Graphene acid quantum dots: A highly active multifunctional carbon nano material that intervene in the trajectory towards neurodegeneration.

Carbon dots (CDs) are carbon nano materials (CNMs) that find use across several biological applications because of their water solubility, biocompatible nature, eco-friendliness, and ease of synthesis. Additionally, their physiochemical properties can be chemically tuned for further optimization towards specific applications. Here, we investigate the efficacy of C70-derived Graphene Acid Quantum Dots (GAQDs) in mitigating the transformation of soluble, monomeric Hen Egg-White Lysozyme (HEWL) to mature fibrils during its amyloidogenic trajectory. Our findings reveal that GAQDs exhibit dose-dependent inhibition of HEWL fibril formation (up to 70 % at 5 mg/mL) without affecting mitochondrial membrane potential or inducing apoptosis at the same density. Furthermore, GAQDs scavenged reactive oxygen species (ROS); achieving a 50 % reduction in ROS levels at a mere 100 µg/mL when exposed to a standard free radical generator. GAQDs were not only found to be biocompatible with a human neuroblastoma-derived SHSY-5Y cell line but also rescued the cells from rotenone-induced apoptosis. The GAQD-tolerance of SHSY-5Y cells coupled with their ability to restitute cells from rotenone-dependent apoptosis, when taken in conjunction with the biocompatibility data, indicate that GAQDs possess neuroprotective potential. The data position this class of CNMs as promising candidates for resolving aberrant cellular outputs that associate with the advent and progress of multifactorial neurodegenerative disorders including Parkinson's (PD) and Alzheimer's diseases (AD) wherein environmental causes are implicated (95 % etiology). The data suggest that GAQDs are a multifunctional carbon-based sustainable nano-platform at the intersection of nanotechnology and neuroprotection for advancing green chemistry-derived, sustainable healthcare solutions.

Thiophene derivative inflicts cytotoxicity via an intrinsic apoptotic pathway on human acute lymphoblastic leukemia cells.

In an effort to identify novel anti-cancer agents, we employed a well-established High Throughput Screening (HTS) assay to assess the cytotoxic effect of compounds within the ChemBridge DIVERSet Library on a lymphoma cell line. This screen revealed a novel thiophene, F8 (methyl 5-[(dimethylamino)carbonyl]-4-methyl-2-[(3-phenyl-2-propynoyl) amino]-3-thiophenecarboxylate), that displays anti-cancer activity on lymphoma, leukemia, and other cancer cell lines. Thiophenes and thiophene derivatives have emerged as an important class of heterocyclic compounds that have displayed favorable drug characteristics. They have been previously reported to exhibit a broad spectrum of properties and varied uses in the field of medicine. In addition, they have proven to be effective drugs in various disease scenarios. They contain anti-inflammatory, anti-anxiety, anti-psychotic, anti-microbial, anti-fungal, estrogen receptor modulating, anti-mitotic, kinase inhibiting and anti-cancer activities, rendering compounds with a thiophene a subject of significant interest in the scientific community. Compound F8 consistently induced cell death at a low micromolar range on a small panel of cancer cell lines after a 48 h period. Further investigation revealed that F8 induced phosphatidylserine externalization, reactive oxygen species generation, mitochondrial depolarization, kinase inhibition, and induces apoptosis. These findings demonstrate that F8 has promising anti-cancer activity.

Current status of geriatric dentistry education in selected dental schools in Latin America and the Caribbean.

