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Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%->50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity ( p = 0.043) and MMP-3 percentage ( p = 0.018) and intensity, ( p = 0.025) present statistically significant associations with the variable group (control-case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.

Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.

Pancreatic cancer is one of the most lethal cancers worldwide due to its symptoms, early metastasis, and chemoresistance. Thus, the mechanisms contributing to pancreatic cancer progression require further exploration. Circadian rhythms are the daily oscillations of multiple biological processes regulated by an endogenous clock. Several evidences suggest that the circadian clock may play an important role in the cell cycle, cell proliferation and apoptosis. In addition, timing of chemotherapy or radiation treatment can influence the efficacy and toxicity treatment. Here, we revisit the studies on circadian clock as an emerging target for therapy in pancreatic cancer. We highlight those potential circadian genes regulators that are commonly affected in pancreatic cancer according to most recent reports., (Copyright © 2020 García-Costela, Escudero-Feliú, Puentes-Pardo, San Juán, Morales-Santana, Ríos-Arrabal, Carazo and León.)

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E-cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (-1, -2, -3, -7, -8, -9, -10, -12 and -13) and TIMPs (-1 to -4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP-1 and TIMP-3 levels. Significant correlations were found between MMP-3 and TIMP-4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP-9 and TIMP-3 levels could be predictive of RT toxicity. For this reason, MMP-3, MMP-9, TIMP-3 and TIMP-4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.

The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability to kill CSCs. Although there are no data linking the loss of p53 function and melatonin synthesis or signaling in cancer, melatonin does activate the p53 tumor-suppressor pathway in this disease. In this work, we analyze whether the expression of melatonin synthesis and signaling genes are related to the expression of CSC markers and the implication of p53 status in samples from patients with CRC. Arylalkylamine N-acetyltransferase (AA-NAT), MT1, and MT2 expression decreased in tumor samples versus normal mucosa samples in mutated p53 (mtp53) tumors versus those with wild-type p53 (wtp53). Further, AA-NAT and MT2 expression were lower in advanced stages of the disease in wtp53 tumors. On the contrary, CD44 and CD66c expression was higher in tumor versus normal mucosa in wtp53 tumors. Additionally, CD44 expression was higher in advanced stages of the disease regardless of the p53 status. Patients with CD44 high CD66c high and wtp53 tumors in advanced stages showed low expression of AA-NAT and MT2 in wtp53 tumors. These results could indicate a possible interaction of these pathways in CRC., Competing Interests: The authors declare no conflict of interest.

PARP-1 has been linked to the progression of several types of cancer. We have recently reported that PARP-1 influences tumor progression in CRC through the regulation of CSCs in a p53-dependent manner. In this study, we propose that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) could act as a mediator. We evaluated the expression of iNOS in a cohort of patients previously used to analyze the effects of PARP-1 on CRC in relation to p53 status. We also developed an in vitro model in which PARP-1 was stably overexpressed. In CRC patients, iNOS expression correlated with the differentiation grade, and with a high expression of CSC markers, although only in wild-type p53 tumors, as previously found for PARP-1. In vitro, overexpression of PARP-1 induced increased growth and stemness in wild-type p53 cells, while exerting the opposite effect on mutated ones, as expected. Treatment with 1400 W, a selective inhibitor of iNOS, or gene silencing of the gene counteracted the effects of PARP-1 in both p53 wild-type and p53 mutated cells. Given that the development of resistance has been demonstrated after treatment with PARP-1 inhibitors, iNOS could be considered a new therapeutic target in CRC, although only in patients with wild-type p53 tumors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition., Material and Methods: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)]., Results: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA., Conclusion: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.

Researchers have recently shown an increased interest in free radicals and their role in the tumor microenvironment. Free radicals are molecules with high instability and reactivity due to the presence of an odd number of electrons in the outermost orbit of their atoms. Free radicals include reactive oxygen and nitrogen species, which are key players in the initiation and progression of tumor cells and enhance their metastatic potential. In fact, they are now considered a hallmark of cancer. However, both reactive species may contribute to improve the outcomes of radiotherapy in cancer patients. Besides, high levels of reactive oxygen species may be indicators of genotoxic damage in non-irradiated normal tissues. The purpose of this article is to review recent research on free radicals and carcinogenesis in order to understand the pathways that contribute to tumor malignancy. This review outlines the involvement of free radicals in relevant cellular events, including their effects on genetic instability through (growth factors and tumor suppressor genes, their enhancement of mitogenic signals, and their participation in cell remodeling, proliferation, senescence, apoptosis, and autophagy processes; the possible relationship between free radicals and inflammation is also explored. This knowledge is crucial for evaluating the relevance of free radicals as therapeutic targets in cancer.

