Phytochemical-mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach.

Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro-survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro-survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress-mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical-induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6-gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well-documented mechanistic interplay between autophagy and ER stress, only a one-way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ-tocotrienol): ER stress-dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies.

Non-communicable airway disease and air pollution in three African Countries: Benin, Cameroon and The Gambia.

BACKGROUND: Air pollution exposure can increase the risk of development and exacerbation of chronic airway disease (CAD). We set out to assess CAD patients in Benin, Cameroon and The Gambia and to compare their measured exposures to air pollution. METHODOLOGY: We recruited patients with a diagnosis of CAD from four clinics in the three countries. We collected epidemiological, spirometric and home air pollution data. RESULTS: Of the 98 adults recruited, 56 were men; the mean age was 51.6 years (standard deviation ±17.5). Most (69%) patients resided in cities and ever smoking was highest in Cameroon (23.0%). Cough, wheeze and shortness of breath were reported across the countries. A diagnosis of asthma was present in 74.0%; 16.3% had chronic obstructive pulmonary disease and 4.1% had chronic bronchitis. Prevalence of airflow obstruction was respectively 77.1%, 54.0% and 64.0% in Benin, Cameroon, and Gambia. Across the sites, 18.0% reported >5 exacerbations. The median home particulate matter less than 2.5 µm in diameter (PM2.5) was respectively 13.0 µg/m3, 5.0 µg/m3 and 4.4 µg/m3. The median home carbon monoxide (CO) exposures were respectively 1.6 parts per million (ppm), 0.3 ppm and 0.4 ppm. Home PM2.5 differed significantly between the three countries (P < 0.001) while home CO did not. CONCLUSION: Based on these results, preventive programmes should focus on ensuring proper spirometric diagnosis, good disease control and reduction in air pollution exposure.

CONTEXTE: L'exposition à la pollution de l'air peut accroître le risque de développement et d'aggravation des maladies chroniques des voies respiratoires (CAD). Nous avons entrepris d'évaluer les patients atteints de CAD au Bénin, au Cameroun et en Gambie et de comparer les niveaux d'exposition à la pollution de l'air qu'ils ont subis. MÉTHODOLOGIE: Nous avons sélectionné des patients ayant reçu un diagnostic de CAD dans quatre cliniques de ces trois pays. Nous avons collecté des informations épidémiologiques, des mesures spirométriques ainsi que des données sur la pollution de l'air à leur domicile. RÉSULTATS: En total, 98 individus adultes ont été sélectionnés pour cette étude. Parmi eux, 56 étaient de sexe masculin. L'âge moyen de ces participants était de 51,6 ans, avec un écart-type de ±17,5. La majorité des patients (69%) résidaient en milieu urbain, tandis que le taux de tabagisme le plus élevé était observé au Cameroun (23,0%). Les symptômes de toux, de respiration sifflante et d'essoufflement ont été rapportés dans tous les pays. Parmi les patients, 74% ont reçu un diagnostic d'asthme, 16,3% souffraient de maladie pulmonaire obstructive chronique et 4,1% de bronchite chronique. L'obstruction des voies respiratoires était présente respectivement chez 77,1%, 54,0% et 64,0% des cas au Bénin, au Cameroun et en Gambie. Sur l'ensemble des sites, 18,0% ont signalé plus de cinq exacerbations. La médiane des PM2.5 à domicile était de 13,0 µg/m3, 5,0 µg/m3 et 4,4 µg/m3, respectivement. Les expositions médianes au monoxyde de carbone (CO) à domicile étaient de 1,6 ppm, 0,3 ppm et 0,4 ppm respectivement. Les PM2,5 à domicile présentaient des différences significatives entre les trois pays (P < 0,001), contrairement au CO à domicile. CONCLUSION: En se basant sur ces résultats, il est recommandé que les programmes de prévention se focalisent sur un dépistage spirométrique adéquat, une gestion efficace de la maladie et une diminution de l'exposition à la pollution atmosphérique.

Oncology nurses' lived experience of caring for patients with advanced cancer in healthcare systems without palliative care services.