OBJECTIVE: Latin American and Carribean (LAC) are currently experiencing a rapid aging of their population, coupled with a significant burden of oral diseases. Despites this, there is a scarcity of evidence regarding the manner in wich geriatric dentistry is being taught in dental schools across LAC. So, the objective of this study is to investigate the current status of geriatric dentistry education at undergraduate and postgraduate levels in selected LAC dental schools. METHODS: An electronic questionnaire was developed and emailed to all 539 dental schools in 19 LAC countries. The questionnaire recorded activity levels, contents and methodology of geriatric dentistry education as part of dental degree programmes. Reminders by email and telephone calls were used to encourage non-responders to complete the questionnaire. RESULTS: In total, 317 schools from 17 countries responded to the questionnaire (response rate: 58.8%). Geriatric dentistry was taught in 54.6% of the schools at the undergraduate level and in 6.9% at the postgraduate level. Thirty two percent of the schools had a programme director trained in geriatric dentistry. Geriatric dentistry was taught as an independent course in 14.5% of the schools. Dry mouth, periodontal disease, denture-related conditions and prosthodontic management, oral mucosal disease and age-related changes of the orofacial complex were the most frequently covered topics. Clinical teaching of geriatric dentistry was reported by 26.5% of the schools, with 38.0% providing clinical training in outreach facilities. CONCLUSIONS: Geriatric dentistry education remains incipient in LAC, with only one in every four dental school offering it as a standalone course. There is an urgent need to further develop geriatric dentistry education in the continent, including further research to develop a minimum geriatric dentistry curriculum.

Dose Effects of Flubendiamide and Thiodicarb against Spodoptera Species Developing on Bt and Non-Bt Soybean.

An increase in Spodoptera species was reported in Bt soybean fields expressing Cry1Ac insecticidal proteins in Brazil, requiring additional management with chemical insecticides. Here, we evaluated the dose effects of flubendiamide and thiodicarb on Spodoptera cosmioides (Walker, 1858), Spodoptera eridania (Stoll, 1782), Spodoptera albula (Walker, 1857) and Spodoptera frugiperda (J. E. Smith, 1797) (Lepidoptera: Noctuidae) that survived on MON 87751 × MON 87708 × MON 87701 × MON 89788, expressing Cry1A.105, Cry2Ab2 and Cry1Ac; MON 87701 × MON 89788 soybean, expressing Cry1Ac; and non-Bt soybean. On unsprayed Cry1A.105/Cry2Ab2/Cry1Ac soybean, only S. frugiperda showed ~60% mortality after 10 d, whereas S. cosmioides, S. eridania and S. albula showed >81% mortality. The surviving larvae of all species on this Bt soybean showed >80% mortality when exposed to the field label dose of flubendiamide (70 mL/ha) or thiodicarb (400 g/ha) or at 50% of these doses. In contrast, all four species had <25% and <19% mortality on Cry1Ac and non-Bt soybean, respectively. The surviving S. cosmioides, S. eridania and S. albula on these soybean types presented >83% mortality after exposure to both dose levels of flubendiamide and thiodicarb. Some S. frugiperda larvae surviving on Cry1Ac and non-Bt soybean sprayed with a 50% dose of either insecticide developed into adults. However, the L1 larvae developing on Cry1Ac soybean leaves sprayed with flubendiamide and the L2 larvae on this soybean sprayed with thiodicarb had a prolonged immature stage, and the females displayed lower fecundity, which are likely to impact S. frugiperda population growth on soybean.

A photothermal driven chemotherapy for the treatment of metastatic melanoma.

