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Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and CTLA4, play a pivotal role in modulating immune responses. Blocking these checkpoints unleashes anticancer activity, and the synergy observed when combining multiple checkpoint inhibitors underscores their potential for enhanced efficacy. Nivolumab and ipilimumab harness the host’s immune system to target cancer cells, presenting a powerful approach to prevent tumor development. Despite their efficacy, immune checkpoint inhibitors are accompanied by a distinct set of adverse effects, particularly immune-related adverse effects affecting various organs. Understanding these challenges is crucial for optimizing treatment strategies and ensuring patient well-being. Ongoing clinical trials are actively exploring the combination of checkpoint inhibitory therapies, aiming to decipher their synergistic effects and efficacy against diverse cancer types. This review discusses the mechanisms, adverse effects, and various clinical trials involving nivolumab and ipilimumab across different cancers, emphasizing their transformative impact on cancer treatment.

Breast cancer is caused by aberrant breast cells that proliferate and develop into tumors. Tumors have the potential to spread throughout the body and become lethal if ignored. Metastasis is the process by which invasive tumors move to neighboring lymph nodes or other organs. Metastasis can be lethal and perhaps fatal. The objective of our study was to elucidate the molecular mechanisms underlying the transition of Ductal Carcinoma In Situ (DCIS) to Invasive Ductal Carcinoma (IDC), with a particular focus on hub genes and potential therapeutic agents. Using Weighted Gene Co-expression Network Analysis (WGCNA), we built a comprehensive network combining clinical and phenotypic data from both DCIS and IDC. Modules within this network, correlated with specific phenotypic traits, were identified, and hub genes were identified as critical markers. Receiver Operating Characteristic (ROC) analysis assessed their potential as biomarkers, while survival curve analysis gauged their prognostic value. Furthermore, molecular docking predicted interactions with potential therapeutic agents. Ten hub genes—CDK1, KIF11, NUF2, ASPM, CDCA8, CENPF, DTL, EXO1, KIF2C, and ZWINT—emerged as pivotal fibroblast-specific genes potentially involved in the DCIS to IDC transition. These genes exhibited pronounced positive correlations with key pathways like the cell cycle and DNA repair, Molecular docking revealed Fisetin, an anti-inflammatory compound, effectively binding to both CDK1 and DTL underscoring their role in orchestrating cellular transformation. CDK1 and DTL were selected for molecular docking with CDK1 inhibitors, revealing effective binding of Fisetin, an anti-inflammatory compound, to both. Of the identified hub genes, DTL—an E3 ubiquitin ligase linked to the CRL4 complex—plays a central role in cancer progression, impacting tumor growth, invasion, and metastasis, as well as cell cycle regulation and epithelial-mesenchymal transition (EMT). CDK1, another hub gene, is pivotal in cell cycle progression and associated with various biological processes. In conclusion, our study offers insights into the complex mechanisms driving the transition from DCIS to IDC. It underscores the importance of hub genes and their potential interactions with therapeutic agents, particularly Fisetin. By shedding light on the interplay between CDK1 and DTL expression, our findings contribute to understanding the regulatory landscape of invasive ductal carcinoma and pave the way for future investigations and novel therapeutic avenues.

Although, approximately 30% of the world's population is estimated to be infected with Toxoplasma gondii (T. gondii) with serious manifestations in immunocompromised patients and pregnant females, the available treatment options for toxoplasmosis are limited with serious side effects. Therefore, it is of great importance to identify novel potent, well tolerated candidates for treatment of toxoplasmosis. The present study aimed to evaluate the effect of Zinc oxide nanoparticles (ZnO NPs) synthesized using Zingiber officinale against acute toxoplasmosis in experimentally infected mice. The ethanolic extract of ginger was used to prepare ZnO NPs. The produced ZnO NPs were characterized in terms of structure and morphology using Fourier Transformed Infrared Spectroscopy (FTIR), X-Ray Diffraction (XRD), UV- spectroscopy and scanning electron microscopy (SEM). The prepared formula was used in treatment of T. gondii RH virulent strain. Forty animals were divided into four groups, with ten mice per group. The first group was the uninfected, control group. The second group was infected but untreated. The third and the fourth groups received ZnO NPs and Spiramycin orally in a dose of 10 mg/kg and 200 mg/kg/day respectively. The effect of the used formulas on the animals survival rate, parasite burden, liver enzymes -including Alanine transaminase (ALT) and aspartate transaminase (AST)-, nitric oxide (NO) and Catalase antioxidant enzyme (CAT) activity was measured. Moreover, the effect of treatment on histopathological alterations associated with toxoplasmosis was examined. Mice treated with ZnO NPs showed the longest survival time with significant reduction in the parasite load in the livers and peritoneal fluids of the same group. Moreover, ZnO NPs treatment was associated with a significant reduction in the level of liver enzymes (ALT, AST) and NO and a significant increase in the antioxidant activity of CAT enzyme. SEM examination of tachyzoites from the peritoneal fluid showed marked distortion of T. gondii tachyzoites isolated from mice treated with ZnO NPs in comparison to untreated group. T. gondii induced histopathological alterations in the liver and brain were reversed by ZnO NPs treatment with restoration of normal tissue morphology. The produced formula showed a good therapeutic potential in treatment of murine toxoplasmosis as demonstrated by prolonged survival rate, reduced parasite burden, improved T. gondii associated liver injury and histopathological alterations. Thus, we assume that the protective effect observed in the current research is attributed to the antioxidant capability of NPs. Based on the results obtained from the current work, we suggest greenly produced ZnO NPs as a chemotherapeutic agent with good therapeutic potential and high levels of safety in the treatment of toxoplasmosis.

