Incidence Of Human Cancer Research Articles

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma.

Simple SummaryMultiple drug resistant cancers develop all too soon in patients who received successful cancer treatment. A lack of treatment options often leaves palliative care as the last resort. We tested whether the insulin sensitizer, metformin, known to have anti-cancer activity, could impact canines with drug resistant lymphoma when added to chemotherapy. All canines in the study expressed protein markers of drug resistance and within weeks of receiving metformin, the markers were decreased. A microarray was performed, and from four canines assessed, a common set of 290 elevated genes were discovered in tumor cells compared to control cells. This cluster was enriched with genes that stall the cell cycle, with a large component representing substrates of the Anaphase Promoting Complex (APC), which degrades proteins. One canine entered partial remission. RNAs from this canine showed that APC substrates were decreased during remission and elevated again during relapse, suggesting that the APC was impaired in drug resistant canines and restored when remission occurred. We validated our results in cell lines using APC inhibitors and activators. We conclude that the APC may be a vital guardian of the genome and could delay the onset of multiple drug resistance when activated.Like humans, canine lymphomas are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make canines excellent models to study MDR mechanisms. Insulin-sensitizers have been shown to reduce the incidence of cancer in humans prescribed them, and we previously demonstrated that they also reverse and delay MDR development in vitro. Here, we treated canines with MDR lymphoma with metformin to assess clinical and tumoral responses, including changes in MDR biomarkers, and used mRNA microarrays to determine differential gene expression. Metformin reduced MDR protein markers in all canines in the study. Microarrays performed on mRNAs gathered through longitudinal tumor sampling identified a 290 gene set that was enriched in Anaphase Promoting Complex (APC) substrates and additional mRNAs associated with slowed mitotic progression in MDR samples compared to skin controls. mRNAs from a canine that went into remission showed that APC substrate mRNAs were decreased, indicating that the APC was activated during remission. In vitro validation using canine lymphoma cells selected for resistance to chemotherapeutic drugs confirmed that APC activation restored MDR chemosensitivity, and that APC activity was reduced in MDR cells. This supports the idea that rapidly pushing MDR cells that harbor high loads of chromosome instability through mitosis, by activating the APC, contributes to improved survival and disease-free duration.

Metformin Can Enhance the Inhibitory Effect of Olaparib in Bladder Cancer Cells.

Background Bladder cancer is a common urinary system tumor. In the treatment of clinical patients, it is particularly important to find an effective treatment method to inhibit tumor growth. The world's first PARP inhibitor olaparib is mainly used for the treatment of BRCA1/BRCA2 mutated tumors. Metformin, an antidiabetic drug, has been reported to reduce cancer incidence in humans and improve survival in cancer patients. Methods Cell viability and proliferation were detected by CCK-8 assay and colony formation assay; cell apoptosis was detected by flow cytometry; cell migration and invasion abilities were detected by scratch assay and Transwell assay; STAT3/C-MYC signaling pathway protein were detected by western blotting. Results Olaparib combined with metformin has better effects on the proliferation, clone formation, migration, invasion, and apoptosis of bladder cancer cells than single drug, indicating that metformin can enhance the inhibitory effect of olaparib on tumor growth and regulate the expression of STAT3/C-MYC signaling pathway proteins. Conclusion The results of this study showed that metformin could significantly enhance the antitumor effect of olaparib on bladder cancer cells, and these effects were mediated by downregulating STAT3/C-MYC signaling pathway proteins. This finding may have potential clinical application in the treatment of bladder cancer.

Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity

The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8+ Tcells exhibited impaired effector and stem cell-like properties compared with female CD8+ Tcells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8+ Tcells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8+ Tcells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8+ Tcell exhaustion in cancer patients. Our findings reveal sex-biased CD8+ Tcell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.

Comprehensive expression analysis reveals upregulated LUZP2 in prostate cancer tissues

BackgroundLeucine zipper protein 2 (LUZP2) is a vital gene encoding leucine zipper protein. It is of great importance in the incidence and progress of several human cancers. However, little is known about the role and clinical effects of LUZP2 in prostate cancer (PCa). Therefore, it is crucial to unravel the clinicopathological value of LUZP2 in PCa. In all, 1467 PCa and 549 non-prostate cancer (non-PCa) prostate samples were collected from mRNA chip and RNA-sequencing datasets. The protein levels of LUZP2 were verified in 91 prostate gland tissues by in-house immunohistochemistry (IHC). The standardized mean difference (SMD) was calculated to analyze LUZP2 expression. Survival analysis was also conducted to explore the prognostic significance of LUZP2 in PCa. R software was employed to identify the upregulated differently expressed genes (up-DEGs) and coexpressed genes (CEGs) of LUZP2. Additionally, we explored the prospective molecular mechanism of CEGs of LUZP2 through GO and KEGG pathway analyses. ResultsCompared with non-PCa, LUZP2 showed predominantly higher expression in PCa (SMD = 1.05, AUC = 0.88). IHC indicated the protein expression level of LUZP2 was consistently upregulated in PCa tissues (SMD = 2.23, 95%CI: 1.67–2.79). LUZP2 upregulation had an AUC of 0.88 (95%CI: 0.85–0.90) to distinguish PCa from non-PCa tissues. KEGG pathway analysis showed that the pathways of amino sugar and nucleoside sugar metabolism were chiefly enriched with the LUZP2 CEGs in PCa. Conclusion:LUZP2 upregulation might play a promoting function in the occurrence of PCa.How to cite: Li S-H, Yang Y-P, He R-Q, et al. Comprehensive expression analysis reveals upregulated LUZP2 in prostate cancer tissues. Electron J Biotechnol 2022;59. https://doi.org/10.1016/j.ejbt.2022.06.001

