Growth Of Cells Research Articles

Palladium catalysed cross coupling reactions on 2,3-isoxazol-17α-ethynyltestosterone, their anti-cancer activity, molecular docking studies and ADMET analysis

In the current study, the Sonogashira coupling reaction of danazol with aryl halides was carried out, yielding new aryl substituted danazol derivatives. The synthetic compounds were examined for anti-cancer potential on the HeLa human cervical cancer cell line, and they showed promising cytotoxic action. Synthesized compounds 2, 4 and 5 inhibited the growth of HeLa cervical cancer cells, potentially making them effective anti-cancer drugs in the future. Furthermore, molecular docking studies were performed to evaluate the inhibitory impact of danazol derivatives on the Human Papillomavirus (HPV) target protein (1F9F). The docking results showed a significant inhibitory action against the cervical cancer protein (1F9F). The binding energy (ΔG) values of 1, 2, 3, 4 and 5 against the protein 1F9F were −8.01, −8.70, −9.43, −9.58 and −9.75 kcal/mol, indicating a high affinity of the synthesized compounds to bind with the HPV target proteins compared to their parent compound danazol (1). ADMET analyses of all derivatives have also been carried out

Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting. 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which had better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP in a dose-dependent manner. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

HKDC1 promotes autophagy and proliferation in pancreatic adenocarcinoma through interaction with PARP1 and poly(ADP-ribosyl)ation

BackgroundHKDC1 has been shown to play an important role in promoting malignant progression of pancreatic adenocarcinoma (PAAD), but the exact mechanism is unclear. This study aimed to investigate the function of HKDC1 in autophagy activation and cell proliferation. MethodsBy GSEA analysis of TCGA data of PAAD, we found that HKDC1 was closely associated with autophagy. We evaluated the effects of HKDC1 knockdown and overexpression on the expression of LC3B, an autophagy marker, and Cyclin D1 and PCNA, cell proliferation-associated proteins, by Western blotting (WB) and transmission electron microscopy (TEM) analysis. ResultsKnockdown of HKDC1 decreased LC3B expression and led to a decrease in the accumulation of autophagic vesicles and autophagic lysosomes, while overexpression of HKDC1 produced the opposite effect. Meanwhile, HKDC1 overexpression significantly promoted the proliferation of PAAD cells and increased the expression levels of Cyclin D1 and PCNA. Further studies showed that HKDC1 enhanced PARP1's own poly ADP-ribosylation (PARylation) activity by interacting with PARP1, which in turn promoted autophagy. In vivo experiments showed that knockdown of HKDC1 significantly inhibited the growth of pancreatic cancer cells in nude mice in vivo, reduced tumor volume and weight, and down-regulated the expression of PARP1, LC3, Cyclin D1 and PCNA. ConclusionHKDC1 plays a critical role in the malignant progression of PAAD by activating autophagy and promoting cell proliferation. Our findings suggest that targeting HKDC1 and its downstream signaling pathways may provide novel strategies for PAAD treatment.

A mathematical framework for the statistical interpretation of biological growth models

Biological entities are inherently dynamic. As such, various ecological disciplines use mathematical models to describe temporal evolution. Typically, growth curves are modelled as sigmoids, with the evolution modelled by ordinary differential equations. Among the various sigmoid models, the logistic, Gompertz and Richards equations are well-established and widely used for the purpose of fitting growth data in the fields of biology and ecology. The present paper puts forth a mathematical framework for the statistical analysis of population growth models. The analysis is based on a mathematical model of the population–environment relationship, the theoretical foundations of which are discussed in detail. By applying this theory, stochastic evolutionary equations are obtained, for which the logistic, Gompertz, Richards and Birch equations represent a limiting case. To substantiate the models of population growth dynamics, the results of numerical simulations are presented. It is demonstrated that a variety of population growth models can be addressed in a comparable manner. It is suggested that the discussed mathematical framework for statistical interpretation of the joint population-environment evolution represents a promising avenue for further research.