BACKGROUND: Caring for patients with advanced cancer is complex and challenging, requiring varied expertise, including symptom management, communication skills, care coordination and emotional resilience. Within existing literature, the lived experiences of oncology nurses are poorly articulated in countries with a lower income where formal palliative care (PC) is absent. AIM: To explore the lived experiences of Gazan oncology nurses who provide care to patients with advanced cancer in healthcare systems, without formal palliative care infrastructure. METHODS: A phenomenological approach was adopted. Semi-structured interviews were conducted between January and April 2022, in the Turkish Palestinian Friendship Hospital. Thematic analysis used the themes (corporeality, relationality, spatiality and temporality) to facilitate reflection on the meaning of participants' lived experiences. RESULTS: Interviews were undertaken with 16 oncology nurses. The experience of the 'erosion of nurses' work when coping with anxious attachments to patients and families' was the overarching theme in nurses' views, characterised by five sub-themes: (1) inadequacy of PC training and resources, (2) serving humanity, (3) pride in their profession, (4) existential distress and the coping strategies used by nurses, and (5) reported stress and anxiety when caring for seriously ill patients and their families. CONCLUSIONS: The study sheds light on the challenges and powerful emotions experienced by oncology nurses who care for patients with advanced cancer, yet lack the necessary PC training and institutional resources. The findings indicate an urgent need for PC training for nurses within the Gazan healthcare system and other lower-income settings. Assessing nurses' emotions and relationships with patients and family caregivers is imperative to enable optimum care for patients with cancer and to foster resilience among their nurses.

Exploring the Interplay between Vitamin D, Insulin Resistance, Obesity and Skeletal Health.

Vitamin D (ViD), plays an important role in calcium absorption and bone mineralization, is associated with bone mineral density. Severe deficiency in ViD has long been linked to conditions such as rickets in children and osteomalacia in adults, revealing its substantial role in skeletal health. Additionally, investigations show an existing interconnection between ViD and insulin resistance (Ins-R), especially in patients with type 2 diabetes mellitus (T2DM). Obesity, in conjunction with Ins-R, may augment the risk of osteoporosis and deterioration of skeletal health. This review aims to examine recent studies on the interplay between ViD, Ins-R, obesity, and their impact on skeletal health, to offer insights into potential therapeutic strategies. Cochrane Library, Google Scholar, and Pubmed were searched to investigate relevant studies until December 2023. Current research demonstrates ViD's impact on pancreatic ß-cell function, systemic inflammation, and insulin action regulation. Our findings highlight an intricate association between ViD, Ins-R, obesity, and skeletal health, providing a perspective for the prevention and/or treatment of skeletal disorders in patients with obesity, Ins-R, and T2DM.

Relationship between lncRNA MALAT1 and Chemo-radiotherapy Resistance of Cancer Cells: Uncovered Truths.

The advancement of novel technologies, coupled with bioinformatics, has led to the discovery of additional genes, such as long noncoding RNAs (lncRNAs), that are associated with drug resistance. LncRNAs are composed of over 200 nucleotides and do not possess any protein coding function. These lncRNAs exhibit lower conservation across species, are typically expressed at low levels, and often display high specificity towards specific tissues and developmental stages. The LncRNA MALAT1 plays crucial regulatory roles in various aspects of genome function, encompassing gene transcription, splicing, and epigenetics. Additionally, it is involved in biological processes related to the cell cycle, cell differentiation, development, and pluripotency. Recently, MALAT1 has emerged as a novel mechanism contributing to drug resistance or sensitivity, attracting significant attention in the field of cancer research. This review aims to explore the mechanisms through which MALAT1 confers resistance to chemotherapy and radiotherapy in cancer cells.

A huge benign gastric schwannomas presented with upper and lower gastrointestinal bleeding: a case report and literature review.

Gastric schwannomas (GS) are rare mesenchymal tumors from Schwann cells in the gastrointestinal (GI) tract, representing 2-6% of such tumors. We report a 52-year-old woman who experienced abdominal pain, hematemesis, and melena, initially suspected of having a GI stromal tumor through ultrasound and computed tomography abdomen. Despite no active bleeding found during an upper endoscopy, she underwent a successful open subtotal gastrectomy, with histopathology confirming GS. The diagnosis of GS, which may mimic other GI conditions, relies heavily on imaging and histopathological analysis due to its nonspecific symptomatology, including the potential for both upper and lower GI bleeding. This case underscores the diagnostic challenges of GS and highlights surgical resection as the preferred treatment, generally leading to a favorable prognosis.

Moderate ischemic mitral regurgitation in ischemic heart disease: to operate or not? A meta-analysis.

