From the discovery of helminths to the discovery of their carcinogenic potential.

Cancer involves a major aberration in the normal behaviour of cells, making them divide continuously, which interferes with the normal physiology of the body. The link between helminths and their cancer-inducing potential has been proposed in the last century. The exact pathway is still not clear but chronic inflammation in response to the deposited eggs, immune response against soluble egg antigens, and co-infection with a third party (a bacteria, a virus, or infection leading to a change in microbiome) seems to be the reasons for cancer induction. This review looks into the historical outlook on helminths along with their epidemiology, morphology, and life cycle. It then focuses on providing correlations between helminth infection and molecular mechanism of carcinogenesis by elaborating upon epidemiological, clinical, and surgical studies. While the cancer-inducing potential has been convincingly established only for a few helminths and studies point out towards possible cancer-inducing ability of the rest of the helminths elucidated in this work, however, more insights into the immunobiology of helminths as well as infected patients are required to conclusively comment upon this ability of the latter.

Characterisation of tetraspanins from Schistosoma haematobium and evaluation of their potential as novel diagnostic markers.

Schistosoma haematobium is the leading cause of urogenital schistosomiasis and it is recognised as a class 1 carcinogen due to the robust association of infection with bladder cancer. In schistosomes, tetraspanins (TSPs) are abundantly present in different parasite proteomes and could be potential diagnostic candidates due to their accessibility to the host immune system. The large extracellular loops of six TSPs from the secretome (including the soluble excretory/secretory products, tegument and extracellular vesicles) of S. haematobium (Sh-TSP-2, Sh-TSP-4, Sh-TSP-5, Sh-TSP-6, Sh-TSP-18 and Sh-TSP-23) were expressed in a bacterial expression system and polyclonal antibodies were raised to the recombinant proteins to confirm the anatomical sites of expression within the parasite. Sh-TSP-2, and Sh-TSP-18 were identified on the tegument, whereas Sh-TSP-4, Sh-TSP-5, Sh-TSP-6 and Sh-TSP-23 were identified both on the tegument and internal tissues of adult parasites. The mRNAs encoding these TSPs were differentially expressed throughout all schistosome developmental stages tested. The potential diagnostic value of three of these Sh-TSPs was assessed using the urine of individuals (stratified by infection intensity) from an endemic area of Zimbabwe. The three Sh-TSPs were the targets of urine IgG responses in all cohorts, including individuals with very low levels of infection (those positive for circulating anodic antigen but negative for eggs by microscopy). This study provides new antigen candidates to immunologically diagnose S. haematobium infection, and the work presented here provides compelling evidence for the use of a biomarker signature to enhance the diagnostic capability of these tetraspanins.

The mechanisms of action of Plasmodium infection against cancer.

Our murine cancer model studies have demonstrated that Plasmodium infection activates the immune system that has been inhibited by cancer cells, counteracts tumor immunosuppressive microenvironment, inhibits tumor angiogenesis, inhibits tumor growth and metastasis, and prolongs the survival time of tumor-bearing mice. Based on these studies, three clinical trials of Plasmodium immunotherapy for advanced cancers have been approved and are ongoing in China. After comparing the mechanisms of action of Plasmodium immunotherapy with those of immune checkpoint blockade therapy, we propose the notion that cancer is an ecological disease and that Plasmodium immunotherapy is a systemic ecological counterattack therapy for this ecological disease, with limited side effects and without danger to public health based on the use of artesunate and other measures. Recent reports of tolerance to treatment and limitations in majority of patients associated with the use of checkpoint blockers further support this notion. We advocate further studies on the mechanisms of action of Plasmodium infection against cancer and investigations on Plasmodium-based combination therapy in the coming future. Video Abstract.

Toxoplasma gondii could have a possible role in the cancer mechanism by modulating the host's cell response.

Toxoplasma gondii, which manipulates many signaling pathways to achieve persistence in host cells, is intimately linked to immune and inflammation responses. However, there is still lack of information about the impact of T. gondii on cellular and immune responses. This study was designed to seek the impact of T. gondii infection causing life-long inflammation in brain, on cancer mechanism. To identify molecular effects of the T. gondii and understand the association between the functional perturbations occurring during infection and cancer development, the transcriptomic datasets obtained mice infected with T. gondii were downloaded from GEO. The differentially expressed genes (DEGs) were identified and functional enrichment analysis was performed using IPA platform, then all results were evaluated with comparison analyses. Subsequently, a T. gondii infection model with human neuroepithelioma cell culture was performed in order to validate top DEGs participated in common networks/pathways in cancer mechanism. Transcriptomic analyses of infected mice and in vitro cell culture model revealed a strong immune response and inflammation occurred by parasite-induced damage and parasite-associated immunopathology in host cell and tissue. T. gondii infection could modulate certain signaling pathways of host, which were also common to those perturbed in carcinogenesis. Interestingly, the network analysis of the data sets predicted an activation in development of solid cancer vice versa inhibition in hematological cancer during T. gondii infection. Parasite might also control the tumor growth due to its potent immune-stimulant effects. As result, T. gondii infection generating a continual inflammation in tissues might potentially contribute to cancer development by regulating critical host signaling pathways or reveal an anti-tumoral activity.