Overexpression of proteasome 26S subunit non-ATPase 6 protein and its clinicopathological significance in intrahepatic cholangiocarcinoma

BACKGROUND Currently, intrahepatic cholangiocarcinoma (ICC) poses a continuing, significant health challenge, but the relationship has yet to be established between ICC and the proteasome 26S subunit non-ATPase 6 (PSMD6). AIM To investigate the protein expression and clinicopathological significance of PSMD6 in ICC. METHODS The potential impact of the PSMD6 gene on the growth of ICC cell lines was analyzed using clustered regularly interspaced short palindromic repeat knockout screening technology. Forty-two paired specimens of ICC and adjacent non-cancerous tissues were collected. PSMD6 protein expression was determined by immunohistochemistry. Receiver operating characteristic curve analysis was performed to validate PSMD6 expression level, and its association with ICC patients’ various clinicopathological characteristics was investigated. RESULTS The PSMD6 gene was found to be essential for the growth of ICC cell lines. PSMD6 protein was significantly overexpressed in ICC tissues (P < 0.001), but showed no significant association with patient age, gender, pathological grade, or tumor-node-metastasis stage (P > 0.05). CONCLUSION PSMD6 can promote the growth of ICC cells, thus playing a pro-oncogenic role.

Abstract A038: A targetable tumor-induced wound-healing response is essential for osteosarcoma lung metastasis

Abstract Lung metastasis is responsible for nearly all deaths in children and teenagers affected by osteosarcoma, the most common pediatric sarcoma. The mechanisms by which malignant bone cells manipulate the lung microenvironment to promote the colonization and growth of metastatic tumor cells remain unclear but represent a potential therapeutic opportunity for preventing and treating metastasis. In this study, we sought to understand how osteosarcoma cells educate the lung microenvironment during metastatic progression. To address this gap, we generated several time series datasets of niche-labeled, single-cell RNA-seq of developing metastatic lesions and then used these to characterize the changes occurring in tumor and tumor-associated stromal cells during colonization. After identifying candidate mechanisms, we tested several therapeutic interventions to evaluate their effects on metastasis development in vitro using a tumor-on-lung co-culture system and in vivo using our animal models. Osteosarcoma cells induced acute epithelial injury upon lung dissemination. Shortly after dissemination, a paracrine loop established between a hyper-secretory, hypo-proliferative subpopulation of tumor cells and alveolar epithelial cells triggers the adoption of a chronic, non-resolving wound phenotype within the surrounding tissues that culminates in extensive tissue fibrosis with persistent extracellular matrix deposition, especially fibronectin. Cellular changes observed during this process include the proliferation of type 2 alveolar epithelial cells, the accumulation of highly fibrogenic epithelial intermediates (analogous to those observed in pulmonary fibrosis), and the emergence of a large population of scar-promoting macrophages. The formation of this matrix seems essential for lesion formation—disruption of the matrix-tumor cell interaction eliminated pseudonodules in vivo. Inhibition of pro-fibrotic pathways using nintedanib, an FDA- approved drug used to treat pulmonary fibrosis, or of tumor-epithelial paracrine signals with anakinra, an antagonist of IL1 signaling, effectively blocked metastatic lesion growth in both murine and human xenograft models, showing evidence of microenvironment reprogramming in the single cell data. Combining these therapies, which target primarily the hyper-secretory, hypo-proliferative “anchor” cells, with conventional therapies, which target proliferating tumor cells, proved highly effective in eliminating established metastatic lesions. Our work demonstrates that disseminated osteosarcoma cells trigger an aberrant, non-resolving wound-healing response in tumor-associated lung tissues, similar to that observed in non-malignant pulmonary fibrosis, and that this pathologic wound-healing response promotes metastatic growth. Therapeutic disruption of fibrosis-associated signaling prevents metastasis and treats established metastatic disease in multiple osteosarcoma models. Citation Format: James B. Reinecke, Leyre Jimenez Garcia, Amy C. Gross, Matthew V. Cannon, Yogesh Budhathoki, Ryan D. Roberts. A targetable tumor-induced wound-healing response is essential for osteosarcoma lung metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A038.

Abstract A023: Arachidonic acid metabolism promoting cross resistance in melanoma cells