INTRODUCTION: Deciding whether to perform coronary artery bypass grafting (CABG) alone or in combination with mitral valve repair is a common dilemma encountered by surgeons when treating patients with ischemic mitral regurgitation, a common condition related to coronary artery disease. Although ischemic mitral regurgitation after CABG has been linked to unfavorable results, the benefits of including mitral valve repair are still unknown. This discrepancy led us to undertake a systematic review and meta-analysis to determine whether combining CABG with mitral valve surgery leads to better clinical results than CABG alone. EVIDENCE ACQUISITION: Studies comparing the results of CABG versus CABG with mitral valve replacement were searched in the databases of PubMed and Google Scholar. There were six randomized clinical trials included in this study. EVIDENCE SYNTHESIS: We analyzed 852 patients' data. There were no significant variations between patients who acquired CABG alone or CABG+(MVR) in terms of their risk of death at one year, stroke, atrial fibrillation, or hospitalization for heart failure. For recurrent/residual mitral regurgitation; it revealed an RR=5.42, 95% CI, 0.77 to 37.98, and a P-value of =0.065. According to the analysis of study heterogeneity, no apparent heterogeneity was identified in the outcomes of death after one year, stroke, atrial fibrillation, or hospitalization for heart failure. However, the outcome of recurrent or residual mitral regurgitation showed significant variation (I2=66%). CONCLUSIONS: Patients who underwent CABG alone versus CABG plus MVR did not differ significantly from one another. However, the comparison of CABG alone with CABG plus MVR underlines the need for customized treatment plans based on the unique characteristics of each patient.

Xanthoma of the Jaw Bones: Cases Series and Review of Literature.

BACKGROUND: Intraosseous xanthomas are rare benign lesions sometimes associated with excess lipid production. Xanthoma of the jaw bones (XJB) was first reported in 1964, and fewer than 50 cases have been reported in the English literature to date. The etiopathogenesis of XJB is highly suggestive of a reactive process or a metabolic condition. METHOD: Seven cases of XJBs were retrieved from the archives of 4 oral and maxillofacial pathology services. Clinical, radiographic and histopathologic features of all these cases were retrospectively analyzed. Immunohistochemical (IHC) stains for S100 and CD68 were performed. RESULTS: All seven cases involved the mandible. Patients' age ranged between 13 and 69 years with an evenly distributed female to male ratio. One patient had a medical history of hyperlipidemia, but the medical and dental histories of the others were unremarkable. For most cases, XJB was an incidental finding discovered during routine radiographic examination. Swelling and cortical expansion were noted in a few cases. Radiographically, cases typically presented as either well-defined multilocular or unilocular lesions, which were either radiolucent or mixed radiolucent/radiopaque. All the lesions were treated with surgical curettage and no recurrence was observed during subsequent follow-ups. Each of the seven cases exhibited sheets of foamy macrophages. The diagnosis is established by exclusion of entities with overlapping microscopic features and involved correlation with the clinical, histological, radiographic and IHC profiles. Immunohistochemically, all the cases expressed diffuse positivity for CD68 and were negative for S100. CONCLUSION: XJB is a rare lesion of unknown etiology, which may mimic other benign or reactive jaw lesions. Due to its rarity and the potential diagnostic challenges it presents, clinicians must remain vigilant and consider CXJ in their differential when assessing radiolucent jaw anomalies.

Increased frequency of oral plasma cell mucositis/plasma cell gingivitis after the COVID-19 pandemic: a 23-year retrospective analysis and review of diagnostic challenges relating to this condition.

OBJECTIVE: Oral plasma cell mucositis (PCM) or localized plasma cell gingivitis (PCG) is an idiopathic inflammatory condition often associated with hypersensitivity reactions. This study aimed to evaluate the frequency and features of PCM/PCG in a large biopsy service over a time period of more than 20 years. STUDY DESIGN: The biopsy archives at University of Florida College of Dentistry were searched from 2000 through the first quarter of 2023 for cases of oral PCM or PCG. Case data were aggregated and analyzed. RESULTS: A total of 107 cases were included. Between 2000 and 2019, PCM/PCG was diagnosed in 0.03% of all biopsy cases. Starting in 2020 through 2023, the percentage of biopsies diagnosed as PCM/PCG increased threefold to 0.10% of all biopsy cases, and the mean patient age increased by 3 years. There were no statistically significant differences between cases diagnosed from 2000 to 2019 and those from 2020 to 2023 regarding age, sex, location, or histology. CONCLUSIONS: A significant increase in PCM/PCG was identified in this study at one institution coinciding with the start of the COVID-19 pandemic. Further investigation is recommended to determine if this is a widespread phenomenon and identify possible etiologic mechanisms.