One of the main goals in radiobiology research is to enhance radiotherapy effectiveness without provoking any increase in toxicity. In this context, it has been proposed that electromagnetic fields (EMFs), known to be modulators of proliferation rate, enhancers of apoptosis and inductors of genotoxicity, might control tumor recruitment and, thus, provide therapeutic benefits. Scientific evidence shows that the effects of ionizing radiation on cellular compartments and functions are strengthened by EMF. Although little is known about the potential role of EMFs in radiotherapy (RT), the radiosensitizing effect of EMFs described in the literature could support their use to improve radiation effectiveness. Thus, we hypothesized that EMF exposure might enhance the ionizing radiation effect on tumor cells, improving the effects of RT. The aim of this paper is to review reports of the effects of EMFs in biological systems and their potential therapeutic benefits in radiotherapy.

The p38 Mitogen Activated Protein Kinase (MAPK) signaling pathway has become a major player in the response to DNA-damage. A growing body of evidences has been relating this signaling pathway to the cellular response to ionizing radiation (IR), suggesting a role in radioresistance. Here, we study the implication of this signaling pathway in the response to IR in terms of radioresistance. To this end we used 10 different cell lines derived from several types of tumors (colorectal, non-small cell lung cancer -NSCLC-, renal and glioblastoma). Although p38 MAPK is transiently activated by IR, our data, obtained by genetic and chemical approaches, showed that this signaling pathway is not implicated in cellular viability after IR exposure. Indeed, down-modulation of this signaling pathway promotes a mild radiosensitivity depending on the cell line. However, it is remarkable that lack of p38 MAPK α abrogates the radiosensitizing effect of 5-Fluorouracil (5-FU) in HCT116 cell line, supporting the role of this MAPK in the radiosensitizing action of 5-FU., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

It is now widely accepted that the development and progression of a tumor toward the malignant phenotype is highly dependent on interactions between tumor cells and the tumor microenvironment. Different components of the tumor microenvironment may have stimulatory or inhibitory effects on tumor progression by regulating the gene expression repertoire in tumor cells and stromal cells. This review analyzes novel research findings on breast cancer progression, discussing acquisition of the metastatic phenotype in breast disease in relation to different aspects of cross-talk among components of the tumor microenvironment. Knowledge of the interaction of all of these factors would contribute to elucidating the mechanisms that disrupt regulatory/signaling cascades and downstream effects in breast cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, with significant translational potential for improving patient outcomes. In this study, we evaluated the prognostic significance of ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), and KLOTHO in a retrospective cohort of 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) and multiple statistical analyses (Kaplan–Meier curves, correlograms, and multinomial linear regression models) were performed. Our findings reveal that ferroptosis markers are directly associated with PDAC mortality, while circadian regulators and KLOTHO are inversely associated. Notably, TFRC emerged as the strongest risk marker associated with mortality (HR = 35.905), whereas CLOCK was identified as the most significant protective marker (HR = 0.01832). Correlation analyses indicate that ferroptosis markers are positively correlated with each other, as are circadian regulators, which also positively correlate with KLOTHO expression. In contrast, KLOTHO and circadian regulators exhibit inverse correlations with ferroptosis markers. Among the clinical variables examined, only the presence of chronic pathologies showed an association with the expression patterns of several proteins studied. These findings underscore the complexity of PDAC pathogenesis and highlight the need for further research into the specific molecular mechanisms driving disease progression. [ABSTRACT FROM AUTHOR]

