Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review.

The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.

Closing the Gender Gap Among Canadian Ophthalmology Societies.

OBJECTIVE: To evaluate gender distribution in Canadian ophthalmology societies' leadership and to determine associations between gender, academic productivity, and institutional rank. METHODS: We identified members and assessed their gender composition using publicly available updated webpages. SCOPUS database was used to gather research metrics. RESULTS: In this study, data was collected from 12 Canadian ophthalmology societies, which included 277 executive committee members. Of these, 70.5% (196) were male and 29.1% (81) were female (p < .0001). Males were significantly more prevalent in presidential leadership roles (39 males vs. 23 females, p = .02), while females were more represented in other leadership categories (77 females vs. 61 males, p = .03). The Canadian Ophthalmological Society (COS) showed an upward trend in female representation from 19.2% in 2016 to 42.3% in 2021. Research productivity showed a positive correlation with society leadership rank, with a correlation coefficient of 0.732 for the m-index (p < .001) and 0.356 for the h-index (p < .05). Academic rank was also positively correlated with society leadership rank, with a correlation coefficient of 0.536 (p < .001). There was no significant difference in h-index (12.7 ± 1.0 for males vs. 13.8 ± 1.5 for females, p = .85) or number of publications (48.6 ± 5.1 for males vs. 60.0 ± 11.3 for females, p = .83) between male and female executive members, but females had a higher m-index (0.67 ± 0.05) compared to males (0.58 ± 0.03, p < .05). In academic rank, males were more likely to be associate professors (25% vs. 5% for females, p = .0001) or instructors (14.8% vs. 6.3% for females, p = .05), while a higher proportion of females held assistant professor positions (47.5% for females vs. 30.1% for males, p = .006). CONCLUSION: In this study, we found that males were more prevalent in executive positions, particularly in presidential roles among Canadian ophthalmology societies. The gender distribution in leadership reflected the gender composition of practicing ophthalmologists in Canada. There was a positive correlation between research productivity and society rank, as well as academic position and society rank. Male and female executive members had similar h-index and number of publications, but females had a higher m-index. These findings highlight the need for continued efforts to address gender disparities in ophthalmology leadership.

Evaluation of the Anti-Metastatic Effect of Foeniculum Vulgare on the Protein Expression of HSP 70 & 90 in Balb/c Mice with 4t1 Model of Breast Cancer.

INTRODUCTION: Breast cancer is one of the important factors of cancer-related deaths. Considering the drug resistance, special attention has been paid to natural compounds. This study aimed at evaluating the anti-metastatic activity of fennel in a breast cancer mouse model. METHODS: A total of 35 adult female BALB/C mice were used in this study. Breast cancer was induced by subcutaneous injection of 4T1 cells in the right lower flank. The mice received fennel extracts daily via intraperitoneal injection for two weeks. Meanwhile, tumor volume was measured every day using calipers. After two weeks, each animal was anesthetized. The protein expression of HSP 70 & 90 was measured in liver tissue and ovary. The expression of her2 was measured in tumor tissue. The activity of Glutathione peroxidase and reductase as anti-oxidant agents were measured in serum. RESULTS: Tumor size significantly decreased after nine days' treatment of the fennel. The expression of HER2 increased in the tumor tissue and decrease with different dose of fennel. Fennel treatment caused a decrease in the protein expression of HSP 70 & 90 in the liver tissues. CONCLUSION: Based on our findings, fennel has anti-tumor and anti-metastatic activities against aggressive cancers.

Gene expression analysis of intestinal IL-8, IL-17 A and IL-10 in patients with celiac and inflammatory bowel diseases.

BACKGROUND: Celiac disease (CeD) and inflammatory bowel disease (IBD) are accompanied by impaired immune responses. To study the immune regulation of these diseases, we evaluated the expression levels of pro-inflammatory (IL-8 and IL-17 A) and anti-inflammatory (IL-10) cytokines in intestinal biopsy specimens of CeD and IBD patients in comparison to healthy subjects. METHODS AND RESULTS: Intestinal biopsies were collected from 33 patients with IBD, 47 patients with CeD, and 20 healthy individuals. Total RNA was extracted and mRNA expression levels of IL-8, IL-17 A and IL-10 were assessed by qPCR. P-value < 0.05 was considered statistically significant. The expression levels of IL-8 and IL-17 A were higher in biopsies of IBD (UC and CD) and CeD patients compared to the control group (P < 0.05). IBD patients (UC and CD) had higher IL-8 intestinal level than CeD patients (P < 0.0001 and P = 0.0007, respectively). The expression of IL-10 was significantly down-regulated in intestinal biopsies of CeD and IBD patients compared with controls (P < 0.001). In addition, the expression level of this cytokine was significantly lower in IBD patients (P < 0.001 for UC patients and P < 0.0001 for CD patients) than CeD group. CONCLUSIONS: The three selected pro- and anti-inflammatory cytokines showed a similar expression pattern in both IBD and CeD patients. As IBD and CeD are immune-mediated disorders and are accompanied by inflammatory events, the understanding of the similarities and differences among them can help researchers to find out useful candidate therapeutic protocols. We suggest that larger cohort studies be organized to achieve more insights into this regulation.