Abstract Melanoma patients initially respond well to first line immunotherapy. However, cross resistance to immunotherapy and BRAF/MEK inhibitor is a clinical challenge for melanoma care. To investigate drug tolerant and resistant mechanisms promoting cross resistance, we analyzed RNA-sequencing and gene set enrichment targeted therapy resistant melanoma cells revealing an enriched arachidonic acid gene signature. Intracellular arachidonic acid levels were increased in drug resistant and drug tolerant melanoma models. Arachidonic acid is enzymatically converted by COX1 and COX2 to prostaglandins, which is subsequently secreted into the microenvironment. Drug tolerant and resistant cells had increased protein expression of COX1 and COX2 concurrently with increased secretion of prostaglandin E2. COX1/2 inhibition and COX2 knockdown in vitro had no effect on cell growth in drug tolerant or resistant cells compared to parental cells. However, secreted prostaglandins are known immunomodulators, thus we explored how COX1/2 inhibition in combination with BRAF inhibitor plus MEK inhibitor affected immune cell infiltration. COX1/2 inhibition increased CD4+ and CD8+ T cell infiltration as compared to BRAF inhibitor plus MEK inhibitor alone. Under constant BRAF inhibitor plus MEK inhibitor treatment, we found that COX1/2 inhibition upon reaching MRD status prevented tumor relapse in vivo and increased survival dependent on an immune system. Future studies will evaluate the importance of arachidonic acid metabolism in promoting cross resistance to immune checkpoint blockade and whether T cell depletion prevents the delayed tumor relapse. Overall, COX1/2 inhibition delayed tumor relapse and survival in an immune-dependent manner and demonstrated a potential cross resistant mechanism. Citation Format: Casey D. Stefanski, Daniel A. Erkes, Timothy J. Purwin, Glenn L. Mersky, Erica L. Kitterman, Manal Mustafa, Jelan Haj, Diana Melissaratos, Andrew E. Aplin. Arachidonic acid metabolism promoting cross resistance in melanoma cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A023.

Abstract C048: Intrapatient heterogeneity and targeting microenvironment protection mechanisms in melanoma metastasis

Abstract Intrapatient tumor heterogeneity contributes to immunotherapy and targeted therapy resistance in cutaneous metastatic melanoma patients. More than 50% of melanoma patients develop brain metastases (MBM) during disease progressionand these patients have a very poor prognosis with a median overall survival of 4 months. To assess how tumors persist through treatments and adapt to and rely on organ-specific microenvironments, we utilized samples from a patient who had received anti-CTLA4, BRAFi/MEKi, and BRAFi/MEKi+CDK4/6i treatments during the LOGIC2 clinical trial. Eight short-term melanoma cultures (STMCs) were established from different metastatic site biopsies at chronological time points throughout the patient’s treatment and subsequent post-mortem resection of the bone, ovary, and brain metastatic sites. While the initial treatment naïve metastatic tumor in the breast was BRAF V600E mutant, NRAS Q61 mutations were acquired after treatment with CDK4/6i in the bone and ovary tumors. We performed single-cell RNA sequencing and identified that each STMC consists of 2-10 different subpopulations. By cell viability assay, we determined all STMCs were resistant to CDK4/6i, however had varying degrees of response to BRAFi and MEKi in vitro. Two STMCs (MM150604, MM150859) were sensitive to both BRAFi and MEKi. We identified HER3 was upregulated in the sensitive STMCs and more specifically, HER3 expression was elevated in the MBM STMC and in other MBM patient tumors in publicly available datasets. In publicly available data of the MBM tumor microenvironment (TME), neurons produce NRG1 and NRG2 while astrocytes and pericytes produce NRG2, exogenous sources of NRGs in the MBM TME that act as ligands for the HER3 receptor. Treatment with recombinant NRG1 partially rescued the growth of MBM cells and restored MAPK and AKT-mTOR signaling in the presence of BRAFi/MEKi suggesting that the brain microenvironment may play a role in drug tolerance. This novel finding demonstrates a unique role of HER3 in MBM and targeting the NRG-HER3 signaling axis could have therapeutic potential in melanoma patients with active brain metastases. Citation Format: Haley P. Wilson, Glenn L. Mersky, Jelan I. Haj, Jessica L.F. Teh, Phil F. Cheng, Signe Caksa, Manal Mustafa, Isabella Trachtenberg, Francis J. Waltrich Jr, Casey D. Stefanski, Vivian Chua, Dan A. Erkes, Mitchell P. Levesque, Reinhard Dummer, Timothy J. Purwin, Claudia Capparelli, Andrew E. Aplin. Intrapatient heterogeneity and targeting microenvironment protection mechanisms in melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C048.