The circadian clock regulates biological cycles across species and is crucial for physiological activities and biochemical reactions, including cancer onset and development. The interplay between the circadian rhythm and cancer involves regulating cell division, DNA repair, immune function, hormonal balance, and the potential for chronotherapy. This highlights the importance of maintaining a healthy circadian rhythm for cancer prevention and treatment. This article investigates the complex relationship between the circadian rhythm and cancer, exploring how disruptions to the internal clock may contribute to tumorigenesis and influence cancer progression. Numerous databases are utilized to conduct searches for articles, such as NCBI, MEDLINE, and Scopus. The keywords used throughout the academic archives are "circadian rhythm", "cancer", and "circadian clock". Maintaining a healthy circadian cycle involves prioritizing healthy sleep habits and minimizing disruptions, such as consistent sleep schedules, reduced artificial light exposure, and meal timing adjustments. Dysregulation of the circadian clock gene and cell cycle can cause tumor growth, leading to the need to regulate the circadian cycle for better treatment outcomes. The circadian clock components significantly impact cellular responses to DNA damage, influencing cancer development. Understanding the circadian rhythm's role in tumor diseases and their therapeutic targets is essential for treating and preventing cancer. Disruptions to the circadian rhythm can promote abnormal cell development and tumor metastasis, potentially due to immune system imbalances and hormonal fluctuations. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) has a very high mortality rate globally. Despite ongoing efforts, its prognosis has not improved significantly over the last two decades. Thus, further approaches for optimizing treatment are required. Various biological processes oscillate in a circadian rhythm and are regulated by an endogenous clock. The machinery controlling the circadian cycle is tightly coupled with the cell cycle and can interact with tumor suppressor genes/oncogenes; and can therefore potentially influence cancer progression. Understanding the detailed interactions may lead to the discovery of prognostic and diagnostic biomarkers and new potential targets for treatment. Here, we explain how the circadian system relates to the cell cycle, cancer, and tumor suppressor genes/oncogenes. Furthermore, we propose that circadian clock genes may be potential biomarkers for some cancers and review the current advances in the treatment of PC by targeting the circadian clock. Despite efforts to diagnose pancreatic cancer early, it still remains a cancer with poor prognosis and high mortality rates. While studies have shown the role of molecular clock disruption in tumor initiation, development, and therapy resistance, the role of circadian genes in pancreatic cancer pathogenesis is not yet fully understood and further studies are required to better understand the potential of circadian genes as biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Cancer is an uncontrollable growth of abnormal cells that leads to tumor formation, invading neighboring tissues by migrating to distant organs to form secondary tumors through metastasis. Metastasis also involves the degradation of the Extracellular Matrix (ECM), which maintains the integrity of the organs. ECM degradation occurs during pathophysiological conditions by matrix metalloproteinases (MMPs). MMPs remodel the components of the ECM by their proteolytic activity. MMPs have a role in normal biological processes, like embryogenesis, morphogenesis, tissue remodeling, etc., and pathological processes like atheroma, arthritis, cancer, etc. MMPs are regulated at the transcription level by activating endogenous inhibitors-tissue inhibitors of metalloproteinases (TIMPs) that control the local activities of MMPs in tissues. Variations in MMPs and TIMPs expression contribute to the development and metastasis of cancers. Therefore, MMPs and TIMPs have become important therapeutic and diagnostic cancer targets. We studied MMP-2, MMP-9, TIMP-1, and TIMP-2 plasma levels in cancer patients and healthy controls. MMPs and TIMPs levels were analyzed by ELISA (Immunoassay). We hypothesized that the ratio of MMP-2 to TIMP-2 and MMP-9 to TIMP-1 in cancer patients could be higher compared to healthy controls, contributing to their pathophysiological implication. [ABSTRACT FROM AUTHOR]

Pan-cyclin-dependent-kinase (CDK) inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as a monotherapy, an interesting approach could be to combine it with radiotherapy. Here, we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter serine-protein kinase ATM signalling or cell cycle profiling after ionising-radiation exposure, which have been described for other CDK inhibitors. Interestingly, in terms of apoptosis, although the combination renders a clear increase, no potentiation of the ionising-radiation-induced apoptosis was observed. Mechanistically, inhibition of CDK12 by dinaciclib diminishes BRCA1 expression, which decreases homologous recombination (HR) and probably promotes the nonhomologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising-radiation-associated cellular senescence in a TP53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12-BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

We aimed to explore the relationship of adipose tissue concentrations of some persistent organic pollutants (POPs) with the risk of endometriosis and the endometriotic tissue expression profile of genes related to the endometriosis-related epithelial–mesenchymal transition (EMT) process. This case–control study enrolled 109 women (34 cases and 75 controls) between January 2018 and March 2020. Adipose tissue samples and endometriotic tissues were intraoperatively collected to determine concentrations of nine POPs and the gene expression profiles of 36 EMT-related genes, respectively. Associations of POPs with endometriosis risk were explored with multivariate logistic regression, while the relationship between exposure and gene expression profiles was assessed through Spearman correlation or Mann–Whitney U tests. After adjustment, increased endometriosis risk was associated with p,p'-DDT, PCB-180, and ΣPCBs. POP exposure was also associated with reduced gene expression levels of the CLDN7 epithelial marker and increased levels of the ITGB2 mesenchymal marker and a variety of EMT promoters (HMGA1, HOXA10, FOXM1, DKK1, CCR1, TNFRSF1B, RRM2, ANG, ANGPT1, and ESR1). Our findings indicate that exposure to POPs may increase the risk of endometriosis and might have a role in the endometriosis-related EMT development, contributing to the disease onset and progression. Further studies are warranted to corroborate these findings. [ABSTRACT FROM AUTHOR]

