ABSTRACT
Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers. Kindlin-2 is highly expressed in many cancers and is particularly prominent in prostate cancer cells. CRISPR/cas9 was used as a primary approach to knockout expression of Kindlin-2 in both androgen-independent and dependent prostate cancer cell lines, and the effects of Kindlin-2 suppression on oncogenic properties of these prostate cancer cell lines was examined. Adhesion to extracellular matrix proteins was markedly blunted, consistent with the control of integrin function by Kindlin-2. Migration across matrices was also affected. Anchorage independent growth was markedly suppressed. These observations indicate that Kindlin-2 regulates hallmark features of prostate cancer cells. In androgen expressing cells, testosterone-stimulated adhesion was Kindlin-2-dependent. Furthermore, tumor growth of a prostate cancer cell line lacking Kindlin-2 and implanted into the prostate gland of immunocompromised mice was markedly blunted and was associated with suppression of angiogenesis in the developing tumor. These results establish a key role of Kindlin-2 in prostate cancer progression and suggest that Kindlin-2 represents an interesting therapeutic target for treatment of prostate cancer.
Subject(s)
Cell Adhesion , Membrane Proteins , Neoplasm Proteins , Prostatic Neoplasms , Male , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Humans , Animals , Neoplasm Proteins/metabolism , Neoplasm Proteins/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics , Cell Line, Tumor , Mice , Cell Movement , Cell Proliferation , Integrins/metabolismABSTRACT
Functional blockade of the transforming growth factor-beta (TGFß) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFß type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFß levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Multiple Myeloma , Receptor, Transforming Growth Factor-beta Type I , Thalidomide , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Thalidomide/analogs & derivatives , Thalidomide/administration & dosage , Thalidomide/therapeutic use , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Receptor, Transforming Growth Factor-beta Type I/metabolism , Middle Aged , Female , Male , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Transforming Growth Factor beta/metabolism , Neoplasm Recurrence, Local/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Adult , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Aniline Compounds , TriazolesABSTRACT
CONTEXT: The childcare center (CCC) setting has the potential to be a strong foundation that supports the introduction of sustainable healthy lifestyle behaviors to prevent childhood obesity. It is important to assess barriers and facilitators to healthy weight development initiatives via program evaluation, including measuring CCC staff readiness to change. OBJECTIVE: The overall goal of this study was to assess the readiness level over 1 school year among CCC staff who participated in "Healthy Caregivers-Healthy Children" (HC2), a cluster randomized controlled trial that evaluated the effectiveness of a childhood obesity prevention program from 2015 to 2018 in 24 low-income, racially/ethnically diverse centers. A secondary outcome was to assess how a CCC's stage of readiness to change was associated with CCC nutrition and physical activity environment, measured via the Environment and Policy Assessment and Observation (EPAO) tool. DESIGN: Mixed-models analysis with the CCC as the random effect assessed the impact of readiness to change over time on EPAO outcomes. PARTICIPANTS: Eighty-eight CCC teachers and support staff completed the HC2 readiness to change survey in August 2015 and 68 in August 2016. Only teachers and staff randomized to the treatment arm of the trial were included. MAIN OUTCOME: Readiness to change and the EPAO. RESULTS: Results showed the majority of CCC staff in advanced stages of readiness to change at both time points. For every increase in readiness to change stage over 1 year (eg, precontemplation to contemplation), there was a 0.28 increase in EPAO nutrition scores (95% confidence interval [CI], 0.04-0.53; P = .02) and a 0.52 increase in PA score (95% CI, 0.09-0.95; P = .02). CONCLUSIONS: This analysis highlights the importance between CCC staff readiness to change and the CCC environment to support healthy weight development. Future similar efforts can include consistent support for CCC staff who may not be ready for change to support successful outcomes.