Solid tumors are abnormal mass of tissue, which affects the organs based on its malignancy and leads to the dysfunction of the affected organs. The major problem associated with treatment of solid tumors is delivering anticancer therapeutics to the deepest layers/core of the solid tumor. Deposition of excessive extracellular matrix (ECM) hinders the therapeutics to travel towards the core of the tumor. Therefore, conventional anticancer therapeutics can only reduce the tumor size and that also for a limited duration, and tumor recurrence occurs once the therapy is discontinued. Additionally, by the time the cancer is diagnosed, the cancer cells already started affecting the major organs of the body such as lung, liver, spleen, kidney, and brain, due to their ability to metastasize and lung is the primary site for them to be infiltrated. To facilitate the anticancer therapeutics to penetrate the deeper layers of tumor, and to provide concurrent treatment of both the solid tumor and metastasis, we have designed and developed a Bimodal Light Assisted Skin Tumor and Metastasis Treatment (BLAST), which is a combination of photothermal and chemotherapeutic moieties. The BLAST is composed of 2D boron nitride (BN) nanosheet with adsorbed molecules of BCL-2 inhibitor, Navitoclax (NAVI) on its surface, that can breakdown excessive ECM network and thereby facilitate dissociation of the solid tumor. The developed BLAST was evaluated for its ability to penetrate solid tumors using 3D spheroids for the uptake, cytotoxicity, growth inhibition, reactive oxygen species (ROS) detection, penetration, and downregulation of proteins upon laser irradiation. The in vivo therapeutic studies on a skin cancer mice model revealed that the BLAST with and without laser were able to penetrate the solid tumor, reduce tumor volume in mice, dissociate the protein network, and prevent lung metastasis as confirmed by immunohistochemistry and western blot analysis. Post analysis of serum and blood components revealed the safety and efficacy of BLAST in mice. Hence, the developed BLAST holds strong promise in solid tumor treatment and metastasis prevention simultaneously.

Synthesis of Novel Pyrazole-Oxindole Conjugates with Cytotoxicity in Human Cancer Cells via Apoptosis.

A novel series of pyrazole-oxindole conjugates were prepared and characterized as potential cytotoxic agents by FT-IR, NMR and HR-MS. The cytotoxic activity of these compounds was tested in the Jurkat acute T cell leukemia, CEM acute lymphoblastic leukemia, MCF10 A mammary epithelial and MDA-MB 231 triple negative breast cancer cell lines. Among the tested conjugates, 5-methyl-3-((3-(1-phenyl)-3-(p-tolyl)-1H-pyrazol-4-yl)methylene)indolin-2-one 6h emerged as the most cytotoxic with a CC50 of 4.36+/-0.2 µM against Jurkat cells. The mechanism of cell death induced by 6h was investigated through the Annexin V-FITC assay via flow cytometry. Reactive oxygen species (ROS) accumulation, mitochondrial health and the cell cycle progression were also evaluated in cells exposed to 6h. Results demonstrated that 6h induces apoptosis in a dose-response manner, without generating ROS and/or altering mitochondrial health. In addition, 6h disrupted the cell cycle distribution causing an increase in DNA fragmentation (Sub G0-G1), and an arrest in the G0-G1 phase. Taken together, the 6h compound revealed a strong potential as an antineoplastic agent evidenced by its cytotoxicity in leukemia cells, the activation of apoptosis and restriction of the cell cycle progression.

Mechanistic investigation of liver injury induced by BMS-932481, an experimental ɣ-secretase modulator.

BMS-932481 was designed to modulate ɣ-secretase activity to produce shorter and less amyloidogenic peptides, potentially averting liabilities associated with complete enzymatic inhibition. Although it demonstrated the intended pharmacology in the clinic, BMS-932481 unexpectedly caused drug-induced liver injury (DILI) in a multiple ascending dose study characterized by dose- and exposure-dependence, delayed onset manifestation, and a high incidence of hepatocellular damage. Retrospective studies investigating the disposition and probable mechanisms of toxicity of BMS-932481 are presented here. These included a mass balance study in bile-duct-cannulated rats and a metabolite profiling study in human hepatocytes, which together demonstrated oxidative metabolism followed by biliary elimination as the primary means of disposition. Additionally, minimal protein covalent binding in hepatocytes and lack of bioactivation products excluded reactive metabolite formation as a probable toxicological mechanism. However, BMS-932481 and 3 major oxidative metabolites were found to inhibit the bile salt export pump (BSEP) and multidrug resistance protein 4 (MRP4) in vitro. Considering human plasma concentrations, the IC50 values against these efflux transporters were clinically meaningful, particularly in the high dose cohort. Active uptake into human hepatocytes in vitro suggested the potential for hepatic levels of BMS-932481 to be elevated further above plasma concentrations, enhancing DILI risk. Conversely, measures of mitochondrial functional decline in hepatocytes treated with BMS-932481 were minimal or modest, suggesting limited contributions to DILI. Collectively, these findings suggested that repeat administration of BMS-932481 likely resulted in high hepatic concentrations of BMS-932481 and its metabolites, which disrupted bile acid transport via BSEP and MRP4, elevating serum biomarkers of liver injury.