Assessment of the effect of drying on Brassica greens via a multiplex approach based on LC-QTOF-MS/MS, molecular networking, and chemometrics along with their antioxidant and anticancer activities.

Turnip (Brassica rapa var rapa L.) leaves are a rich source of versatile bioactive phytochemicals with great potential in the food and herbal industries. However, the effect of drying on its constituents has never been studied before. Hereto, three drying techniques were compared, namely, lyophilization (LY), vacuum oven (VO), and shade drying (SD). Chemical profiling utilizing liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS) combined with chemometrics showed the different impacts of the drying methods on the phytochemical composition of the alcoholic leaf extracts. Unsupervised principal component analysis (PCA) and supervised partial least squares-discriminant analysis (PLS-DA) of the LC-QTOF-MS/MS data showed distinct distant clustering across the three drying techniques. Loading plots and VIP scores demonstrated that sinapic acid, isorhamnetin glycosides, and sinapoyl malate were key markers for LY samples. Meanwhile, oxygenated and polyunsaturated fatty acids were characteristic for SD samples and oxygenated polyunsaturated fatty acids and verbascoside were characteristic for VO samples. LY resulted in the highest total phenolics (TP) and total flavonoid (TF) contents followed by SD and VO. LY and SD samples had much higher antioxidant activity than VO measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC), and iron metal chelation assays. According to the anticancer activity, the drying methods were ranked in descending order as SD > LY â‰« VO when tested against colon, breast, liver, and lung cancer cell lines. Among the identified compounds, flavonoids and omega-3 fatty acids were key metabolites responsible for the anticancer activity as revealed by partial least squares (PLS) regression and correlation analyses. In conclusion, compared to LY, SD projected out as a cost-effective drying method without compromising the phytochemical and biological activities of Brassica greens. The current findings lay the foundation for further studies concerned with the valorization of Brassica greens.

An Extremely Rare and Aggressive Case of Undifferentiated Carcinoma With Osteoclast-Like Giant Cells of the Pancreas Presenting as a Paraneoplastic Syndrome: A Case Report and Literature Review.

Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) is a rare tumor type of pancreatic cancer. Paraneoplastic syndromes, an idiopathic inflammatory myositis characterized by various skin manifestations (such as dermatomyositis (DM)), cannot be attributed to the primary tumor itself. Here, we report an unusual case of UC-OGC presenting as a paraneoplastic syndrome, the first reported from Saudi Arabia and the Arabian Gulf states. A 49-year-old Eritrean woman with known DM was referred to our hospital with a left-sided pleural effusion. Computed tomography of the abdomen revealed a large necrotic splenic mass (~17 × 12.9 × 18.2 cm). The patient underwent exploratory laparotomy with en bloc resection of the mass (splenectomy, distal pancreatectomy, and partial excision of the left hemidiaphragm). Following a histopathological examination of the mass, UG-OGC of the pancreas, presenting as a paraneoplastic syndrome, was diagnosed. To our knowledge, this case is the first to present a paraneoplastic syndrome associated with UC-OGC. The identification of an exceedingly rare tumor presenting atypically as a paraneoplastic syndrome shows the importance of conducting comprehensive examinations of patients with malignancies, emphasizing the need for more reports of similar cases.

Designing, DFT, biological, & molecular docking analysis of new Iron(III) & copper(II) complexes incorporating 1-{[-(2-Hydroxyphenyl)methylene]amino}-5,5-diphenylimidazolidine-2,4-dione (PHNS).