Therapeutic potential and pharmacological activities of ß-eudesmol.

Herbal medicines are attracting the attention of researchers worldwide. ß-Eudesmol is one of the most studied and major bioactive sesquiterpenes, mainly extracted from Atractylodes lancea (Thunb) DC. rhizomes. It has potential anti-tumor and anti-angiogenic activities and is an inhibitor of tumor growth by inhibiting angiogenesis by suppressing CREB activation of the growth factor signaling pathway. It also stimulates neurite outgrowth in rat pheochromocytoma cells with activation of mitogen-activated protein kinases. It may be a promising lead compound for enhancing neural function, and it may help to explain the underlying mechanisms of neural differentiation. In this review, we summarized the currently available clinical and preclinical studies describing the therapeutic applications of ß-eudesmol.

Malignant tumours of temporomandibular joint.

BACKGROUND: Malignant tumours of the temporomandibular joint (MTTMJ) are extremely rare. Studies describing its unique epidemiology, clinicopathological features, treatment and prognosis comprehensively are limited. To address these issues, current investigation was performed. METHODS: A retrospective research was carried out by using population-based data from the Surveillance, Epidemiology, and End Results database (1973-2016). RESULTS: Data for a total of 734 patients, including 376 men and 358 women, was found. The median age was 47 years. The 5-year and 10-year disease specific survival (DSS) rates were 69.2 and 63.6%, respectively. Significant differences in DSS were found according to age, race, tumour type, AJCC/TNM stage, surgery, radiotherapy, chemotherapy and different treatment modalities (P < 0.05). In the multivariate survival analysis, age > 44 years and AJCC stage III and IV were associated with poor DSS. CONCLUSION: MTTMJ was mostly found in white people with a median age of 47 years without any sex predominance. Patient's age and AJCC stage was independent predictor of DSS.

Intestinal protozoan and helminthic infections among hemodialysis and cancer patients.

Intestinal parasitic infections (IPIs) can be a severe threat to immunocompromised patients. This is particularly true for those undergoing chemotherapy and hemodialysis. The present research is aimed at identifying intestinal parasites that might be present in immunocompromised patients. In this cross-sectional study 1040 stool samples were collected from March to September 2017. Six hundred and forty-one stool samples from immunocompromised patients (279 samples from hemodialysis patients and 362 samples from chemotherapy patients) and 399 samples from the control group were collected in Guilan province, Iran. The samples were tested by direct, formalin-ether methods for protozoa and ova of intestinal parasites and Ziehl-Neelsen staining methods for coccidian parasites such as Cryptosporidium species. The overall parasitic infection rate was highest (15%) in hemodialysis patients and 11.3% in chemotherapy patients, whereas the lowest rate was observed (7.3%) in the control group. The infectivity rates were statistically significant (P = 0.008) when compared with the control group. The parasites found were Blastocystis hominis (8.9% of the cases), Entamoeba coli (1.6%), Iodamoeba butschlii (0.8%), Endolimax nana (0.6%), Chilomastix mesnili (0.5%), Strongyloides stercoralis (0.5%), and Taenia species (0.15%), whereas Giardia lamblia was detected only in the control group. There was not a correlation between prevalence of parasites with age or education levels of the infected individuals. Results of the present study suggest that periodic stool examinations in special parasitological laboratories should be included as part of routine and general medical care.

Cancer in Mozambique: Results from two population-based cancer registries.