Background: Managing polytrauma victims poses a significant challenge to clinicians since applying the same therapy to patients with similar injury patterns may result in different outcomes. Using serum biomarkers hopefully allows for treating each multiple injured in the best possible individual way. Since matrix metalloproteinases (MMPs) play pivotal roles in various physiological processes, they might be a reliable tool in polytrauma care. Methods: We evaluated 24 blunt polytrauma survivors and 12 fatalities (mean age, 44.2 years, mean ISS, 45) who were directly admitted to our Level I trauma center and stayed at the intensive care unit for at least one night. We determined their MMP3, MMP8, MMP9, MMP10, MMP12, and MMP13 serum levels at admission (day 0) and on days 1, 3, 5, 7, and 10. Results: Median MMP8, MMP9, and MMP12 levels immediately rose after the polytrauma occurred; however, they significantly decreased from admission to day 1 and significantly increased from day 1 to day 10, showing similar time trajectories and (very) strong correlations between each two of the three enzyme levels assessed at the same measurement point. For a two-day lag, autocorrelations were significant for MMP8 (− 0.512) and MMP9 (− 0.302) and for cross-correlations between MMP8 and MMP9 (− 0.439), MMP8 and MMP12 (− 0.416), and MMP9 and MMP12 (− 0.307). Moreover, median MMP3, MMP10, and MMP13 levels significantly increased from admission to day 3 and significantly decreased from day 3 to day 10, showing similar time trajectories and an (almost) strong association between every 2 levels until day 7. Significant cross-correlations were detected between MMP3 and MMP10 (0.414) and MMP13 and MMP10 (0.362). Finally, the MMP10 day 0 level was identified as a predictor for in-hospital mortality. Any increase of the MMP10 level by 200 pg/mL decreased the odds of dying by 28.5%. Conclusions: The time trajectories of the highly varying individual MMP levels elucidate the involvement of these enzymes in the endogenous defense response following polytrauma. Similar time courses of MMP levels might indicate similar injury causes, whereas lead–lag effects reveal causative relations between several enzyme pairs. Finally, MMP10 abundantly released into circulation after polytrauma might have a protective effect against dying. [ABSTRACT FROM AUTHOR]