Subject(s)
Child Day Care Centers , Pediatric Obesity , Humans , Pediatric Obesity/prevention & control , Child Day Care Centers/standards , Child Day Care Centers/statistics & numerical data , Female , Male , Child, Preschool , Program Evaluation/methods , Adult , Surveys and Questionnaires , Health Promotion/methods , Health Promotion/standards , Child , Middle AgedABSTRACT
AIM: The current study was carried out to assess the interaction between fibrin clots and dental implants following various surface treatments. MATERIALS AND METHODS: In this investigation, 45 dental implants with dimensions of 16 mm in length and 5 mm in diameter were utilized. They were divided up into three groups, each consisting of fifteen samples. Group I: Control; Group II: Ultraviolet (UV) light treated; and group III: Sandblasted and acid-etching (SLA) treated. Healthy volunteers' venous blood samples were drawn into vacutainer tubes without the use of anticoagulants. The samples were centrifuged for 3 minutes at 2700 rpm in a table centrifuge. The entire implant was submerged in room-temperature liquid fibrinogen for 60 minutes. Then, scanning electronic microscopy (SEM) was used to examine each sample. The inter- and intragroup assessments were obtained using the Mann-Whitney U test and the Kruskal-Wallis test; p-values less than 0.05 were regarded as statistically significant. RESULTS: The maximum adhesion of fibrin clot was found in SLA treated group (2.42 ± 0.10) followed by the UV light-treated group (2.18 ± 0.08) and control group (1.20 ± 0.02). There was a statistically significant difference found between the three surface-treated groups (p < 0.001). CONCLUSION: All surface-treatment methods exhibit adhesion between the implant surface and the fibrin clot. However, the highest adherence of fibrin clot was found in SLA treated group compared to the UV light-treated and control group. CLINICAL SIGNIFICANCE: The physical and chemical characteristics of an implant's surface have a significant impact on the way blood clots organize. At the interface between the implant and the bone, blood clot production can initiate and facilitate the healing process. How to cite this article: Jalaluddin M, Ramanna PK, Swain M, et al. Evaluation of Fibrin Clot Interaction with Dental Implant after Different Surface Treatments: An In Vitro Study. J Contemp Dent Pract 2024;25(3):276-279.
Subject(s)
Dental Implants , Fibrin , Microscopy, Electron, Scanning , Surface Properties , Humans , In Vitro Techniques , Blood Coagulation , Ultraviolet Rays , Acid Etching, DentalABSTRACT
Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However, tumors subvert the antigen presentation machinery to escape immunosurveillance. We hypothesized that proteasome activation could concomitantly increase antigen abundance and diversity in multiple myeloma cells. High-throughput screens revealed that histone deacetylase 6 (HDAC6) inhibitors activated proteasomes to unmask neoantigens and amplify the tumor-specific antigenic landscape. Treatment of patient CD138+ cells with HDAC6 inhibitors significantly promoted the antimyeloma activity of autologous CD8+ T cells. Pharmacologic blockade and genetic ablation of the HDAC6 ubiquitin-binding domain released HR23B, which shuttles ubiquitinylated cargo to proteasomes, while silencing HDAC6 or HR23B in multiple myeloma cells abolished the effect of HDAC6 inhibitors on proteasomes, antigen presentation, and T-cell cytotoxicity. Taken together, our results demonstrate the paradigm-shifting translational impact of proteasome activators to expand the myeloma immunopeptidome and have revealed novel, actionable antigenic targets for T cell-directed immunotherapy. SIGNIFICANCE: The elimination of therapy-resistant tumor cells remains a major challenge in the treatment of multiple myeloma. Our study identifies and functionally validates agents that amplify MHC class I-presented antigens and pave the way for the development of proteasome activators as immune adjuvants to enhance immunotherapeutic responses in patients with multiple myeloma.