Topical Administration of an Apoptosis Inducer Mitigates Bleomycin-Induced Skin Fibrosis.

Pathological fibrosis is distinguished from physiological wound healing by persistent myofibroblast activation, suggesting that therapies that induce myofibroblast apoptosis selectively could prevent progression and potentially reverse the established fibrosis, such as for scleroderma (a heterogeneous autoimmune disease characterized by multiorgan fibrosis). Navitoclax (NAVI) is a BCL-2/BCL-xL inhibitor with antifibrotic properties and has been investigated as a potential therapeutic for fibrosis. NAVI makes myofibroblasts particularly vulnerable to apoptosis. However, despite NAVI's significant potency, clinical translation of BCL-2 inhibitors, NAVI in this case, is hindered due to the risk of thrombocytopenia. Therefore, in this work, we utilized a newly developed ionic liquid formulation of NAVI for direct topical application to the skin, thereby avoiding systemic circulation and off-target-mediated side effects. The ionic liquid composed of choline and octanoic acid (COA) at a 1:2 molar ionic ratio increases skin diffusion and transportation of NAVI and maintains their retention within the dermis for a prolonged duration. Topical administration of NAVI-mediated BCL-xL and BCL-2 inhibition results in the transition of myofibroblast to fibroblast and ameliorates pre-existing fibrosis, as demonstrated in a scleroderma mouse model. We have observed a significant reduction of α-SMA and collagen, which are known as fibrosis marker proteins, as a result of the inhibition of anti-apoptotic proteins BCL-2/BCL-xL. Overall, our findings show that COA-assisted topical delivery of NAVI upregulates apoptosis specific to myofibroblasts, with minimal presence of the drug in the systemic circulation, resulting in an accelerated therapeutic effect with no discernible drug-associated toxicity.

Translation, cross-cultural adaptation and measurement properties of three implementation measures into Brazilian-Portuguese.

BACKGROUND: To translate and cross-culturally adapt into Brazilian-Portuguese, and to test the measurement properties of the following items of implementation outcome measures: Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). METHODS: This was a measurement properties study in accordance with the Consensus-based Standards for the selection of health status Measurement Instruments (COSMIN). We conducted a translation and cross-cultural adaptation of three implementation measures according to guidelines for translation and cross-cultural adaptation, then we collected information from patients who had participated in remotely delivered physical therapy treatment for musculoskeletal condition. The patients answered the translated versions of the implementation outcome measures. The measurement properties of the three implementation outcome measures were collected in a test-retest assessment, with an interval of 7 to 14 days.. The measurement properties evaluated in this study were interpretability, measured using Ceiling and Floor Effects, reliability in test-retest evaluation, measured using Cronbach's Alpha Coefficient, internal consistency, measured using Intraclass Correlation Coefficient and construct validity, measured using Pearson Correlation. RESULTS: We included 104 participants (76 female). The average age of the sample was 56.8 (SD 14.8) years old. The items of implementation outcome measures (AIM, IAM, and FIM) showed 66.39%, 63.11%, and 63.93% of ceiling effects. The items of implementation outcome measures showed adequate internal consistency measured using Cronbach's Alpha Coefficient (AIM: 0.89, IAM: 0.91, FIM: 0.93) and values of Standard Error of Measurement between 5 and 10%, showing good measurement error. The results of AIM and IAM was classified as moderate reliability and the FIM as substantial reliability. In a total 96 correlations, > 75% of correlations met our prior hypothesis. CONCLUSION: The three Brazilian-Portuguese versions of items of implementation outcome measures had adequate internal consistency, measurement error and construct validity. The three implementation outcome measures showed moderate to substantial reliability values. The Ceiling Effect was observed in the three measures, showing maximum values ​​in more than 15% of the evaluations.