Population-Based Analysis of Trends in Incidence and Survival of Human Papilloma Virus-Related Oropharyngeal Cancer in a Low-Burden Region of Southern Europe.

Introduction: Human papilloma virus (HPV)-related oropharyngeal carcinoma (OPC) can be considered a new subtype of cancer with different clinical characteristics and prognosis than that related to tobacco. Its incidence is increasing worldwide. Its epidemiology has been widely studied in areas such as North America and Northern Europe, but less is known in Southern Europe. Methods: We analyzed the epidemiology of OPC using the database from Girona’s population-based Cancer Registry, in the North-East of Spain, from 1994 to 2018. To analyze differences between neoplasms related to human papillomavirus or not, we determined the immunohistochemical expression of p16 in cases within four time periods: 1997–1999, 2003–2005, 2009–2011, and 2016–2018. Results: Oropharyngeal cancer incidence increased significantly from 2001 to 2018 with an Annual Percentage of Change (APC) of 4.1. OPC p16-positive cases increased with an APC of 11.1. In the most recent period, 2016–2018, 38.5% of OPC cases were p16-positive. European age-standardized incidence rate was 4.18 cases/100.000 inhabitants-year for OPC cancer and 1.58 for those p16-positive. Five-year observed survival was 66.3% for p16-positive OPC and 37.7% for p16-negative. Conclusions: Although with lower burden than in other regions, p16-positive oropharyngeal cancer is increasing in our area and has a better prognosis than p16-negative OPC.

Human papillomavirus-related oropharyngeal carcinoma.

It was not until around 2000 that human papillomavirus-related oropharyngeal carcinoma was recognized as carcinoma with clinical presentations different from nonrelated head and neck carcinoma. Twenty years after and with the revision of the tumor-node-metastasis classification in 2017, various clinical trials focused on human papillomavirus-related oropharyngeal carcinoma to improve the prognosis and quality of life of patients with this disease. However, the incidence of human papillomavirus-related cancers is increasing, which is expected to be particularly prominent in Japan, where human papillomavirus vaccination is not widely available. In this review, we describe the current status of clinical trials (mainly focused on initial surgery and radiation dose reduction) for, primary and secondary prevention of, and the present status of human papillomavirus-related oropharyngeal carcinoma in Japan.

β-Carotene Oxygenase 2 Genotype Modulates the Impact of Dietary Lycopene on Gene Expression during Early TRAMP Prostate Carcinogenesis

Epidemiologic studies suggest lycopene and tomato intake are inversely associated with human prostate cancer incidence. In the genetically driven murine prostate carcinogenesis model transgenic adenocarcinoma of the mouse prostate (TRAMP), prostate cancer is inhibited by feeding of lycopene or tomatoes, and these effects are modulated by the β-carotene oxygenase 2 (Bco2) genotype. We sought insight into this interaction through evaluation of prostate gene expression patterns during early TRAMP carcinogenesis. Three-week-old TRAMP/+ or TRAMP/- × Bco2+/+ or Bco2-/- mice were fed a control, lycopene beadlet, or 10% tomato powder-containing semipurified diet (providing 0, 384 and 462 mg lycopene/kg diet, respectively) for 5 wk. Gene expression patterns were evaluated by prostate cancer- and cholesterol and lipoprotein metabolism-focused arrays at age 8 wk. The TRAMP genotype profoundly alters gene expression patterns, specifically inducing pathways associated with cell survival [z-score = 2.09, -log(P value) = 29.2, p53 signaling (z-score 1.13, -log(P value) = 13.5], and phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling [z-score = 0.302, -log(P value) = 12.1], while repressing phosphatase and tensin homolog (PTEN) signaling [(z-score = -0.905, -log(P value) = 12.3], cholesterol synthesis [z-score = -1.941, -log(P-value) = 26.2], and LXR/RXR pathway activation [z-score = -1.941, -log(P value) = 23.1]. In comparison, lycopene- and tomato-feeding modestly modulate strong procarcinogenic TRAMP signaling. Lycopene decreased gene expression related to carcinogenesis [ Nkx3-1(NK3 homeobox 1)], tomato feeding increased expression of a gene involved in circadian regulation [Arntl (aryl hydrocarbon receptor nuclear translocator like)], and tomato and/or lycopene increased expression of genes involved in lipid metabolism [Fasn (fatty acid synthase), Acaca(acetyl-CoA carboxylase alpha), Srebf1 (sterol regulatory element binding transcription factor 1), Hmgcr (3-hydroxy-3-methylglutaryl-coA reductase), and Ptgs1 (prostaglandin-endoperoxide synthase 1)] (all P < 0.05). The impact of Bco2 genotype was limited to a subset of lycopene-impacted genes [Apc (adenomatous polyposis coli), Mto1 (mitochondrial TRNA translation optimization 1), Nfkb1 (nuclear factor kappa B subunit 1), andRbm39 (RNA binding motif protein 39)]. The TRAMP genotype strongly impacts procarcinogenic gene expression prior to emergence of histopathologic disease. Dietary tomato and lycopene modestly temper these processes, while Bco2 genotype has a limited impact at this early stage. These observed patterns provide insight into the complex interactions between a dietary variable, here tomatoes and lycopene, genes impacting nutrient metabolism, and their modulating influences on oncogene-driven prostate carcinogenesis. These findings provide further mechanistic support, consistent with cancer outcomes in rodents experiments and human epidemiologic studies.