Subject(s)
Histone Deacetylase 6 , Histone Deacetylase Inhibitors , Multiple Myeloma , Proteasome Endopeptidase Complex , Humans , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/immunology , Proteasome Endopeptidase Complex/drug effects , Multiple Myeloma/immunology , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Histone Deacetylase Inhibitors/pharmacology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Antigen Presentation/drug effects , Antigens, Neoplasm/immunology , Antigens, Neoplasm/metabolismABSTRACT
Background: Stroke is one of the leading causes of mortality and morbidity worldwide accounting for 85% of global deaths from stroke. This study aimed to evaluate the role of homocysteine (HCY) in modulating various stroke parameters and it's with carotid intima-media thickness (IMT). Methods: 78 patients of radiology-confirmed acute ischemic stroke were recruited for this study and National Institutes of Health Stroke Scale (NIHSS) score was evaluated upon admission. Blood samples were tested for serum HCY, fasting blood glucose (FBG) and lipid profile. Ultrasonography of neck ascertained IMT of Common (CCA) and internal carotid artery (ICA). Results: Average age of male and female subjects was 57.88 ± 13.97 & 59.16 ± 13.62 years respectively. 71.93% of stroke patients were hyperhomocysteinemic (HHcyc) and 24.36% were hyperlipidemic. Patients with NIHSS ≥ 5 had higher low-density lipoprotein cholesterol (LDLC) than those with NIHSS < 5. HCY cutoff of ≥ 15 µmol/L had 91.7% sensitivity & 66.7% specificity for predicting. HHcyc state was associated with increased ICA IMT. HHcyc state was best predicted by ICA IMT with which it is positively correlated (P-Value = 0.012). Conclusion: HHcyc state holds a good predictive value for severity of stroke. We also came to a conclusion that ICA IMT measurement may also reduce the need for a homocysteine test as it predicts higher HCY levels; this will reduce the burden on resources. We suggest that evaluating HCY and ICA IMT should be made part of the standard protocol for management of stroke.
ABSTRACT
The fate and effects of fluoroquinolone antibacterial (FQ) on the environment are important since there appears to be a surge in FQ resistance like enrofloxacin (ENR) in both environmental and clinical organisms. Numerous reports indicate that the sensing capabilities of these antibiotics need to be improved. Here, we have investigated the interaction of ENR with our synthesized pentacenequinone-modulated gadolinium-tin (GdSn-PQ) nanosheets and the formation of intermolecular interactions that caused the occurrence of aggregation-induced emission enhancement. The concept for designing hybrid metallic nanosheets comes from the unique features inherited from the parent organic precursor. Due to the distinct interaction between ENR and GdSn-PQ, the interstate conversion (ISC) between GdSn-PQ and ENR induces a significant wavelength shift in photoluminescence (PL), improving reliability, selectivity, and visibility compared to quenching- or AIEE-based methods without peak shifts, allowing for highly sensitive and visually detectable analyses. The fluorescence signal of GdSn-PQ exhibited a linear relationship (R2 = 0.9911), with the added ENR concentrations ranging from 5 to 90 nM, with a detection limit of 0.10 nM. We have demonstrated its potential and wide use in the detection of ENR in biological samples (human urine and blood serum) and environmental samples (tap water and seawater) with a recovery rate of 98- 108%. The current approach has demonstrated that the 2D GdSn-PQ nanosheet is a novel and powerful platform for future biological and environmental studies.
Subject(s)
Enrofloxacin , Fluorescent Dyes , Enrofloxacin/analysis , Enrofloxacin/blood , Enrofloxacin/urine , Fluorescent Dyes/chemistry , Gadolinium/chemistry , Nanostructures/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/urine , Humans , Limit of Detection , Spectrometry, Fluorescence , Naphthacenes/chemistryABSTRACT
Iron proteins are of great scientific interest due to their importance as an excellent biomarker for human diseases. Ferritin (Fe3+), being an iron-rich blood protein, is related to various diseases like anemia and cancer. For the first time, we have developed a highly sensitive and selective ferritin biosensor based on fluorescent oxygen-deficient zinc oxide nanosheets through hydrothermal and probe-ultrasonication combined methods. The fluorescence study showed an intense bluish-green fluorescence at λex = 370 nm, after optimization at different excitation wavelengths. In addition, the fluorescence of ZnO1-x nanosheets can be efficiently quenched due to electron transfer reactions in order to achieve quantification analysis. The limit of detection (LOD) was calculated to be 0.015 nM (7.2 ng mL-1) with high linearity (R2 = 0.9930). In addition, the real-world application of the proposed biosensor has been performed on human blood serum samples in the presence of various interfering analytes showing high selectivity and sensitivity with a regression value R2 = 0.9980 indicating the current approach is an excellent biosensor platform.