Results from two recently established population-based registries in Mozambique are reported: Beira in the central region (2014-2017) and Maputo, the capital city, in the South (2015-2017). The results are compared to those from Maputo (Lourenço Marques at the time) in 1956-1960 (appearing Cancer Incidence in Five Continents Vol 1), and with estimated incidence rates from other regions of Africa. The elevated prevalence of HIV infection (12.6% of adults in 2018) results in high rates for HIV-related cancers, and the greater prevalence in central Mozambique, compared to the south, largely explains the rather higher rates of Kaposi sarcoma (males), non-Hodgkin lymphoma, squamous cell carcinoma of conjunctiva and cervical cancer in Beira than in Maputo. Burkitt lymphoma is the commonest childhood cancer in Beira, with high rates typical of East Africa, while the low rates in Maputo are more typical of Southern Africa. Overall, 44% of cancers in Maputo and 52% in Beira are estimated to be caused by infectious agents. In the last 60 years, cancers more frequent in developed countries, such as breast and prostate, are emerging in Mozambique. The incidence of the former in Maputo has increased fivefold since 1956-1960, that of prostate cancer 2.5-fold, and that of large bowel cancer doubled. The results reported here were used to make national estimates of incidence, mortality and prevalence in Globocan 2018. The two registries were important in providing data to establish priority actions in the National Cancer Control Plan, and are a valuable resource to monitor progress toward its goals.

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs.

Infections caused by Schistosoma haematobium and Opisthorchisviverrini are classified as Group 1 biological carcinogen and it has been postulated that parasites produce oxysterol and estrogen-like metabolites that might be considered as initiators of infection-associated carcinogenesis. Chemotherapy for these helminthic infections relies on a single drug, praziquantel, (PZQ) that mainly targets the parasite. Additionally, PZQ has some major drawbacks as inefficacy against juvenile form and alone it is not capable to counteract pathologies associated to infections or prevent carcinogenesis. There is an urgent need to develop novel therapeutic approaches that not only target the parasite but also improve the pathologies associated to infection, and ultimately, counteract or/and prevent the carcinogenesis processes. Repurposing the drug in combination of compounds with different modes of action is a promising strategy to find novel therapeutics approaches against these helminthic infections and its pathologies. Here, we emphasized that using antioxidants either alone or combined with anthelmintic drugs could ameliorate tissue damage, infection-associated complications, moreover, could prevent the development of cancer associated to infections. Hence, antioxidants represent a potential adjuvant approach during treatment to reduce morbidity and mortality. Despite the success of some strategies, there is a long way to go to implement novel therapies for schistosomiasis.

Enhancing Tumor Targeting Efficiency of Radiolabeled Uridine (via) Incorporation into Nanocubosomal Dispersions.

Background: Several nanosystems are currently being utilized to enhance the targeting efficiency of several cancer chemotherapeutic agents. This study was designed to improve tumor accumulation of iodine-125 (125I)-uridine via incorporation into a nanocubosomal preparation. Materials and Methods: Nanocubosomes were prepared with the aid of Glycerol mono-oleate and Pluronic F127. Each prepared nanocubosomal preparation was adequately characterized by testing their particle size, polydispersity index (PDI), ζ potential (ZP), and transmission electron microscopy. The radiolabeling of uridine with 125I was attempted using several oxidizing agents to achieve a high radiochemical yield, and the factors affecting the reaction yield were studied in detail. A comparative biodistribution study of free 125I-uridine and 125I-uridine loaded nanocubosomes was performed in normal and tumor bearing mice. The biodistribution was evaluated by intravenous injection of the sterile test solution, and animals were anesthetized and dissected at different time intervals postinjection (p.i.). Results: 125I-uridine was obtained in a high radiochemical yield (92.5% ± 0.8%). Afterward, 125I uridine was incorporated in a selected nanocubosome formulation, which showed nanosized cubic particles (178.6 ± 0.90 nm) with PDI (0.301 ± 0.04) and a ZP (34.35 ± 0.4). The biodistribution studies revealed that 125I-uridine nanocubosomes showed higher tumor localization (3.1 ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 6.2) compared with the free 125I-uridine (2.7% ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 3.3). Conclusion: The results of this study confirmed that 125I-uridine loaded nanocubosome had better efficiency in targeting the tumor site, which makes it an adequate targeting agent for tumor imaging.

Association between Cryptosporidium infection and cancer: A systematic review and meta-analysis.