Localized ocular crystal-storing histiocytosis and associated lymphoma - Report of two cases and review of literature.

PURPOSE: To add to the existing yet limited body of knowledge around crystal-storing histiocytosis (CSH) with two case reports of localized ocular CSH and associated mucosa-associated lymphoid tissue (MALT) lymphoma involving the lacrimal and orbital soft tissues without underlying systemic lymphoproliferative disorders and to provide a literature review of all cases of CSH with associated ophthalmic findings reported to date. OBSERVATIONS: A 62-year-old male presented with a one-year history of right greater than left upper eyelid swelling and epiphora. Ophthalmic exam and computed tomography (CT) head scan revealed bilateral soft tissue masses superior to the globe encasing the supraorbital artery with poor margins from the superior rectus muscle. A biopsy of the lesion showed low grade B-cell lymphoma and associated CSH with lymphoma making up the bulk of the tumor and with CSH comprising a minor component of the overall tumor volume. Further investigations did not show any evidence of systemic lymphoproliferative disorders. He received local irradiation of orbits, which resulted in complete resolution of disease.An 85-year-old female with no significant past ocular history referred to ophthalmology services for an incidental finding of an enlarged left lacrimal gland on a CT head scan. Ophthalmic exam and subsequent magnetic resonance imaging (MRI) demonstrated an enlarged left lacrimal gland. A biopsy of the lesion showed MALT lymphoma associated with CSH. In this case, CSH comprised the bulk of the clinical mass rather than lymphoma. Following negative systemic investigations, she received a short course of localized radiotherapy with a 50% regression of disease seen on follow-up CT scan. CONCLUSION AND IMPORTANCE: These two cases demonstrate a spectrum of morphology associated with CSH. In addition, they show that although localized ocular CSH is rare, CSH should be considered in the differential of an orbital mass and should lead to consideration of further investigation for systemic lymphoproliferative disorders.

Smart arginine-equipped polycationic nanoparticles for p/CRISPR delivery into cells.

An efficient and safe delivery system for the transfection of CRISPR plasmid (p/CRISPR) into target cells can open new avenues for the treatment of various diseases. Herein, we design a novel nonvehicle by integrating an arginine-disulfide linker with low-molecular-weight PEI (PEI1.8k) for the delivery of p/CRISPR. These PEI1.8k-Arg nanoparticles facilitate the plasmid release and improve both membrane permeability and nuclear localization, thereby exhibiting higher transfection efficiency compared to native PEI1.8kin the delivery of nanocomplexes composed of PEI1.8k-Arg and p/CRISPR into conventional cells (HEK 293T). This nanovehicle is also able to transfect p/CRISPR in a wide variety of cells, including hard-to-transfect primary cells (HUVECs), cancer cells (HeLa), and neuronal cells (PC-12) with nearly 5-10 times higher efficiency compared to the polymeric gold standard transfection agent. Furthermore, the PEI1.8k-Arg nanoparticles can edit the GFP gene in the HEK 293T-GFP reporter cell line by delivering all possible forms of CRISPR/Cas9 system (e.g. plasmid encoding Cas9 and sgRNA targeting GFP, and Cas9/sgRNA ribonucleoproteins (RNPs) as well as Cas9 expression plasmid andin vitro-prepared sgRNA) into HEK 293T-GFP cells. The successful delivery of p/CRISPR into local brain tissue is also another remarkable capability of these nanoparticles. In view of all the exceptional benefits of this safe nanocarrier, it is expected to break new ground in the field of gene editing, particularly for therapeutic purposes.

Immunological response of fallopian tube epithelial cells to spermatozoa through modulating cytokines and chemokines.