Subject(s)
Biosensing Techniques , Zinc Oxide , Humans , Fluorescent Dyes , Ferritins , Electrons , Biosensing Techniques/methods , IronABSTRACT
BACKGROUND: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30-40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. METHODS: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. RESULTS: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA-approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. CONCLUSION: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm.
Subject(s)
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Humans , NF-kappa B , Lipopolysaccharides/pharmacology , Olopatadine Hydrochloride , Cytokine Release Syndrome , Signal Transduction , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , I-kappa B Proteins , CytokinesABSTRACT
Synthetic cosmetics, particularly hair dyes, are becoming increasingly popular among people of all ages and genders. 2,4,5,6-tetraaminopyrimidine sulfate (TAPS) is a key component of oxidative hair dyes and is used as a developer in several hair dyes. TAPS has previously been shown to absorb UVB strongly and degrade in a time-dependent manner, causing phototoxicity in human skin cells. However, the toxic effects of UVB-degraded TAPS are not explored in comparison to parent TAPS. Therefore, this research work aims to assess the toxicity of UVB-degraded TAPS than TAPS on two different test systems, that is, HaCaT (mammalian cell) and Staphylococcus aureus (a bacterial cell). Our result on HaCaT has illustrated that UVB-degraded TAPS is less toxic than parent TAPS. Additionally, UVB-exposed TAPS and parent TAPS were given to S. aureus, and the bacterial growth and their metabolic activity were assessed via CFU and phenotype microarray. The findings demonstrated that parent TAPS reduced bacterial growth via decreased metabolic activity; however, bacteria easily utilized the degraded TAPS. Thus, this study suggests that the products generated after UVB irradiation of TAPS is considered to be safer than their parent TAPS.
Subject(s)
Hair Dyes , Female , Male , Animals , Humans , Hair Dyes/toxicity , Hair Dyes/metabolism , Sulfates/toxicity , Staphylococcus aureus , Skin , Hair , Ultraviolet Rays/adverse effects , Keratinocytes/metabolism , MammalsABSTRACT
The majority of T-cell responses involve proteasome-dependent protein degradation and the downstream presentation of oligopeptide products complexed with major histocompatibility complex (MHC) class I (MHC-I) molecules to peptide-restricted CD8+ T-cells. However, evasion of host immunity is a cancer hallmark that is achieved by disruption of host antigen processing and presentation machinery (APM). Consequently, mechanisms of immune evasion promote cancer growth and survival as well as de novo and acquired resistance to immunotherapy. A multitude of cell signaling pathways modulate the APM and MHC-I-dependent antigen presentation. Pharmacologics that specifically target and modulate proteasome structure and activity represent a novel emerging strategy to improve the treatment of cancers and other diseases characterized by aberrant protein accumulation. FDA-approved pharmacologics that selectively activate proteasomes and/or immunoproteasomes can be repositioned to overcome the current bottlenecks that hinder drug development to enhance antigen presentation, modulate the immunopeptidome, and enhance the cytotoxic activity of endogenous or engineered T-cells. Strategies to enhance antigen presentation may also improve the antitumor activity of T-cell immunotherapies, checkpoint inhibitors, and cancer vaccines. Proteasomes represent actionable therapeutic targets to treat difficult-to-treat infectious processes and neurodegenerative diseases that are characterized by the unwanted accrual of insoluble, deleterious, and potentially toxic proteins. Taken together, we highlight the breadth and magnitude of the proteasome and the immense potential to amplify and unmask the immunopeptidomic landscape to improve the treatment of a spectrum of human diseases.