The exploration encompassed the synthesis and characterization of two innovative complexes, namely FePHNS and CuPHNS, employing a diverse array of analytical techniques such as elemental analysis, infrared and ultraviolet-visible spectroscopy, mass spectrometry, molar conductivity measurements, magnetic susceptibility assessments, and thermal analysis (TGA). In the spectral domain, infrared spectroscopy substantiated the tridentate ONS coordination of the PHNS ligand to the central metal atom. Thermal analysis offered valuable insights into the distribution and content of water molecules within the complexes. Density functional theory (DFT) calculations were harnessed to validate the molecular structures of both the PHNS ligand and its complex entities, providing an intricate comprehension of their quantum chemical parameters. The investigation extended to an evaluation of the in vitro antibacterial, antifungal, and antioxidant efficacy of the PHNS ligand and its complexes, revealing heightened biological activities for the complexes in comparison to the free PHNS ligand, notably with the CuPHNS complex demonstrating the highest activity, while the PHNS ligand exhibited the lowest. To delve into potential physiological activities, molecular docking studies were conducted, predicting the binding affinity of the compounds to proteins 2vf5 (Glucosamine-6-phosphate synthase in complex with glucosamine-6-phosphate) from Escherichia coli, 3cku (rate oxidase from Aspergillus flavus complexed with its inhibitor 8-azaxanthin and chloride) from Aspergillus flavus, and 5IJT (Crystal structure of Human Peroxiredoxin 2 Oxidized). The ensuing analysis of protein-ligand interactions and binding energies underscored the promising physiological activities of the investigated compounds, warranting further exploration for their potential in novel drug development.

Efficacy of Adjunctive Fotoenticine Photodynamic Therapy and Sapindus mukorossi Therapy on Clinical, Radiographic, and Cytokine Profile of Diabetics with Peri-Implantitis.

Objective: To evaluate effectiveness of Fotoenticine (FTC)-mediated photodynamic therapy (PDT) and Sapindus mukorossi (SM) as adjunct to mechanical debridement (MD) on peri-implant clinical parameters and levels of proinflammatory cytokines among diabetics. Background: FTC has exhibited robust photodynamic impact against Streptococcus mutans (i.e., an established caries-associated bacterium); however, its efficacy against periodontal pathogens is not known. Methods: One hundred six diabetics with peri-implantitis were randomly categorized into three groups: Group I consisted of 37 participants who were treated with only MD; group II comprised 35 participants who were treated with FTC-mediated PDT, in addition to MD; and group III consisted of 34 participants who were treated with SM, in addition to MD. Peri-implant clinical parameters [plaque index (PI), bleeding on probing (BOP), and probing depth (PD)] and radiographic outcomes [crestal bone loss (CBL)] (PI, BOP, and PD), together with peri-implant sulcular fluid (PISF) interleukin (IL)-1ß and IL-6 levels were measured at baseline and 6-month follow-up. Results: In group I (n = 37; 24 males +13 females), group II (n = 35; 20 males +15 females), and group III (n = 34; 17 males +17 females), the mean age of participants was 54.3 ± 4.6, 52.0 ± 5.5, and 50.8 ± 4.5 years, respectively. Significant improvement was observed in the scores of peri-implant PI (p = 0.01), BOP (p = 0.01), and PD (p = 0.02) at the 6-month follow-up among all study groups. Significant improvement in peri-implant CBL among group I subjects at 6-month follow-up compared to baseline (p < 0.05) was observed. PISF levels of IL-1ß and IL-6 improved at 6 months. Conclusions: As an adjunct to conventional MD, FTC-mediated PDT and SM might be used as potential therapeutic modalities among diabetics with peri-implantitis.

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance.

The majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer-related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting-edge targeted medications are now the go-to option for customized and all-encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC-targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well-known due to developments in precision diagnostics and the extensive use of second-generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI-H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast-growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.

Role of genetically engineered mesenchymal stem cell exosomes and LncRNAs in respiratory diseases treatment.

The term acute respiratory disease encompasses a wide range of acute lung diseases, which in recent years have been ranked among the top three deadly diseases in the world. Since conventional treatment methods, including the use of anti-inflammatory drugs, have had no significant effect on the treatment process of these diseases, the attention of the medical community has been drawn to alternative methods. Mesenchymal stem cells (MSC) are multipotential stem/progenitor cells that have extensive immunomodulatory and anti-inflammatory properties and also play a critical role in the microenvironment of injured tissue. MSC secretomes (containing large extracellular vesicles, microvesicles, and exosomes) are a newly introduced option for cell-free therapies that can circumvent the hurdles of cell-based therapies while maintaining the therapeutic role of MSC themselves. The therapeutic capabilities of MSCs have been showed in many acute respiratory diseases, including chronic respiratory disease (CRD), novel coronavirus 2019 (COVID -19), and pneumonia. MSCs offer novel therapeutic approaches for chronic and acute lung diseases due to their anti-inflammatory and immunomodulatory properties. In this review, we summarize the current evidence on the efficacy and safety of MSC-derived products in preclinical models of lung diseases and highlight the biologically active compounds present in the MSC secretome and their mechanisms involved in anti-inflammatory activity and tissue regeneration.