Extracranial Jugular Foramen Schwannomas Treated with the Extreme Lateral Juxtacondylar Approach: Surgical Technique and Our Experience.

BACKGROUND: Schwannoma that arises in the jugular foramen (JF) represents an important challenge for neurosurgeons for its precise location, extension, and neurovascular relationship. Nowadays, different managements are proposed. In this study, we present our experience in the treatment of extracranial JF schwannomas (JFss) with the extreme lateral juxtacondylar approach (ELJA). OBJECTIVE: To present our experience in the treatment of extracranial JF schwannomas (JFss) with the ELJA. METHODS: Between January 2013 and January 2017, 12 patients with extracranial JFs underwent surgery by ELJA. All lesions were type C of the Samii classification. Indocyanine green videoangiography was used to evaluate the relationship between the internal jugular vein and the tumor and to control the presence of spasm in the vertebral artery. RESULTS: A complete exeresis was achieved in 9 patients while in 3 patients, it was subtotal. The complete regression of symptoms was obtained in 7 patients with a total resection. The remaining cases experienced a persistence of symptoms. CONCLUSION: The success of this surgery is achieved through a management that starts from the patient's position. We promote an accurate evaluation of JFs through the Samii classification: Type C tumors allow the use of ELJA that reduces surgical complications. Furthermore, we recommend the use of indocyanine green videoangiography to preserve the vessels and prevent vasospasm.

Characterizing the lethal and sub-lethal effects of genetically modified soybean expressing Cry1A.105, Cry2Ab2, and Cry1Ac insecticidal proteins against Spodoptera species (Lepidoptera: Noctuidae) in Brazil.

BACKGROUND: MON 87701 × MON 89788 × MON 87751 × MON 87708 soybean, that expresses Cry1A.105, Cry2Ab2, and Cry1Ac insecticidal proteins and confers tolerance to glyphosate and dicamba, is a potential tool for managing Spodoptera species in soybean fields in Brazil. In this study, we characterized the lethal and sub-lethal effects of Cry1A.105/Cry2Ab2/Cry1Ac soybean against Spodoptera species and genotypes of Spodoptera frugiperda resistant and susceptible to Cry1 and Cry2 proteins. These evaluations were also conducted with MON 87701 × MON 89788 soybean, which expresses Cry1Ac protein. RESULTS: Cry1A.105/Cry2Ab2/Cry1Ac soybean caused high lethality in neonates of Spodoptera cosmioides and Spodoptera albula. However, it showed low lethality in S. frugiperda genotypes homozygous for resistance to Cry1 and Cry2 proteins but reduced their population growth potential. No relevant lethal effects of Cry1Ac soybean were detected in the Spodoptera species and genotypes evaluated. Spodoptera frugiperda genotypes heterozygous for Cry1 and Cry2 resistance were controlled by Cry1A.105/Cry2Ab2/Cry1Ac soybean, with no insects developing into adults. This Bt soybean also caused intermediate mortality of neonates of Spodoptera eridania (60%-83%) but no surviving larvae developed to adulthood, resulting in population suppression. CONCLUSIONS: Cry1A.105/Cry2Ab2/Cry1Ac soybean caused high mortality of S. cosmioides, S. albula, and S. frugiperda genotypes susceptible to Cry1 and Cry2 and heterozygous for Cry1 and Cry2 resistance. This Bt soybean also suppressed population growth of S. eridania but had minimal impact on S. frugiperda homozygous for resistance to Cry1 and Cry2 proteins. Cry1Ac soybean had minimal impact on all Spodoptera species and genotypes evaluated. © 2022 Society of Chemical Industry.