Background: The Hajj pilgrimage is one of the largest annual mass gatherings in the world, and it presents unique healthcare issues due to the vast number and diversity of participants. Optimizing the delivery and planning of health services requires an understanding of prevalent diseases and healthcare usage patterns. The aim of the study was to examine the patterns of disease burden and healthcare utilization among 2024 Hajj pilgrims. Methods: This study used a retrospective, descriptive cross‑sectional design. Data from 37,758 adult patient records in the outpatient clinics (OPCs) of the primary healthcare centers (PHCs) and hospitals located at the holy sites (Mena, Arafat, and Muzdalifah) during Hajj 2024 were analyzed. Data covered demographics, nationality, diagnoses, discharge outcomes, and healthcare utilization in holy sites. Patterns and associations were assessed using descriptive statistics and chi‑square testing (p < 0.05). Results: Most pilgrims were men (65.5%), and older than 60 years of age (26.4%). They came from more than 100 different countries. The most frequent diagnosis (44.6%) was upper respiratory tract infections (URTIs), which was followed by dermatitis (6.3%), gastrointestinal disorders (7.4%), headaches (7.8%), and musculoskeletal problems (7.3%). Geographically, disease prevalence varied: URTIs were most common in Mena (46.3%), dermatitis peaked in Muzdalifah (14.8%), and heat exhaustion was most common in Arafat (9.4%). Primary care use peaked in Mena (14,500 visits), mirroring pilgrim mobility. Conclusion: The results emphasize the necessity for flexible, data‑driven resource allocation by highlighting the dynamic and site‑specific character of healthcare demands during the Hajj. To improve health outcomes in upcoming Hajj seasons, it is imperative to enhance infection control, heat illness prevention, and culturally competent care, in addition to tailored interventions for older pilgrims and those with chronic illnesses.

Schistosomiasis affects approximately 250 million people worldwide, with 200,000 deaths annually. It has been documented that the granulomatous response to ( ) oviposition is the root cause of progressive liver fibrosis in chronic infection, in 20% of the patients, and can lead to liver cirrhosis and/or liver cancer. The influence of helminths coinfection on schistosomiasis-induced liver pathological alterations remains poorly understood. Therefore, in this study, we investigated the effect of ( ) infection on -induced hepatic fibrosis. Thirty adult male Balb-c mice were divided into three groups. Group 1 was left uninfected; group 2 was infected with cercariae and group 3 was orally infected with larvae, then 28 days later, this group was infected with cercariae. All groups were sacrificed at the end of the 8 week post infection with the effect of pre-infection with on induced liver fibrosis was evaluated parasitologically (worm burden and egg count in tissues), biochemically (levels of alanine aminotransferase and aspartate aminotransferase), histopathologically (H&E and MT staining, and immunohistochemical staining for the expression of α-SMA, IL-6, IL-1β, IL-17, IL-23, TNF-α, and TGF-β). The results in the present study demonstrated marked protective effect of against induced liver pathology. We demonstrated that pre-infection with caused marked reduction in the number of adult worms (3.17 ± 0.98 vs. 18 ± 2.16, = 0.114) and egg count in both the intestine (207.2 ± 64.3 vs. 8,619.43 ± 727.52, = 0.009) and liver tissues (279 ± 87.2 vs. 7,916.86 ± 771.34; = 0.014). Consistently, we found significant reductions in both number (3.4 ± 1.1 vs. 11.8.3 ± 1.22; = 0.007) and size (84 ± 11 vs. 294.3 ± 16.22; = 0.001) of the hepatic granulomas in mice pre-infected with larvae compared to those infected with only . Furthermore, pre- infection with markedly reduced - induced hepatic fibrosis, as evidenced by decreased collagen deposition, low expression of α-SMA, and significantly reduced levels of IL-17, IL-1B, IL-6, TGF-B, IL-23, and TNF-α compared to mice infected with only. Our data show that pre-infection with effectively protected mice from severe schistosomiasis and liver fibrosis. We believe that our findings support the potential utility of helminths for the preventing and ameliorating severe pathological alterations induced by schistosomiasis.