The link between cryptosporidiosis and cancer has been suggested by some epidemiological studies. This systematic review and meta-analysis was conducted to further understand this relationship. In the current study, six electronic databases were reviewed for Cryptosporidium infection in cancer patients. We used random effects model and 95% confidence intervals (CI) to determine the overall odds ratio (OR). Heterogeneity was calculated with Cochran's Q test and I2statistic. In total, 19 studies involving 3562 individuals with case-control (nine) and cross-sectional (ten) designs were included in our project. The pooled overall random effect favored a statistically significant increased risk of Cryptosporidium infection in cancer patients compared with non-cancer individuals [OR = 3.3; 95% CI: 2.18-4.98]. The overall heterogeneity was medium (χ2 = 25.77; I2 = 30.2%, P = .11). The pooled ORs in case-control and cross-sectional studies were [OR = 5.60; 95% CI: 3.43-9.13; χ2 = 5.51; I2 = 0.00%, P = .70] and [OR = 2.08; 95% CI: 1.18-3.67; χ2 = 13.69; I2 = 34.3, P = .13], respectively. T-value and P-value were 0.54 and 0.57 based on the results of Harbord's modified's regression test. In summary, this meta-analysis demonstrates that Cryptosporidium infection is associated with cancer. Also, it found that study design and year of publication are the specific sources of heterogeneity. Further studies should be carried out to investigate the impact of Cryptosporidium infection in the onset or development of cancer in the future.

Inhibition of the Formation In Vitro of Putatively Carcinogenic Metabolites Derived from S. haematobium and O. viverrini by Combination of Drugs with Antioxidants.

Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as carcinogenic. Although carcinogenesis might be a multifactorial process, it has been postulated that these helminth produce/excrete oxysterols and estrogen-like metabolites that might act as initiators of their infection-associated carcinogenesis. Current treatment and control of these infections rely on a single drug, praziquantel, that mainly targets the parasites and not the pathologies related to the infection including cancer. Thus, there is a need to search for novel therapeutic alternatives that might include combinations of drugs and drug repurposing. Based on these concepts, we propose a novel therapeutic strategy that combines drugs with molecule antioxidants. We evaluate the efficacy of a novel therapeutic strategy to prevent the formation of putative carcinogenic metabolites precursors and DNA adducts. Firstly, we used a methodology previously established to synthesize metabolites precursors and DNA adducts in the presence of CYP450. Then, we evaluated the inhibition of their formation induced by drugs and antioxidants alone or in combination. Drugs and resveratrol alone did not show a significant inhibitory effect while N-acetylcysteine inhibited the formation of most metabolite precursors and DNA adducts. Moreover, the combinations of classical drugs with antioxidants were more effective rather than compounds alone. This strategy might be a valuable tool to prevent the initiation of helminth infection-associated carcinogenesis.

Antiparasitic and Antifungal Medications for Targeting Cancer Cells Literature Review and Case Studies.

CONTEXT: Chronic inflammation is a new catch phrase for the explanation of all chronic degenerative diseases, from asthma, arthritis, heart disease, auto-immune disease, and irritable bowel disease to cancer. Occult infections from oncovirus, bacterial, and fungal infections as well as from lesser known parasitic infections are driving forces in the cellular evolution and degeneration of cancer cells. An approach using currently available medications that target both fungal and parasitic metabolism appears to interfere with the metabolic synergy that is associated with tumor growth and aggressiveness. OBJECTIVE: The review examined whether antiparasitic and antifungal medications that interfere with the metabolism of cancers, can be useful in cancer therapy by treating cancer as an infectious disease and as a metabolic parasite. DESIGN: The research team searched the National Center for Biotechnology Information (NCBI) PubMed database databases, using different keyword combinations, including repurposed drug, antifungal, antiparasitic, cancer, parasite, anti-cancer repurposed. SETTING: Prevention and Healing, St Louis, Mo, USA. RESULTS: The literature search identified a number of studies, including in vitro, in vivo and clinical, which support the use of antifungal and antiparasitic medication in the treatment of cancer. In the clinical area, the authors observed benefit from the use of antifungal and antiparasitic medication in the treatment of a variety of cancer cases. CONCLUSIONS: Due to the complexity of the behavior and biology of cells, scientists' primary focus should be on detection and elimination of sources of inflammation. Antiparasitic medications, and also antiviral, antibiotic, and antifungal medications should be thought of as underrecognized, underappreciated, and forgotten medications that can be part of cancer therapy. The information offered in this review suggests scientists should think of cancer not only as a metabolic disease but also as a metabolic parasite and should consider using antiparasitic medications under a new understanding of the role of inflammation, infection, and mitochondrial dysfunction in the development of cancer cells.

5-Fluorouracil and Capecitabine: Assessment and Treatment of Uncommon Early-Onset Severe Toxicities Associated With Administration.