ABSTRACT
Space is a complex and challenging setting encompassing the region beyond Earth's atmosphere where astronauts and spacecraft operate. The unique conditions of spaceflights, particularly microgravity and radiation, pose significant challenges to astronaut health, including the orofacial region. It has effects on saliva production, microbial composition, and oral hygiene practices, which influence oral health status, such as increased risk of dental caries, gum diseases, oral discomfort, temporomandibular joint dysfunctions, sialoliths, pain and dysesthesia in the teeth and oral mucosa, masticatory muscle atrophy, and oral cancer which can be detrimental during prolonged missions. Hence, a comprehensive approach to dental care in space is imperative to ensure astronauts' well-being and overall health as we strive to extend our presence beyond Earth. This literature review paper sheds light on the intricate effects of space on the orofacial region and delves into the unique challenges astronauts face in upholding optimal oral health while in space. It explores the current state of dentistry in space and discusses advancements and strategies that aim to maintain optimal oral health for astronauts during extended space missions.
ABSTRACT
Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients.
ABSTRACT
Autism spectrum disorders (ASD) are a complex sequelae of neurodevelopmental disorders which manifest in the form of communication and social deficits. Currently, only two agents, namely risperidone and aripiprazole have been approved for the treatment of ASD, and there is a dearth of more drugs for the disorder. The exact pathophysiology of autism is not understood clearly, but research has implicated multiple pathways at different points in the neuronal circuitry, suggesting their role in ASD. Among these, the role played by neuroinflammatory cascades like the NF-KB and Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a bearing on the development of ASD. Similarly, the GPR40 receptor, present in both the gut and the blood brain barrier, has also been said to be involved in the disorder. Consequently, molecules which can act by interacting with one or multiple of these targets might have a potential in the therapy of the disorder, and for this reason, this study was designed to assess the binding affinity of taurine, a naturally-occurring amino acid, with these target molecules. The same was scored against these targets using in-silico docking studies, with Risperidone and Aripiprazole being used as standard comparators. Encouraging docking scores were obtained for taurine across all the selected targets, indicating promising target interaction. But the affinity for targets actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel > GPR 40. Given the potential implication of these targets in the pathogenesis of ASD, the drug might show promising results in the therapy of the disorder if subjected to further evaluations.
ABSTRACT
Functional blockade of the transforming growth factor-beta (TGF-ß) signaling pathway improves the efficacy of cytotoxic and immunotherapies. We conducted a phase 1b study to determine the safety, efficacy, and maximal tolerated dose (200 mg po bid) of the potent, orally-available TGF-ß type I receptor kinase inhibitor vactosertib in relapsed and/or refractory multiple myeloma patients who had received ≥2 lines of chemoimmunotherapy. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, while pomalidomide alone historically achieved 20% PFS-6. Following treatment, the immunosuppressive marker PD-1 expression was reduced on patient CD8+ T-cells. Following ex vivo treatment, vactosertib decreased PD-1 expression on patient CD138+ cells, reduced PD-L1/PD-L2 on patient CD138+ cells and enhanced the anti-myeloma activity of autologous T-cells. Taken together, vactosertib is a safe immunotherapy that modulates the T-cell immunophenotype to reinvigorate T-cell fitness. Multiple myeloma (MM) is a genetically heterogeneous hematologic malignancy characterized by the excessive proliferation of clonal plasma cells (1, 2). MM remains mostly incurable but a small group of patients can achieve long-term remission (3). Treatment of MM presents unique challenges due to the complex molecular pathophysiology and genetic heterogeneity (4, 5). Given that MM is the second most common blood cancer characterized by cycles of remission and relapse, the development of new therapeutic modalities is crucial (6, 7). The prognosis for MM patients has improved substantially over the past two decades with the development of more effective therapeutics, e.g., proteasome inhibitors, and regimens that demonstrate greater anti-tumor activity (8-10). The management of RRMM represents a vital aspect of the overall care for patients with disease and a critical area of ongoing scientific and clinical research (10-12).