Research Infrastructure Core Facilities at Research Centers in Minority Institutions: Part I-Research Resources Management, Operation, and Best Practices.

Funded by the National Institutes of Health (NIH), the Research Centers in Minority Institutions (RCMI) Program fosters the development and implementation of innovative research aimed at improving minority health and reducing or eliminating health disparities. Currently, there are 21 RCMI Specialized (U54) Centers that share the same framework, comprising four required core components, namely the Administrative, Research Infrastructure, Investigator Development, and Community Engagement Cores. The Research Infrastructure Core (RIC) is fundamentally important for biomedical and health disparities research as a critical function domain. This paper aims to assess the research resources and services provided and evaluate the best practices in research resources management and networking across the RCMI Consortium. We conducted a REDCap-based survey and collected responses from 57 RIC Directors and Co-Directors from 98 core leaders. Our findings indicated that the RIC facilities across the 21 RCMI Centers provide access to major research equipment and are managed by experienced faculty and staff who provide expert consultative and technical services. However, several impediments to RIC facilities operation and management have been identified, and these are currently being addressed through implementation of cost-effective strategies and best practices of laboratory management and operation.

Physical therapists and public perceptions of telerehabilitation: An online open survey on acceptability, preferences, and needs.

BACKGROUND: During the COVID-19 pandemic, telerehabilitation allowed the continuation of physical therapy care in parallel with public health measures to prevent the virus spread. However, in low- and middle-income countries including Brazil, telerehabilitation was unfamiliar to most of the population. OBJECTIVE: To investigate acceptability, preferences, and needs in telerehabilitation by Brazilian physical therapists and the general population. METHODS: We conducted an observational cross-sectional study with an online survey consisting of 13 multiple-choice items. Items were distributed among acceptability, preferences, and needs sections, and encompassed confidence in delivering or receiving telerehabilitation, its perceived efficacy and costs, and suitable content. RESULTS: A total of 1107 responses were registered, 717 from physical therapists. Half of them self-reported confidence in conducting telerehabilitation through the internet (synchronous or asynchronous). The same proportion disagreed that telerehabilitation is as effective as in-person interventions. Physical therapists agreed telerehabilitation should contain educational, self-management strategies, and exercises information, but the general population endorsed the provision of technical advice on exercise execution. The general population mostly reported that telerehabilitation could help their specific health condition (86%), but only 14% of respondents would pay the same as they pay for in-person consultations. Participants reported an overall preference for synchronous communication and concern about the lack of a hands-on approach. CONCLUSION: Physical therapists and the general population appear to demonstrate apprehension towards telerehabilitation. Insufficient preparation or inadequate knowledge might influence participants' acceptance, preferences, and needs.

A virus changed my life.

The E. E. Just Award commemorates the great African-American cell biologist Dr. Ernest Everett Just, who was a successful pioneer in an era of systemic exclusion of minorities in science and academia. Receiving this award is not only an honor but a recognition of my long-standing commitment to helping Persons Excluded due to Ethnicity or Race (PEERS) to achieve success in biomedical careers. As a proud member of this group, I have devoted most of my career to training underrepresented undergraduate and graduate students to pursue scientific careers. My early work as a molecular immunologist focused on the search for enzymes involved in antigen-receptor gene recombination, as well as the characterization of nuclear factors involved in recombination and the transcriptional regulation of the murine recombination-activating genes. Over the past two decades, my research has focused on discovering and evaluating novel anticancer agents that can be used to treat various cancer types.

Novel Unsymmetric 3,5-Bis(benzylidene)-4-piperidones That Display Tumor-Selective Toxicity.