There has been limited research on assessing metalloproteinases (MMPs) 1, 2, and 7, as well as their tissue inhibitors (TIMPs) 1, 2, 3, and 4 in the context of polytrauma. These proteins play crucial roles in various physiological and pathological processes and could be a reliable tool in polytrauma care. We aimed to determine their clinical relevance. We assessed 24 blunt polytrauma survivors and 12 fatalities (mean age, 44.2 years, mean ISS, 45) who were directly admitted to our Level I trauma center and spent at least one night in the intensive care unit. We measured serum levels of the selected proteins on admission (day 0) and days 1, 3, 5, 7, and 10. The serum levels of the seven proteins varied considerably among individuals, resulting in similar median trend curves for TIMP1 and TIMP4 and for MMP1, MMP2, TIMP2, and TIMP3. We also found a significant interrelationship between the MMP2, TIMP2, and TIMP3 levels at the same measurement points. Furthermore, we calculated significant cross-correlations between MMP7 and MMP1, TIMP1 and MMP7, TIMP3 and MMP1, TIMP3 and MMP2, and TIMP4 and TIMP3 and an almost significant correlation between MMP7 and TIMP1 for a two-day-lag. The autocorrelation coefficient reached statistical significance for MMP1 and TIMP3. Finally, lower TIMP1 serum levels were associated with in-hospital mortality upon admission. The causal effects and interrelationships between selected proteins might provide new insights into the interactions of MMPs and TIMPs. Identifying the underlying causes might help develop personalized therapies for patients with multiple injuries. Administering recombinant TIMP1 or increasing endogenous production could improve outcomes for those with multiple injuries. However, before justifying further investigations into basic research and clinical relevance, our findings must be validated in a multicenter study using independent cohorts to account for clinical and biological variability. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a musculoskeletal disease that can lead to the loss and inability of those affected to perform normal daily functions, which leads to a decrease in quality of life. The main symptoms of osteoarthritis are tenderness, joint pain, stiffness, crepitus, limited movement, and local inflammation. The selected patents were deposited from 2010 to April 2022 involving 57 documents that were in line with the study objective in the final selection. The patents were classified in years, country, and applicants. Also, the therapeutic fields that presented the most documents were electrical stimulation, phototherapy, and ultrasound, followed by magnetic, electromagnetic, and thermotherapy. Therefore, the most current therapies used in the documents are already on the market. Although the OA is cureless, non-surgical treatments are classified as the primary management approach for this disease. The pharmacological and non-pharmacological therapies are employed to reduce its prevalence and ensure the effectiveness of treatments. A strategy for relieving OA symptoms is non-pharmacological treatment, which can be based on exercise and patient education, combined with other alternative therapies. These therapies are used as supplements to the main OA treatments, enhancing the effectiveness of treatment outcomes. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy. Results: In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC. Conclusion: For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of mortality worldwide. B-cells are a keystone of the adaptive immune response and are essential for the presentation of tumor-associated antigens to various types of T-cells. Approximately 1.5% of global cancer cases, including breast and gastric carcinomas and both Hodgkin's and non-Hodgkin's lymphomas, are linked with prior Epstein–Barr Virus (EBV) infection. Such properties make EBV-infected lymphocytes ideal models for understanding the effect of oxyhydrogen gas on dysfunctional cell cycling. The aim of this study is to assess the effects of the direct infusion of oxyhydrogen gas on the replicative capacity of EBV-immortalised B-lymphocytes. Oxyhydrogen gas was directly infused into cell culture media. Cells were incubated in 95% air and 5% CO2 for up to 72 h. Cell enumeration was assessed with and without the addition of mitogenic growth stimuli, and subsequent cell-cycle analysis was performed. Cell enumeration: An initial trend of replicative inhibition of TK6 cells is noted with a single oxyhydrogen treatment at the 24 and 48 h time points. The daily addition of oxyhydrogen-infused media showed statistically relevant data at 24 and 48 h but not at 72 h. In mitogen-stimulated cells, a non-statistical trend of inhibition was observed at 24, 48 and 72 h. Analysis details a significant increase in DNA in the Sub G1 phase, indicating increased apoptosis. [ABSTRACT FROM AUTHOR]

The fifth generation (5G) network is currently being worldwide spread out, raising questions about the potential impact of this new technology, particularly on immature organisms. The current study aimed to investigate the effects of daily 5G electromagnetic field (EMF) perinatal exposure on the neurodevelopment of rats. The exposure level was set to the limit of whole-body public exposure defined by the International Commission on Non-Ionizing Radiation Protection. The mother rat specific absorption rate (SAR) was 0.07 W/kg for 22 h/day at 3500 MHz continuous wave from gestational day (GD) 8 to post-natal day (PND) 21. Clinical observations were performed on weight, length, sex ratio, number of pups per litter, and number of stillborn in sham and EMF-exposed groups (n = 7). The age of pinna ear detachment, incisor eruption, and eye opening were recorded. Behavior was assessed on righting, gripping, and negative geotaxis reflexes at PND 3 or 7 and on stereotyped and horizontal movements in the open field at PND 43. Our results indicated that both male and female pups showed delayed incisor eruption in the EMF-exposed group compared to the sham group (+ 1 day). Regarding activity in the open field, adolescent females showed less stereotyped movements (− 70%), while adolescent males showed more stereotyped movements (+ 50%) compared to the sham-exposed adolescent rats. Thus, the present study suggested that perinatal exposure to 5G at SAR level below reglementary threshold led to perturbations in the descendants seen in juveniles and adolescents. [ABSTRACT FROM AUTHOR]