ABSTRACT
Pathways that govern cellular bioenergetics are deregulated in tumor cells and represent a hallmark of cancer. Tumor cells have the capacity to reprogram pathways that control nutrient acquisition, anabolism and catabolism to enhance their growth and survival. Tumorigenesis requires the autonomous reprogramming of key metabolic pathways that obtain, generate and produce metabolites from a nutrient-deprived tumor microenvironment to meet the increased bioenergetic demands of cancer cells. Intra- and extracellular factors also have a profound effect on gene expression to drive metabolic pathway reprogramming in not only cancer cells but also surrounding cell types that contribute to anti-tumor immunity. Despite a vast amount of genetic and histologic heterogeneity within and between cancer types, a finite set of pathways are commonly deregulated to support anabolism, catabolism and redox balance. Multiple myeloma (MM) is the second most common hematologic malignancy in adults and remains incurable in the vast majority of patients. Genetic events and the hypoxic bone marrow milieu deregulate glycolysis, glutaminolysis and fatty acid synthesis in MM cells to promote their proliferation, survival, metastasis, drug resistance and evasion of immunosurveillance. Here, we discuss mechanisms that disrupt metabolic pathways in MM cells to support the development of therapeutic resistance and thwart the effects of anti-myeloma immunity. A better understanding of the events that reprogram metabolism in myeloma and immune cells may reveal unforeseen vulnerabilities and advance the rational design of drug cocktails that improve patient survival.
ABSTRACT
Tattooing is a very common fashion trend across all the ages and gender of the society worldwide. Although skin inflammatory diseases are very frequent among tattoo users because of the active chemical ingredients used in tattoo ink, yet no ingredient-specific toxicity study has been performed. Benzo(ghi)perylene (BgP) is one of the PAHs and an important ingredient of black tattoo ink that shows strong absorption in UVA and UVB radiation of sunlight. Therefore, understanding the hazardous potential of BgP especially under UVA exposure is important for the safety of skin of tattoo users by considering the fact that penetration of UVA is in the dermis region where tattoo ingredients reside. To evaluate the hazardous potential of BgP on human skin under UVA exposure, different experimental tools i.e., in-chemico, in-silico and in-vitro were utilized. Our results illustrated that BgP photosensitized under UVA (1.5 mW/cm2) irradiation shows a degradation pattern till 4 h exposure. Photosensitized BgP reduced significant cell viability (%) at 1 µg/ml concentration. However, the pretreatment of singlet and hydroxyl radical quenchers, restoration of cell viability observed, confirmed the role of type-I and type-II photodynamic reactions in phototoxicity of BgP. Further, intracellular uptake of BgP in HaCaT cells was estimated and confirmed by UHPLC analysis. Molecular docking of BgP with DNA and formation of γ-H2AX foci demonstrated the DNA intercalation and double-stranded DNA damaging potential of BgP. Furthermore, acridine orange and ethidium bromide (AO/EB) dual staining showed apoptotic cell death via photosensitized BgP under UVA irradiation. The above findings suggest that BgP reached the human skin cell and induced dermal toxicity via direct and indirect mode of DNA damage under UVA exposure finally promoting the skin cell death. Thus, BgP-containing tattoo ink may be hazardous and may induce skin damage and diseases, especially in presence of UVA radiation of sunlight. To minimize the risk of skin diseases from synthetic ingredients in tattoo ink, the study highlights the importance of developing eco-friendly and skin-friendly tattoo ingredients by companies.
Subject(s)
Tattooing , Humans , Tattooing/adverse effects , Molecular Docking Simulation , Ultraviolet Rays/adverse effects , Skin/metabolism , DNA Damage , DNA/metabolismABSTRACT
BACKGROUND: Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of ß-catenin stabilization. METHODS: The Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and ß-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and ß-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/ß-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors. RESULTS: Genetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of ß-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo. CONCLUSION: We identified a novel WAVE3/ß-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.