Abstract A016: Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality

Abstract Non-small cell lung cancer (NSCLC) is a primary type of lung cancer and a leading cause of cancer-related mortality worldwide. The Warburg effect, characterized by increased glycolysis and reduced oxidative phosphorylation, is a hallmark of NSCLC and presents a therapeutic target. Annonacin, a natural compound found in fruits from the Annonaceae family, interferes with oxidative phosphorylation by inhibiting mitochondrial complex I. 2-deoxy-d-glucose (2DG), a glucose analog, disrupts glycolysis. This study examines the effects of Annonacin and 2DG on NSCLC A549 cells, both individually and in combination, with the hypothesis that inhibiting both metabolic pathways simultaneously will lead to more effective cancer treatment. In addition, we explored how these treatments might alter the tumor microenvironment, oxidative stress, and effects on normal epithelial bronchial cells. A549 NSCLC cells were exposed to different concentrations of Annonacin (0, 1, 2, 4, 6 µM) and 2DG (0,1.25, 2.5, 5, 10 mM), separately and together. Cell viability was measured using the MTT assay. Genotoxicity was assessed through the Comet Assay, and oxidative stress was evaluated by measuring superoxide dismutase and glutathione peroxidase activities. The long-term ability of the cells to proliferate was tested using colony-forming assays. The NL20 bronchial epithelial cell line was tested as a parallel control. Both Annonacin and 2DG showed a dose-dependent ability to kill A549 cells. However, when used together, these substances had a stronger effect, significantly lowering the number of surviving cells compared to when each was used alone. The response of this combination treatment on genotoxicity using Comet Assay is being pursued. Changes in oxidative stress responses were found, as shown by the altered superoxide dismutase and glutathione peroxidase enzyme activities. The ability of A549 cells to form colonies was greatly reduced following combination treatment, indicating a reduction in their long-term proliferative capacity. The combination of Annonacin and 2DG effectively inhibits the growth of NSCLC A549 cells by targeting their metabolic weaknesses, which may lead to increased DNA damage and oxidative stress. These results suggest simultaneous targeting glycolysis and oxidative phosphorylation could be a promising new approach for treating NSCLC. Future in vivo studies will evaluate this combination in live models and can offer insights into efficacy and possible translation to clinical application. Citation Format: Bhoj Raj Bhattarai, Cora Teets, Avinash Tope. Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A016.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer

AbstractTargeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase–positive non-small cell lung cancer (ALK + NSCLC) patient–derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK + NSCLC.

ENDOMETRIOSE E SEUS IMPACTOS NA FERTILIDADE FEMININA: UMA REVISÃO DE LITERATURA

Endometriosis, characterized by the growth of endometrial cells outside the uterine cavity, has a significant impact on women’s lives, especially during reproductive age. The progression of the disease is unpredictable, and despite having individual repercussions in each woman, it is a pathology known for directly affecting female fertility. Among the most relevant factors are pelvic adhesions, tubal obstruction, inflammatory factors, immunological alterations, genetic changes, as well as hormonal dysfunctions, which can impact ovarian function and embryo implantation. The article aimed to analyze the pathology of endometriosis and the pathophysiological aspects involved in the reduction of female fertility in women with endometriosis. It was widely discussed how infertility can occur in women with different stages of endometriosis, as well as addressing other forms of diagnosis and treatment of infertility in women. The article also points to genetic studies showing that epigenetic alterations impact endometrial function, being one of the theories cited for the development of infertility as a consequence of endometriosis. The analysis of data used for the study and preparation of this article showed that endometriosis can impact female fertility, highlighting the importance of expanding studies in this area to carry out an individualized approach for each patient and achieve positive results with the proposed treatment.

Carotenoids as modulators of the PI3K/Akt/mTOR pathway: innovative strategies in cancer therapy.

Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds.

Biological control of nosemosis in Apis mellifera L. with Acacia nilotica extract.