As Australian lupin cultivars are rich sources of polyphenols, dietary fibers, high-quality proteins, and abundant bioactive compounds with significant antioxidant, antidiabetic, and anticancer activities, this research work is aimed at investigating the colon cancer alleviation activity of nine cultivars of lupin seeds on HCT116 and HT29 colon carcinoma cell lines through anti-proliferation assay, measurement of apoptosis, and identification of the mechanism of apoptosis. Nine cultivars were pre-screened for anti-proliferation of HCT116 and HT29 cells along with consideration of the impact of heat processing on cancer cell viability. Mandelup and Jurien showed significant inhibition of HCT116 cells, whereas the highest inhibition of HT29 cell proliferation was attained by Jurien and Mandelup. Processing decreased the anti-proliferation activity drastically. Lupin cultivars Mandelup, Barlock, and Jurien (dose: 300 μg/mL) induced early and late apoptosis of colon cancer cells in Annexin V-FITC assay. The mechanism of apoptosis was explored, which involves boosting of caspases-3/7 activation and intracellular reactive oxygen species (ROS) generation in HCT116 cells (Mandelup and Barlock) and HT29 cells (Jurien and Mandelup). Thus, the findings showed that lupin cultivars arrest cell cycles by inducing apoptosis of colorectal carcinoma cells triggered by elevated ROS generation and caspases-3/7 activation. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) is primarily classified by immunohistochemistry (IHC) and digital image analysis (DIA) based on distinct immunophenotypes of malignant epithelial cells. When antiangiogenic and immunomodulatory therapies are used for BC, the stromal components such as tumor vessels and immune cells have received more attention. Cancer-associated fibroblasts (CAFs) are extensively investigated, but measuring them in immunostained tissues and determining how they relate to clinical and pathological criteria is still difficult in BC. Our earlier research using CD34 and α-smooth muscle actin (αSMA) immunohistochemistry showed a decrease of CD34-positive CAFs and an increase of αSMA-positive CAFs inside the tumor stroma. This early basic microscopic finding gives us the intention to employ DIA to improve SMA-positive CAF quantification accuracy. Additional DIA processed data correlations to pathologic parameters, survival, invasion, and recurrence indicated substantial differences between BC molecular subtypes, suggesting a unique CD34- and αSMA-positive CAF impact for each subtype. Background: Breast cancer (BC) stroma has CD34- and αSMA-positive cancer-associated fibroblasts (CAFs) differently distributed. During malignant transformation, CD34-positive fibroblasts decrease while αSMA-positive CAFs increase. The prevalence of αSMA-positive CAFs in BC stroma makes microscopic examination difficult without digital image analysis processing (DIA). DIA was used to compare CD34- and αSMA-positive CAFs among breast cancer molecular subgroups. DIA-derived data were linked to age, survival, tumor stroma vessels, tertiary lymphoid structures (TLS), invasion, and recurrence. Methods: Double immunostaining for CD34 and αSMA showed different CAF distribution patterns in normal and BC tissues. Single CD34 immunohistochemistry on supplemental slides quantified tumor stroma CD34_CAFs. Digital image analysis (DIA) data on CAF density, intensity, stromal score, and H-score were correlated with clinico-pathologic factors. Results: CD34/αSMA CAF proportion was significantly related to age in Luminal A (LA), Luminal B (LB), and HER2 subtypes. CD34_CAF influence on survival, invasion, and recurrence of LA, LB-HER2, and TNBC subtypes was found to be significant. The CD34/αSMA-expressing CAFs exhibited a heterogeneous impact on stromal vasculature and TLS. Conclusion: BC stromal CD34_CAFs/αSMA_CAFs have an impact on survival, invasion, and recurrence differently between BC molecular subtypes. The tumor stroma DIA assessment may have predictive potential to prognosis and long-term follow-up of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: The most common and deadly cancer in female is breast cancer (BC) and new incidence and deaths related to this cancer are rising. Aims: Several issues, that is, high cost, toxicity, allergic reactions, less efficacy, multidrug resistance, and the economic cost of conventional anti‐cancer therapies, has prompted scientists to discover innovative approaches and new chemo‐preventive agents. Materials: Numerous studies are being conducted on plant‐based and dietary phytochemicals to discover new‐fangled and more advanced therapeutic approaches for BC management. Result: We have identified that natural compounds modulated many molecular mechanisms and cellular phenomena, including apoptosis, cell cycle progression, cell proliferation, angiogenesis and metastasis, up‐regulation of tumor‐suppressive genes, and down‐regulation of oncogenes, modulation of hypoxia, mammosphere formation, onco‐inflammation, enzymatic regulation, and epigenetic modifications in BC. We found that a number of signaling networks and their components such as PI3K/Akt/mTOR, MMP‐2 and 9, Wnt/‐catenin, PARP, MAPK, NF‐κB, Caspase‐3/8/9, Bax, Bcl2, Smad4, Notch1, STAT3, Nrf2, and ROS signaling can be regulated in cancer cells by phytochemicals. They induce up‐regulation of tumor inhibitor microRNAs, which have been highlighted as a key player for ani‐BC treatments followed by phytochemical supplementation. Conclusion: Therefore, this collection offers a sound foundation for further investigation into phytochemicals as a potential route for the development of anti‐cancer drugs in treating patients with BC. [ABSTRACT FROM AUTHOR]