Subject(s)
Triple Negative Breast Neoplasms , Female , Humans , beta Catenin/genetics , beta Catenin/metabolism , beta Catenin/therapeutic use , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Neoplasm Recurrence, Local , Signal Transduction , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
Breast cancer is the most frequently diagnosed malignancy in women and the major cause of death because of its invasion, metastasis, and resistance to therapies capabilities. The most aggressive subtype of breast cancer is triple-negative breast cancer (TNBC) due to invasive and metastatic properties along with early age of diagnosis and poor prognosis. TNBC tumors do not express estrogen, progesterone, and HER2 receptors, which limits their treatment with targeted therapies. Cancer invasiveness and metastasis are known to be promoted by increased cell motility and upregulation of the WAVE proteins. While the contribution of WAVE2 to cancer progression is well documented, the WAVE2-mediated regulation of TNBC oncogenic properties is still under investigated, as does the molecular mechanisms by which WAVE2 regulates such oncogenic pathways. In this study, we show that WAVE2 plays a significant role in TNBC development, progression, and metastasis, through the regulation of miR-29 expression, which in turn targets Integrin-ß1 (ITGB1) and its downstream oncogenic activities. Conversely, we found WAVE2 expression to be regulated by miR-29 in a negative regulatory feedback loop. Reexpression of exogenous WAVE2 in the WAVE2-deficient TNBC cells resulted in reactivation of ITGB1 expression and activity, further confirming the specificity of WAVE2 in regulating Integrin-ß1. Together, our data identify a novel WAVE2/miR-29/ITGB1 signaling axis, which is essential for the regulation of the invasion-metastasis cascade in TNBC. Our findings offer new therapeutic strategies for the treatment of TNBC by targeting WAVE2 and/or its downstream effectors. Significance: Identification of a novel WAVE2/miR-29/ITGB1 signaling axis may provide new insights on how WAVE2 regulates the invasion-metastasis cascade of TNBC tumors through the modulation of ITGB1 and miR-29.
Subject(s)
MicroRNAs , Triple Negative Breast Neoplasms , Humans , Female , Triple Negative Breast Neoplasms/genetics , Integrin beta1/genetics , Cell Line, Tumor , Cell Proliferation/genetics , MicroRNAs/geneticsABSTRACT
MOTIVATION: Subcellular localization of human proteins is essential to comprehend their functions and roles in physiological processes, which in turn helps in diagnostic and prognostic studies of pathological conditions and impacts clinical decision-making. Since proteins reside at multiple locations at the same time and few subcellular locations host far more proteins than other locations, the computational task for their subcellular localization is to train a multilabel classifier while handling data imbalance. In imbalanced data, minority classes are underrepresented, thus leading to a heavy bias towards the majority classes and the degradation of predictive capability for the minority classes. Furthermore, data imbalance in multilabel settings is an even more complex problem due to the coexistence of majority and minority classes. RESULTS: Our studies reveal that based on the extent of concurrence of majority and minority classes, oversampling of minority samples through appropriate data augmentation techniques holds promising scope for boosting the classification performance for the minority classes. We measured the magnitude of data imbalance per class and the concurrence of majority and minority classes in the dataset. Based on the obtained values, we identified minority and medium classes, and a new oversampling method is proposed that includes non-linear mixup, geometric and colour transformations for data augmentation and a sampling approach to prepare minibatches. Performance evaluation on the Human Protein Atlas Kaggle challenge dataset shows that the proposed method is capable of achieving better predictions for minority classes than existing methods. AVAILABILITY AND IMPLEMENTATION: Data used in this study are available at https://www.kaggle.com/competitions/human-protein-atlas-image-classification/data. Source code is available at https://github.com/priyarana/Protein-subcellular-localisation-method. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.