Nosemosis is one of the most devastating diseases of Apis mellifera (Honey bees) caused by the single-celled spore-forming fungiNosema apis,N. ceranae and N. neumanii, causing a severe loss on the colony vitality and productivity. Fumagillin, a MetAP2 inhibitor, was a certified treatment for controlling nosemosis, nevertheless, due to its deleterious effects on honey bees and humans, it is prohibited. So, searching for novel biological agents with affordable selectivity to target Nosema species infecting Apis mellifera, with nil toxicity to bees and humans is the main objective of this study. Nosema species were isolated from naturally infected honey bees. The methanolic extracts of Acacia nilotica, Elaeis guineensis, and Catharanthus roseus were tested to selectively control the growth of Nosema spp of honeybees. The spores of Nosema species were molecularly and morphologically identified. Among the tested plant extracts, the methanolic extracts (0.1%) of A. nilotica had the most activity towards Nosema spp causing about 37.8 and 32.5% reduction in the spores' load at 5- and 9-days post-infection, respectively, compared to the untreated control. At 0.1%, the A. nilotica methanolic extract exhibited the highest inhibitory effect for Nosema spores, without any obvious bee mortality. Catharanthus roseus displayed a reduction of spores by 27.02%, with bee mortality rate of 27.02%. At 1% for 5 dpi, the A. nilotica extracts led to 18.18% bee mortality, while the C. roseus extracts resulted in 100% mortality, as revealed from the toxicity and quantification bioassays. So, the extracts of A. nilotica and C. roseus had a significant effect in controlling the N. apis and N. ceranae titer compared to the infected untreated control at both time points. The titer of N. apis and N. ceranae was noticeably decreased by more than 80% and 90%, in response to A. nilotica, compared to the control. From the metabolic profiling by GC-MS analysis, the most frequent active compounds of A. nilotica were 2,4,6-trihy-droxybenzoic acid, 1,2-dihydroxybenzene, myristic acid, and linoleic acid. These compounds were analyzed in silico to assess their binding affinity to the ATP binding protein, methionine aminopeptidase and polar tube protein of Nosema species as target enzymes. The compound 2,4,6-trihydroxybenzoic acid had the lowest energy to bind with ATP binding protein, methionine aminopeptidase and polar tube protein of Nosema, followed by 1,2-dihydroxybenzene and myristic acid, compared to fumagilin. So, from the experimental and molecular docking analysis, the extracts of A. nilotica had the highest activity to attack the cellular growth machinery of Nosema species without an obvious effect to the honeybees, ensuring their prospective promising application.

Metamaterial-based Artificial magnetic conductor for efficient breast cancer diagnosis using a low-cost antenna array.

Breast cancer is the most common malignancy in women globally, stemming from gene mutations that prompt irregular cellular growth and subsequent tumor development. Early-stage detection of cancer cells results in a remarkable 99% survival rate. This research presents a microwave imaging technique for the non-invasive identification of tumors in the initial stages within the women's breast. A low-cost antenna array with an Artificial Magnetic Conductor (AMC) is proposed, featuring a compact structure size of 37.2 37.2 mm . The AMC, a metamaterial, acts as a reflective surface to enhance frequency selectivity, specifically at 8.48 GHz. The maximum gains reached 9.35 dBi in simulated results and 10.51 dBi in measured results. The fabricated antenna validates the simulated findings, and its operational efficiency has undergone experimental validation. Moreover, fidelity factors in face-to-face (FtF) and side-by-side (SbS) scenarios are delineated. The antenna, operating as a transceiver, is applied to a modeled breast phantom across five distinct cases for numerical simulations pertaining to cancer cell detection applications. The outcomes of this research bear considerable implications for advancing early-stage breast cancer detection methodologies.

Unveiling the Anticancer Potential of a New Ciprofloxacin-Chalcone Hybrid as an Inhibitor of Topoisomerases I & II and Apoptotic Inducer

The current study has yielded promising results in the evaluation of a new ciprofloxacin-chalcone hybrid (CP derivative) for its anticancer activity as potential Topoisomerases (Topo) I and II inhibitors. The in vitro results showed that the CP derivative significantly suppressed the growth of HCT-116 and LOX IMVI cells, with IC50 values of 5.0 μM and 1.3 μM, respectively, outperforming Staurosporine, which had IC50 values of 8.4 μM and 1.6 μM, respectively. Flow cytometry analysis revealed that the new CP derivative triggered apoptosis and cell cycle arrest at the G2/M phase, associated with the up-regulation of pro-apoptotic genes (Bax and Caspase 9) and downregulation of the anti-apoptotic gene (Bcl-2). Further investigations showed that the CP derivative inhibited Topo I and II enzymes, as expected molecular targets; docking studies further supported its dual inhibitory action on Topo I and II. These findings suggest that the ciprofloxacin-chalcone hybrid could be a promising lead compound for developing new anticancer therapy.

Senescence as a therapeutic target in cancer and age-related diseases.

Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.

Sirtuin inhibitors reduce intracellular growth of M. tuberculosis in human macrophages via modulation of host cell immunity.