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift.

BACKGROUND: It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. METHODS: We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using 18 F-NaF for HAP and 18 F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods. RESULTS: Within 24 h of adding the small concentration of 1X of NSPS (~7 µM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18 F-Na Fuptake post NSPS treatment as expected; 18 F- uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that 18 F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone. CONCLUSION: Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study.

The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.

The mechanistic role of NAT10 in cancer: Unraveling the enigmatic web of oncogenic signaling.

N-acetyltransferase 10 (NAT10), a versatile enzyme, has gained considerable attention as a significant player in the complex realm of cancer biology. Its enigmatic role in tumorigenesis extends across a wide array of cellular processes, impacting cell growth, differentiation, survival, and genomic stability. Within the intricate network of oncogenic signaling, NAT10 emerges as a crucial agent in multiple cancer types, such as breast, lung, colorectal, and leukemia. This compelling research addresses the intricate complexity of the mechanistic role of NAT10 in cancer development. By elucidating its active participation in essential physiological processes, we investigate the regulatory role of NAT10 in cell cycle checkpoints, coordination of chromatin remodeling, and detailed modulation of the delicate balance between apoptosis and cell survival. Perturbations in NAT10 expression and function have been linked to oncogenesis, metastasis, and drug resistance in a variety of cancer types. Furthermore, the bewildering interactions between NAT10 and key oncogenic factors, such as p53 and c-Myc, are deciphered, providing profound insights into the molecular underpinnings of cancer pathogenesis. Equally intriguing, the paradoxical role of NAT10 as a potential tumor suppressor or oncogene is influenced by context-dependent factors and the cellular microenvironment. This study explores the fascinating interplay of genetic changes, epigenetic changes, and post-translational modifications that shape the dual character of NAT10, revealing the delicate balance between cancer initiation and suppression. Taken together, this overview delves deeply into the enigmatic role of NAT10 in cancer, elucidating its multifaceted roles and its complex interplay with oncogenic networks.

Effective exosomes in breast cancer: focusing on diagnosis and treatment of cancer progression.

Breast cancer (BC) is the most prevalent aggressive malignant tumor in women worldwide and develops from breast tissue. Although cutting-edge treatment methods have been used and current mortality rates have decreased, BC control is still not satisfactory. Clarifying the underlying molecular mechanisms will help clinical options. Extracellular vesicles known as exosomes mediate cellular communication by delivering a variety of biomolecules, including proteins, oncogenes, oncomiRs, and even pharmacological substances. These transferable bioactive molecules can alter the transcriptome of target cells and affect signaling pathways that are related to tumors. Numerous studies have linked exosomes to BC biology, including therapeutic resistance and the local microenvironment. Exosomes' roles in tumor treatment resistance, invasion, and BC metastasis are the main topics of discussion in this review.

Analysis of Gremlin 1 Levels Following Sleeve Gastrectomy.

BACKGROUND: In the current study, we aimed to assess the levels of Gremlin 1, an adipokine with a rich repertoire of metabolic effects, in association with the glycemic and lipid parameters after sleeve gastrectomy. MATERIAL AND METHODS: This study was conducted on 31 males with obesity aged 25 to 50 years who underwent sleeve gastrectomy. Plasma Gremlin 1 levels were evaluated using enzyme-linked immunosorbent assay (ELISA) at baseline and 6-12 months after the operation, along with body mass index, insulin, glucose, and lipid profile. RESULTS: Plasma Gremlin 1 levels were elevated (148.19±17.43 vs. 193.29±19.82 ng/mL, p < 0.05) after sleeve gastrectomy. This was accompanied by a decrease in body mass index (from 51.47±1.71 to 39.23±1.56 kg/m2, p < 0.05). Insulin and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) also exhibited a significant decrease (19.69±1.81 vs. 8.98±1.09 mIU/L and 6.52±0.98 vs. 2.57±0.036 p < 0.05, respectively) in the postoperative period. Total cholesterol levels were significantly increased after surgery (4.29±0.16 to 5.10±0.16, p < 0.05). Pearson correlation analysis showed that Gremlin 1 was positively correlated with insulin before surgery, but there was no significant correlation after surgery. CONCLUSION: The circulating Gremlin 1 levels were elevated postoperatively among our participants. The improvement in insulin sensitivity appears to be independent of the reported antagonistic effects of Gremlin 1.