Chemoresistance remains the foremost challenge in cancer therapy. Targeting reactive oxygen species (ROS) manipulation is a promising strategy in cancer treatment since tumor cells present high levels of intracellular ROS, which makes them more vulnerable to further ROS elevation than normal cells. Nevertheless, dynamic redox evolution and adaptation of tumor cells are capable of counteracting therapy-induced oxidative stress, which leads to chemoresistance. Hence, exploring the cytoprotective mechanisms of tumor cells is urgently needed to overcome chemoresistance. Heme oxygenase-1 (HO-1), a rate-limiting enzyme of heme degradation, acts as a crucial antioxidant defense and cytoprotective molecule in response to cellular stress. Recently, emerging evidence indicated that ROS detoxification and oxidative stress tolerance owing to the antioxidant function of HO-1 contribute to chemoresistance in various cancers. Enhanced HO-1 expression or enzymatic activity was revealed to promote apoptosis resistance and activate protective autophagy, which also involved in the development of chemoresistance. Moreover, inhibition of HO-1 in multiple cancers was identified to reversing chemoresistance or improving chemosensitivity. Here, we summarize the most recent advances regarding the antioxidant, antiapoptotic, and pro-autophagy properties of HO-1 in mediating chemoresistance, highlighting HO-1 as a novel target for overcoming chemoresistance and improving the prognosis of cancer patients. [ABSTRACT FROM AUTHOR]

Electromagnetic fields (EMF) are increasing in popularity as a safe and non-invasive therapy. On the one hand, it is widely acknowledged that EMF can regulate the proliferation and differentiation of stem cells, promoting the undifferentiated cells capable of osteogenesis, angiogenesis, and chondroblast differentiation to achieve bone repair purpose. On the other hand, EMF can inhibit tumor stem cells proliferation and promote apoptosis to suppress tumor growth. As an essential second messenger, intracellular calcium plays a role in regulating cell cycle, such as proliferation, differentiation and apoptosis. There is increasing evidence that the modulation of intracellular calcium ion by EMF leads to differential outcomes in different stem cells. This review summarizes the regulation of channels, transporters, and ion pumps by EMF-induced calcium oscillations. It furtherly discusses the role of molecules and pathways activated by EMF-dependent calcium oscillations in promoting bone and cartilage repair and inhibiting tumor stem cells growth. [ABSTRACT FROM AUTHOR]

Bisphenols, parabens (PBs), and benzophenones (BPs) are widely used environmental chemicals that have been linked to several adverse health effects due to their endocrine disrupting properties. However, the cellular pathways through which these chemicals lead to adverse outcomes in humans are still unclear, suggesting some evidence that inflammation might play a key role. Thus, the aim of this study was to summarize the current evidence on the relationship between human exposure to these chemicals and levels of inflammatory biomarkers. A systematic review of peer-reviewed original research studies published up to February 2023 was conducted using the MEDLINE, Web of Science, and Scopus databases. A total of 20 articles met the inclusion/exclusion criteria. Most of the reviewed studies reported significant associations between any of the selected chemicals (mainly bisphenol A) and some pro-inflammatory biomarkers (including C-reactive protein and interleukin 6, among others). Taken together, this systematic review has identified consistent positive associations between human exposure to some chemicals and levels of pro-inflammatory biomarkers, with very few studies exploring the associations between PBs and/or BPs and inflammation. Therefore, a larger number of studies are required to get a better understanding on the mechanisms of action underlying bisphenols, PBs, and BPs and the critical role that inflammation could play. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a group of enzymes that mediate both physiological and pathological processes such as carcinogenesis. The role of matrix metalloproteinase-3 (MMP-3) and (MMP-7) in the pathogenesis of breast cancer (BC) has been demonstrated, suggesting that they may be considered as potential markers of this condition. The aim of this study was to assess plasma concentrations and diagnostic utility of MMP-3 and MMP-7 in 100 patients with early-stage breast cancer with Luminal A subtype or Luminal B HER-negative subtype, before and after surgical treatment, and in the following control groups: patients with a benign tumor (fibroadenoma) and healthy subjects. The concentrations of MMP-3 and MMP-7 were referenced to the levels of the widely recognized marker for BC diagnosis CA 15-3. MMP-3 and MMP-7 was measured by ELISA method and CA 15-3 by CMIA. Plasma levels of MMP-7 were significantly higher in Luminal A and Luminal B HER2-negative subtype breast cancer patients as compared to the healthy group. MMP-7 demonstrated comparable but mostly higher to CA 15-3 or MMP-3 values of diagnostic sensitivity, specificity, positive and negative predictive values and AUC (0.6888 for Luminal A subtype; 0.7612 for Luminal B HER2-negative; 0.7250 for BC total group, respectively) in the groups tested. The combined use of the tested parameters resulted in a further increase in diagnostic criteria and AUC. These results suggest the usefulness of combining MMP-7 with CA 15-3 in the diagnostics of breast cancer, especially in Luminal B HER2-negative subtypes patients, as a new candidate for tumor markers. [ABSTRACT FROM AUTHOR]