BACKGROUND: Spermatozoa interactions with fallopian tubes may influence fertilization. The purpose was to investigate cytokines, chemokines and growth factors expression from human fallopian tube epithelial cells (OE-E6/E7) exposed to spermatozoa. METHODS: Fresh semen samples were obtained from 10 healthy normozoospermic men. Sperms were prepared and co-cultured with OE-E6/E7. The cell line without spermatozoa was considered as the control group. Afterwards, Expression of 84 cytokines from OE-E6/E7 cell line in the presence and absence of spermatozoa were measured using PCR-array. Quantitative PCR was performed on seven genes to confirm the results of PCR-array analysis. Differentially expressed genes were subjected to www.geneontology.org and www.pantherdb.org to perform GO enrichment and panther pathway analysis. The concentration of IL-8, IL-10, IL-1B and BMP-4 in culture medium were analyzed by ELISA. RESULTS: Sperm interaction with the epithelial cells resulted in a significant increase in expression of TGF-ß2, BMP-4, IL-10, IL-9, and CD40LG markers. Moreover, expression of IL-16, IL-17F, SPP-1, CXCL-13, MSTN, IL-1A, IL-1B, IL-8, BMP-7, CSF-2, CSF-3, VEGF-A, OSM, LTA, TNF, TNFRSF11B, TNFSF11, CCL-11, CCL-20, CCL-24, CCL-3, CCL-8, CX3CL1 and CXCL-9 were considerably reduced in presence of spermatozoa. Panther pathway analysis discovered 3 pathways for upregulated genes including gonadotropin-releasing hormone receptor, TGF-beta and interleukin signaling pathways. Furthermore, 9 pathways were detected for down-regulated genes. Inflammation signaling pathway which is mediated by chemokine and cytokine contains the most number of genes. CONCLUSION: This study indicates that sperm modifies expression of cytokines, chemokines and growth factors from OE-E6/E7. Moreover, altered genes expression are toward higher survival chance of the spermatozoa.

Quantification of aerosol generation during cataract surgery.

PURPOSE: To determine whether phacoemulsification cataract surgery is an aerosol-generating medical procedure (AGMP) and, therefore, to help determine the personal protective equipment required by healthcare providers in the era of the COVID-19. SETTING: The Surgery, Teaching and Research Wet Lab of the Department of Ophthalmology and Visual Sciences, Faculty of Medicine, UBC. DESIGN: Laboratory-based simulation. METHODS: Phacoemulsification cataract surgery was performed on porcine eyes. At a fixed distance, a DRX Aerosol Monitor 8534 (DustTrak) was used to measure particulate matter (PM) mass fractions for each of 3 particle sizes, PM1, PM2.5, and PM4 (in microns), every 2 seconds during surgery and for 1 minute after. The main outcome measure was an increase in the mass fraction of aerosolized particles of various sizes. RESULTS: There was no significant aerosolization of particles during cataract surgery for both the 2.4 and 2.75 mm wound sizes. CONCLUSIONS: Phacoemulsification cataract surgery was not found to be an AGMP. In the midst of the COVID-19 pandemic, ophthalmologists can continue to use droplet precautions while performing this surgery.

Inflammatory Microenvironment of Acute Myocardial Infarction Prevents Regeneration of Heart with Stem Cells Therapy.

Over the past years, the benefits of stem cell therapy approach for treatment of the cardiovascular diseases have been shown through the rebuilding of new cardiomyocytes and blood vessels. while a successful regeneration of the myocardium has been proven on the animal models of acute myocardial injuries resulted from the stem cells transplantation, no significant long-term regenerative with autologous stem cell therapy in patients with acute myocardial infarction have been reported based on recent meta-analyses. It seems that the inflammatory microenvironment of acute myocardial infarction has an inhibitory effect on the stem cells potential for regenerating the injured myocardium. Secretion of critical cytokines with pro-inflammatory properties including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 as well as induction of hypoxic condition and finally formation of cytotoxic elements cause the cellular death and hinder the stem cells proliferation and differentiation. Based on the evidence, application of some approaches like co-delivery of mesenchymal stem cells with the other useful cells, using the stem cells derived productions, administration of preconditioned and modified cells, and also using the anti-inflammatory agents besides the cell therapy are hypothesized as the primary developed safe and practical approaches for decreasing destructive effects of the inflammation on the implanted stem/progenitor cells. In this review, we critically discuss the quiddity of the inflammatory microenvironment and its promoted mechanisms as the main elements to hinder the efficacy of stem cell therapy in the cases of acute myocardial infarction. Also, we finally propose some applied solutions to the problem of cardiac regeneration with stem cells therapy.

Some notes on stem cell therapy in cardiovascular diseases.

Cardiovascular diseases have become an increasing clinical issue worldwide. Acute ischaemic injury and chronic cardiomyopathies lead to permanent loss of cardiac tissue and ultimately heart failure. Current therapies widely aim to attenuate the pathological changes that occur after injury and to reduce risk factors of cardiovascular diseases. However, they do not improve the patient's quality of life or the prognosis more than moderate. A new challenge in the treatment of the cardiovascular disease is cellular transplantation or cellular cardiomyoplasty. Different types of stem cells have been used for stem cell therapy. Clinical trials using primary bone-marrow-derived cells and skeletal myoblasts have also shown some encouraging results. An additional clinical and pre-clinical study to further enhance the beneficial effects of cell therapy is necessary. Recent studies have shown that there are various pools of putative resident stem cells in an adult heart, raising the hope that these cells can contribute to the treatment of cardiovascular diseases.