Two series of novel unsymmetrical 3,5-bis(benzylidene)-4 piperidones 2a-f and 3a-e were designed as candidate antineoplastic agents. These compounds display potent cytotoxicity towards two colon cancers, as well as several oral squamous cell carcinomas. These compounds are less toxic to various non-malignant cells giving rise to large selectivity index (SI) figures. Many of the compounds are also cytotoxic towards CEM lymphoma and HL-60 leukemia cells. Representative compounds induced apoptotic cell death characterized by caspase-3 activation and subG1 accumulation in some OSCC cells, as well as the depolarization of the mitochondrial membrane potential in CEM cells. A further line of inquiry was directed to finding if the SI values are correlated with the atomic charges on the olefinic carbon atoms. The potential of these compounds as antineoplastic agents was enhanced by an ADME (absorption, distribution, metabolism, and excretion) evaluation of five lead molecules, which revealed no violations.

Autoantibody against Tumor-Associated Antigens as Diagnostic Biomarkers in Hispanic Patients with Hepatocellular Carcinoma.

BACKGROUND: Tumor-associated antigens (TAAs) have been investigated for many years as potential early diagnosis tools, especially for hepatocellular carcinoma (HCC). Nonetheless, very few studies have focused on the Hispanic HCC group that may be associated with distinct etiological risk factors. In the present study, we investigated novel anti-TAA autoantibodies as diagnostic biomarkers for Hispanic HCC patients. METHODS: Novel TAA targets were identified by the serological proteome analysis (SERPA) and from differentially expressed HCC driver genes via bioinformatics. The autoantibody levels were validated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among 19 potential TAA targets, 4 anti-TAA autoantibodies were investigated as potential diagnostic biomarkers with significantly high levels in Hispanic HCC sera, including DNA methyltransferase 3A (DNMT3A), p16, Hear shock protein 60 (Hsp60), and Heat shock protein A5 (HSPA5). The area under the ROC curve (AUC) value of the single autoantibodies varies from 0.7505 to 0.8885. After combining all 4 autoantibodies, the sensitivity of the autoantibody panel increased to 75% compared to the single one with the highest value of 45.8%. In a separate analysis of the Asian cohort, autoantibodies against HSPA5 and p16 showed significantly elevated levels in HCC compared to normal healthy controls, but not for DNMT3A or HSP60. CONCLUSION: Anti-DNMT3A, p16, HSPA5, and HSP60 autoantibodies have the potential to be diagnostic biomarkers for Hispanic HCC patients, of which DNMT3A and HSP60 might be exclusive for Hispanic HCC diagnosis.

Two novel piperidones induce apoptosis and antiproliferative effects on human prostate and lymphoma cancer cell lines.

Cancer remains the second most common cause of death in the US. Due to a recurrent problem with anticancer drug resistance, there is a current need for anticancer drugs with distinct modes of action for combination drug therapy We have tested two novel piperidone compounds, named 2608 (1-dichloroacetyl - 3,5-bis(3,4-difluorobenzylidene)-4-piperidone) and 2610 (1-dichloroacetyl-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone), for their potential cytotoxicity on numerous human cancer cell lines. We found that both compounds were cytotoxic for breast, pancreatic, leukemia, lymphoma, colon, and fibroblast cell lines, with a cytotoxic concentration 50% (CC50) in the low micromolar to nanomolar concentration range. Further assays focused primarily on an acute lymphoblastic lymphoma and colon cancer cell lines since they were the most sensitive and resistant to the experimental piperidones. The cell death mechanism was evaluated through assays commonly used to detect the induction of apoptosis. These assays revealed that both 2608 and 2610 induced reactive oxygen species (ROS) accumulation, mitochondrial depolarization, and activated caspase-3/7. Our findings suggest that the piperidones induced cell death via the intrinsic apoptotic pathway. Additional assays revealed that both piperidones cause cell cycle alteration in lymphoma and colon cell lines. Both piperidones elicited DNA fragmentation, as evidenced by an increment in the sub-G0/G1 subpopulation in both cell lines. Similar to other related compounds, both piperidones were found to act as proteasome inhibitors by increasing the levels of poly-ubiquitinated proteins in both lymphoma and colon cell lines. Hence, the two piperidones exhibited attractive cytotoxic properties and suitable mechanisms of action, which makes them good candidates as anticancer drugs.