Host-directed therapies aiming to strengthen the body's immune system, represent an underexplored opportunity to improve treatment of tuberculosis (TB). We have previously shown in Mycobacterium tuberculosis (Mtb)-infection models and clinical trials that treatment with the histone deacetylase (HDAC) inhibitor, phenylbutyrate (PBA), can restore Mtb-induced impairment of antimicrobial responses and improve clinical outcomes in pulmonary TB. In this study, we evaluated the efficacy of different groups of HDAC inhibitors to reduce Mtb growth in human immune cells. A panel of 21 selected HDAC inhibitors with different specificities that are known to modulate infection or inflammation was tested using high-content live-cell imaging and analysis. Monocyte-derived macrophages or bulk peripheral blood cells (PBMCs) were infected with the green fluorescent protein (GFP)-expressing Mtb strains H37Ra or H37Rv and treated with HDAC inhibitors in the micromolar range in parallel with a combination of the first-line antibiotics, rifampicin, and isoniazid. Host cell viability in HDAC inhibitor treated cell cultures was monitored with Cytotox-red. Seven HDAC inhibitors were identified that reduced Mtb growth in macrophages > 45-75% compared to average 40% for PBA. The most effective compounds were inhibitors of the class III HDAC proteins, the sirtuins. While these compounds may exhibit their effects by improving macrophage function, one of the sirtuin inhibitors, tenovin, was also highly effective in extracellular killing of Mtb bacilli. Antimicrobial synergy testing using checkerboard assays revealed additive effects between selected sirtuin inhibitors and subinhibitory concentrations of rifampicin or isoniazid. A customized macrophage RNA array including 23 genes associated with cytokines, chemokines and inflammation, suggested that Mtb-infected macrophages are differentially modulated by the sirtuin inhibitors as compared to PBA. Altogether, these results demonstrated that sirtuin inhibitors may be further explored as promising host-directed compounds to support immune functions and reduce intracellular growth of Mtb in human cells.

Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review

Cancer is a complex disease characterized by specific “mission-critical” events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways—such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and—allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

BHLHE40-mediated transcriptional activation of GRIN2D in gastric cancer is involved in metabolic reprogramming.

Gastric cancer (GC) is the third leading cause of death in developed countries. The reprogramming of energy metabolism represents a hallmark of cancer, particularly amplified dependence on aerobic glycolysis. Here, we aimed to illustrate the functional role of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2D (GRIN2D) in the regulation of glycolysis in GC and the mechanisms involved. Differentially expressed genes were analyzed using the GEO and GEPIA databases, followed by prognostic value prediction using the Kaplan-Meier Plotter database. The effect of GRIN2D knockdown on the malignant behavior and glycolysis of GC cells was explored. GRIN2D expression was upregulated in GC cells and promoted the malignant behavior of GC cells by activating glycolysis. Class E basic helix-loop-helix protein 40 (BHLHE40) was overexpressed in GC cells and mediated transcriptional activation of GRIN2D. The anti-tumor effects of BHLHE40 knockdown on GC cells in vitro and in vivo were reversed by GRIN2D overexpression. Knockdown of GRIN2D or BHLHE40 downregulated the expression of mRNA of electron transport chain subunits and phosphorylation of p38 MARK and inhibited calcium efflux in GC cells. Overexpression of GRIN2D promoted calcium efflux, phosphorylation of p38 MARK protein, and proliferation of GES1 cells. Altogether, the findings derived from this study suggest that BHLHE40 knockdown suppresses the growth, mobility, and glycolysis of GC cells by inhibiting GRIN2D transcription and disrupting the BHLHE40/GRIN2D axis may be an attractive therapeutic strategy for GC.

An Ecologically Consistent Model of Growth for Hard-Bodied Marine Organisms

There are several factors to account for marine growth including but not limited to temperature, salinity, chlorophyll-a content, existing species in the environment and predating. This paper proposes a model of biological growth for hard species on marine structures, which can be compatible with site-specific and realistic ecology while also being able to translate the results for analyses linked to lifetime hydrodynamic or structural effects via commercial software or computing. The model preserves fundamentals of ecological aspects rather than using heuristics or random sampling to data fitting on sparsely collected information. The coefficients used in the proposed model align to the real world, with location-specific values, and can be adapted to new information. The growth model is demonstrated for Mythulis Edulis (blue mussel) colonisation to assess the lifetime hydrodynamic effects for the West Coast of Ireland and the Gulf of Guinea. The model can be extended to any hard growth approach.