with the aid of the recent advances in high throughput screening approaches. Various protein kinases came into focus as valuable targets in cancer therapy. Meanwhile, benzimidazole-based scaffolds have gained significant attention as promising protein kinase inhibitors with high potency and varied selectivity. Great diversity of these scaffolds has inspired the medicinal chemists to inspect the effect of structural changes upon inhibitory activity on the molecular level through modeling studies. The present review gathers all the considerable attempts to develop benzimidazole-based compounds; designed as protein kinase inhibitors with anticancer activity since 2015; that target aurora kinase, CDK, CK2, EGFR, FGFR, and VEGFR-2; to allow further development and progression regarding benzimidazoles.