Cryptosporidiosis is an opportunistic parasitic disease widely distributed worldwide. Although sp. causes asymptomatic infection in healthy people, it may lead to severe illness in immunocompromised individuals. Limited effective therapeutic alternatives are available against cryptosporidiosis in this category of patients. So, there is an urgent need for therapeutic alternatives for cryptosporidiosis. Recently, the potential uses of Eugenol (EUG) have been considered a promising novel treatment for bacterial and parasitic infections. Consequently, it is suggested to investigate the effect of EUG as an option for the treatment of cryptosporidiosis. The bioinformatics analysis was used to predict and determine the binding affinities and intermolecular interactions of EUG and Nitazoxanide (NTZ) toward several ( ) lowa II target proteins. For animal study, five groups of immunosuppressed Swiss albino mice (10 mice each) were used. Group I was left uninfected (control), and four groups were infected with 1,000 oocysts of sp. The first infected group was left untreated. The remaining three infected groups received NTZ, EUG, and EUG + NTZ, respectively, on the 6th day post-infection (dpi). All mice were sacrificed 30 dpi. The efficacy of the used formulas was assessed by counting the number of oocysts excreted in stool of infected mice, histopathological examination of the ileum and liver tissues and determination of the expression of iNOS in the ileum of mice in different animal groups. treatment with EUG resulted in a significant reduction in the number of oocysts secreted in stool when compared to infected untreated mice. In addition, oocyst excretion was significantly reduced in mice received a combination therapy of EUG and NTZ when compared with those received NTZ alone. EUG succeeded in reverting the histopathological alterations induced by infection either alone or in combination with NTZ. Moreover, mice received EUG showed marked reduction of the expression of iNOS in ileal tissues. Based on the results, the present study signified a basis for utilizing EUG as an affordable, safe, and alternative therapy combined with NTZ in the management of cryptosporidiosis.

The oncogenic potential of human papillomavirus (HPV) has been widely acknowledged in relation to multiple types of cancer. The objective of this investigation was to conduct a comprehensive assessment of the available evidence pertaining to the correlation between HPV and various types of cancer, such as cervical, colon, ovarian, and head and neck cancers, in the Kingdom of Saudi Arabia (KSA). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were complied with to conduct a systematic literature search aimed at identifying studies that explore the correlation between HPV and the specified cancers. Databases such as Web of Science, Embase, PubMed, and the Cochrane Library were queried up until May of 2023. Relevant literature was obtained, information was extracted, and the methodological rigor was evaluated. The high-risk HPV, namely HPV-16 and HPV-18, were detected as the most prevalent variants in KSA. A significant proportion of cervical cancer cases in the region were found to be associated HPV infection. The molecular tests have furnished evidence that establishes a connection between HPV infection and colonic polyps as well as colorectal cancer. This finding suggests that HPV may have a plausible role in the etiology of these medical conditions. The results of genotyping and integration analyses suggest a probable correlation between HPV and the development of ovarian cancer. Additionally, the prevalence of head and neck squamous cell cancer related to HPV was notably reduced in this particular geographical area. This study presents persuasive findings that establish a connection between HPV and cervical cancer and proposes plausible correlations with squamous cell carcinomas in the colon, ovaries, and head and neck. The aforementioned results emphasize the necessity for additional inquiry into the function of HPV in the onset and advancement of said malignancies. Further investigations are necessary to augment our comprehension of the role of HPV in these neoplasms.

[This corrects the article DOI: 10.3389/fvets.2024.1374116.].