Ionic liquid-mediated delivery of a BCL-2 inhibitor for topical treatment of skin melanoma.

Skin melanoma is one of the most common cancer types in the United States and worldwide, and its incidence continues to grow. Primary skin melanoma can be removed surgically when feasible and if detected at an early stage. Anti-cancer drugs can be applied topically to treat skin cancer lesions and used as an adjunct to surgery to prevent the recurrence of tumor growth. We developed a topical formulation composed of Navitoclax (NAVI), a BCL-2 inhibitor that results in apoptosis, and an ionic liquid of choline octanoate (COA) to treat early-stage melanoma. NAVI is a small hydrophobic molecule that solubilizes at 20% (w/v) when dissolved in 50% COA. Although NAVI is a highly effective chemotherapeutic, it is equally thrombocytopenic. We found that COA-mediated topical delivery of NAVI enhanced its penetration into the skin and held the drug in the deeper skin layers for an extended period. Topical delivery of NAVI produced a higher cancer-cell killing efficacy than orally administrated NAVI. In vivo experiments in a mouse model of human melanoma-induced skin cancer confirmed the formulation's effectiveness via an apoptotic mechanism without any significant skin irritation or systemic absorption of NAVI. Overall, this topical approach may provide a safe and effective option for better managing skin cancer in the clinic.

Regional pest suppression associated with adoption of Cry1Ac soybean benefits pest management in tropical agriculture.

BACKGROUND: Bacillus thuringiensis (Bt) crops have been adopted worldwide, providing high-level protection from insect pests. Furthermore, Bt crops preserve natural enemies, promote higher yield, and economically benefit farmers. Although regional pest suppression by widespread Bt crop adoption has been observed in temperate regions, this possibility remains uncertain in tropical areas due to the high diversity of alternative hosts and mild winters. RESULTS: Evidence of regional reduction in insecticide use across areas was observed in Brazil where Cry1Ac soybean has been grown since 2013, with up to 50% reduction in the number of insecticide sprays for managing lepidopteran pests on non-Bt soybean observed at specific locations from 2012 to 2019. Pest monitoring data from four mesoregions across 5 years of commercial plantings of Cry1Ac soybean from December 2014 to July 2019 showed reduced numbers of Chrysodeixis includens moths captured in pheromone traps across years at all locations. The number of Helicoverpa spp. moths captured also was reduced at three locations. CONCLUSION: We provide evidence for regional suppression of lepidopteran pests and reduced insecticide use with the widespread adoption of Cry1Ac soybean in Brazil, bringing economic, social and environmental benefits. © 2022 Society of Chemical Industry.

Identification of a Unique Cytotoxic Thieno[2,3-c]Pyrazole Derivative with Potent and Selective Anticancer Effects In Vitro.

In recent years, the thienopyrazole moiety has emerged as a pharmacologically active scaffold with antitumoral and kinase inhibitory activity. In this study, high-throughput screening of 2000 small molecules obtained from the ChemBridge DIVERset library revealed a unique thieno[2,3-c]pyrazole derivative (Tpz-1) with potent and selective cytotoxic effects on cancer cells. Compound Tpz-1 consistently induced cell death at low micromolar concentrations (0.19 µM to 2.99 µM) against a panel of 17 human cancer cell lines after 24 h, 48 h, or 72 h of exposure. Furthermore, an in vitro investigation of Tpz-1's mechanism of action revealed that Tpz-1 interfered with cell cycle progression, reduced phosphorylation of p38, CREB, Akt, and STAT3 kinases, induced hyperphosphorylation of Fgr, Hck, and ERK 1/2 kinases, and disrupted microtubules and mitotic spindle formation. These findings support the continued exploration of Tpz-1 and other thieno[2,3-c]pyrazole-based compounds as potential small-molecule anticancer agents.