BACKGROUND: Uncommon early-onset severe toxicities from 5-fluorouracil (5-FU) and capecitabine can be fatal if early warning signs are not recognized and treated promptly. OBJECTIVES: This article delineates the differences between expected side effects and uncommon early-onset severe toxicities from 5-FU and capecitabine. It also provides background for understanding the reasons patients may develop these toxicities and reviews the efficacy of standard supportive care against a novel therapy (uridine triacetate). METHODS: A panel of nurses convened to review the literature about toxicities associated with 5-FU and capecitabine administration and determined methods to educate nurses about toxicities and treatment. FINDINGS: Standard supportive care for 5-FU and capecitabine toxicities is associated with high fatality rates. Uridine triacetate treatment within 96 hours of administration is associated with survival.

Cancer-malaria: hidden connections.

Cancer and malaria exemplify two maladies historically assigned to separated research spaces. Cancer, on the one hand, ranks among the top priorities in the research agenda of developed countries. Its rise is mostly explained by the ageing of these populations and linked to environment and lifestyle. Malaria, on the other hand, represents a major health burden for developing countries in the Southern Hemisphere. These two diseases also belong to separate fields of medicine: non-communicable diseases for cancer and communicable diseases for malaria.

Parasites as negative regulators of cancer.

Several environmental factors (chemical, physical, and biological) can cause the initiation, promotion, and progression of cancer. Regarding the biological factors, several studies have found that infections caused by some bacteria, viruses and protozoan, and helminth parasites are related to carcinogenesis. However, in recent years a different approach has been implemented on the antitumor impact of parasitic diseases caused by some protozoan and helminths, mainly because such infections may affect several hallmarks of cancer, but the involved mechanisms still remain unknown. The beneficial effects reported for some parasitic diseases on tumorigenesis range from the induction of apoptosis, activation of the immune response, avoiding metastasis and angiogenesis, inhibition of proliferative signals, to the regulation of inflammatory responses that promote cancer. In this work, we reviewed the available information regarding how parasitic infections may modulate cancer progression. Despite the fact that specific mechanisms of action on tumors are not yet totally clear, we consider that detailed studies of the antitumor action of these organisms and their products could lead to the discovery and use of new molecules from these biological agents that may work as adjuvant therapy in the treatment of various types of cancer.

Synthesis and biological evaluation of novel benzofuroxan-based pyrrolidine hydroxamates as matrix metalloproteinase inhibitors with nitric oxide releasing activity.

On the basis of the strategy of "multifunctional drugs", a series of novel matrix metalloproteinase inhibitors (MMPIs) containing benzofuroxan scaffold as a nitric oxide donor were designed, synthesized and evaluated. All synthesized compounds, especially 16a, exhibited potent MMP-2,9 inhibitory activities, anti-proliferative activities and could produce high levels of NO in Hela cells. They were also evaluated for both of their anti-invasion and anti-angiogenesis effects. Furthermore, compared with LY52, 16a demonstrated competitive antitumor activity in vivo. These hybrid NO-MMPIs might offer suitable scaffolds to develop valuable MMP inhibitors for the further discovery of novel anti-cancer drugs.

Exploring tumourigenic potential of the parasite Anisakis: a pilot study.

Anisakiasis is a global disease caused by consumption of raw or lightly cooked fish parasitised with Anisakis spp. third-stage larvae. Cases in the literature show colocalised anisakiasis and colorectal cancer, and the incidental finding of Anisakis larvae at the tumour site was reported. Data from our group suggested an epidemiological link between previous infection and gastrointestinal cancer. Furthermore, it has recently been reported that Anisakis products lead to inflammation and DNA damage. Based on these facts, the aim was to investigate whether Anisakis antigens are able to induce changes in the proliferation of epithelial cells in vitro or in the expression of serum microRNA (miRNA) in Sprague-Dawley rats. Anisakis complete extract (CE) induced increases in cell proliferation and decreases in apoptosis compared with nontreated cells, which resulted in a significant increase in the absolute number of viable cells at 48 h of exposure (P < .05). Furthermore, the miRNAs mmu-miR-1b-5p and mmu-miR-10b-5p (a cancer-related miRNA) were significantly decreased (P < .05) in sera from the rats inoculated with Anisakis CE, compared with control rats inoculated with saline. Additionally, based on their relative quantification values, four other cancer-related miRNAs were considered to be differently expressed, rno-miR-218a-5p and mmu-miR-224-5p (decreased) and rno-miR-125a-3p and rno-miR-200c-3p (increased). Anisakis CE was able to induce changes both in epithelial cells in vitro and in an animal model. The results obtained with Anisakis CE, in terms of increasing cell proliferation, decreasing apoptosis and inducing changes in the expression of serum cancer-related miRNAs in rats, suggest that Anisakis could have tumourigenic potential.