Background: Previous studies have reported involvement of Toxoplasma gondii (T. gondii) infections in the pathogenesis of some autoimmune diseases, such as polymyositis, rheumatoid arthritis, autoimmune thyroiditis, and Crohn’s disease. However, data on the association between T. gondii infections and Type 1 diabetes mellitus (T1DM) are still controversial. Therefore, in the present study, we aimed to investigate the pancreatic pathological changes in mouse models with acute and chronic toxoplasmosis and their association with T1DM. Materials and Methods: Three groups (10 mice each) of male Swiss Albino mice were used. One group of mice was left uninfected, whereas the second and third groups were infected with the acute virulent T. gondii RH strain and the chronic less virulent Me49 T. gondii strain, respectively. T. gondii-induced pancreatic pathological changes were evaluated by histopathological examination of pancreatic tissues. Moreover, the expression of insulin, levels of caspase-3, and the pancreatic infiltration of CD8+ T cells were evaluated using immunohistochemical staining. Results: Pancreatic tissues of T. gondii-infected animals showed significant pathological alterations and variable degrees of insulitis. Mice with acute toxoplasmosis exhibited marked enlargement and reduced numbers of islets of Langerhans. However, mice with chronic toxoplasmosis showed considerable reduction in size and number of islets of Langerhans. Moreover, insulin staining revealed significant reduction in β cell numbers, whereas caspase-3 staining showed induced apoptosis in islets of Langerhans of acute toxoplasmosis and chronic toxoplasmosis mice compared to uninfected mice. We detected infiltration of CD8+ T cells only in islets of Langerhans of mice with chronic toxoplasmosis. Conclusions: Acute and chronic toxoplasmosis mice displayed marked pancreatic pathological changes with reduced numbers of islets of Langerhans and insulin-producing-β cells. Since damage of β cells of islets of Langerhans is associated with the development of T1DM, our findings may support a link between T. gondii infections and the development of T1DM.

Background Toxoplasma gondii ( T. gondii ) infects one third of the world’s population with significant illness, mainly among immunocompromised individuals and pregnant women. Treatment options for toxoplasmosis are limited which signifies the need for novel, potent, and safe therapeutic options. The goal of this study was to assess the effectiveness of the ethanolic extract of Zingiber officinale ( Z. officinale ) in treating mice infected with the RH T. gondii strain. Materials and methods Gas Chromatography/Mass Spectrometry (GC/MS) was used to identify components of ethanolic extract of Z. officinale . A total of 80 mice were randomly allocated into four experimental groups that contained 20 mice each. The first group was left uninfected (uninfected control), while three groups were infected with T. gondii RH virulent strain tachyzoites at 2500 tachyzoites/mouse. One infected group was left untreated (infected, untreated), whereas the other two groups were treated orally with either spiramycin (positive control) or Z. officinale ethanolic extract at doses of 200 mg/kg and 500 mg/kg, respectively for 5 days, starting the day of infection. Ten mice from each group were used to assess mice survival in different groups, whereas the other ten mice in each group were sacrificed on the 5th day post-infectin (dpi) to estimate the treatment efficacy by quantifying liver parasite load, liver function, nitric oxide (NO) production, and levels of antioxidant enzymes. Additionally, histopathological studies were performed to evaluate the therapeutic effect of Z. officinale treatment on toxoplasmosis-induced pathological alterations in liver, brain, and spleen. Results Treatment with Z. officinale ethanolic extract extended the survival of mice till 9th dpi compared to 7th dpi in infected untreated mice. Higher percentage of mice survived in Z. officinale -treated group compared to spiramycin-treatment group at different time points. Liver parasite loads were significantly lower in Z. officinale extract-treated mice and spiramycin-treated mice compared to infected untreated mice which correlated with significantly lower levels of serum liver enzymes (ALT, AST) and nitric oxide (NO), as well as significantly higher catalase (CAT) antioxidant enzyme activity. Scanning electron microscopy (SEM) examination of tachyzoites from the peritoneal fluid revealed marked damage in tachyzoites from Z. officinale -treated group compared to that from infected untreated mice. Moreover, treatment with Z. officinale ethanolic extract alleviated infection-induced pathological alterations and restored normal tissue morphology of liver, brain, and spleen. Conclusion Our results demonstrated that Z. officinale treatment reduced parasite burden and reversed histopathological and biochemical alterations in acute murine toxoplasmosis. These findings support the potential utility of Z. officinale as a future effective natural therapeutic for toxoplasmosis. Further studies are needed to determine the effective active ingredient in Z. officinale extract that can be further optimized for treatment of toxoplasmosis .