The potential use of agomelatine as an alternative treatment for colorectal cancer is evaluated in this work. The effect of agomelatine was studied in an in vitro model using two cell lines with different p53 statuses (HCT-116, wild-type p53, and HCT-116 p53 null) and an in vivo xenograft model. The inhibitory effects of agomelatine and melatonin were stronger in the cells harboring the wild-type p53, although in both cell lines, the effect of agomelatine was greater than that of the melatonin. In vivo, only agomelatine was able to reduce the volumes of tumors generated by the HCT-116-p53-null cells. Both treatments induced changes in the rhythmicity of the circadian-clock genes in vitro, albeit with some differences. Agomelatine and melatonin regulated the rhythmicity of Per1-3, Cry1, Sirt1, and Prx1 in the HCT-116 cells. In these cells, agomelatine also regulated Bmal1 and Nr1d2, while melatonin changed the rhythmicity of Clock. In the HCT-116-p53-null cells, agomelatine regulated Per1-3, Cry1, Clock, Nr1d2, Sirt1, and Prx1; however, melatonin only induced changes in Clock, Bmal1, and Sirt1. The differences found in the regulation of the clock genes may explain the greater oncostatic effect of agomelatine in CRC. [ABSTRACT FROM AUTHOR]

Breast cancer has become the most common cancer worldwide. Despite the major advances made in the past few decades in the treatment of breast cancer using a combination of chemotherapy, endocrine therapy, and immunotherapy, the genesis, treatment, recurrence, and metastasis of this disease continue to pose significant difficulties. New treatment approaches are therefore urgently required. Zinc is an important trace element that is involved in regulating various enzymatic, metabolic, and cellular processes in the human body. Several studies have shown that abnormal zinc homeostasis can lead to the onset and progression of various diseases, including breast cancer. This review highlights the role played by zinc transporters in pathogenesis, apoptosis, signal transduction, and potential clinical applications in breast cancer. Additionally, the translation of the clinical applications of zinc and associated molecules in breast cancer, as well as the recent developments in the zinc-related drug targets for breast cancer treatment, is discussed. These developments offer novel insights into understanding the concepts and approaches that could be used for the diagnosis and management of breast cancer. [ABSTRACT FROM AUTHOR]

5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a metabolite of HO-1, was administered to sarcoma cells via carbon-monoxide-releasing molecule 2 (CORM2), it enhanced sphere-forming ability. We also compared the concentration of biliverdin (BVD) (a co-product of HO-1 activity alongside CO) with sphere-forming ability when HO-1 activity was inhibited using ZnPPIX in the dark. Both cell types showed a peak in sphere-forming ability at 60–80 μM BVD. Furthermore, a cell death inhibitor assay revealed that the HO-1-induced suppression of sphere formation was rescued by apoptosis or ferroptosis inhibitors. These findings suggest that in the absence of excitation, ALA promotes HO-1 expression and enhances the stemness of sarcoma cells, although excessive HO-1 upregulation induces apoptosis and ferroptosis. Our data indicate that systemic ALA administration induces both enhanced stemness and cell death in malignant cells located in dark environments deep in the body and highlight the need to pay attention to drug delivery and ALA concentrations during phototherapy. [ABSTRACT FROM AUTHOR]