Revisiting the MMTV Zoonotic Hypothesis to Account for Geographic Variation in Breast Cancer Incidence.

Human breast cancer incidence varies by geographic location. More than 20 years ago, we proposed that zoonotic transmission of the mouse mammary tumor virus (MMTV) from the western European house mouse, Mus musculus domesticus, might account for the regional differences in breast cancer incidence. In the intervening years, several developments provide additional support for this hypothesis, including the limited impact of genetic factors for breast cancer susceptibility revealed by genome-wide association studies and the strong effect of antiretroviral therapy to reduce breast cancer incidence. At the same time, economic globalization has further expanded the distribution of M. m. domesticus to Asia, leading to a significant increase in breast cancer incidence in this region. Here, we revisit this evidence and provide an update to the MMTV zoonotic hypothesis for human breast cancer at a time when the world is recovering from the global COVID-19 zoonotic pandemic. We present evidence that mouse population outbreaks are correlated with spikes in breast cancer incidence in Australia and New Zealand and that globalization has increased the range of M. m. domesticus and MMTV. Given the success of global vaccination campaigns for HPV to eradicate cervical cancer, a similar strategy for MMTV may be warranted. Until breast cancer incidence is reduced by such an approach, zoonotic transmission of MMTV from mice to humans as an etiologic factor for breast cancer will remain controversial.

Trends in the Incidence of Human Papillomavirus-Associated Cancers by County-Level Income and Smoking Prevalence in the United States, 2000-2018.

Human papillomavirus (HPV)-associated cancer burden is rising in the United States. Trends in the incidence by county-level income and smoking prevalence remain undescribed. We used the Surveillance, Epidemiology, and End Results 21 database to ascertain HPV-associated cancers during 2000-2018. Trends were estimated by county-level income and smoking prevalence quartiles. Anal and vulvar cancer incidence among women and anal cancer incidence among men increased markedly in the lowest-income counties, whereas the increases were slower in the highest-income counties (eg, for vulvar cancer, incidence increased 1.9% per year, 95% confidence interval [CI] = 0.9% to 2.9%, in the lowest-income counties vs 0.8% per year, 95% CI = 0.6% to 1.1%, in the highest-income counties). In recent years, cervical cancer incidence plateaued (0.0% per year [95% CI = −0.5% to 0.5%]) in the highest-income counties; in the lowest-income counties, the annual percentage change was 1.6% per year (95% CI = −0.7% to 4.0%). Counties with high smoking prevalence had marked increases in incidence compared with their counterparts (eg, anal cancer among men increased 4.4% per year [95% CI = 2.7% to 6.0%] for those living in counties with the highest smoking prevalence vs 1.2% per year [95% CI = 0.7% to 1.7%] for those living in counties with the lowest smoking prevalence). Improved and targeted prevention is needed to combat the widening disparities.

Assessment the effect of vitamin D supplementation on plasma vitamin D levels, inflammation, and oxidative stress biomarkers based on vitamin D receptor genetic variation in breast cancer survivors: a protocol for clinical trial

BackgroundBoth human genes and environmental exposures, due to complex interplay, play important role in the cancer etiology. Vitamin D is associated with a reduced risk of incidence and mortality of several human cancers. This study will aim to investigate the possible effects of individual polymorphisms in vitamin D receptor (VDR) as well as effects of VDR haplotypes on response to vitamin D supplementation in breast cancer survivors.MethodsThis is an interventional study in which the effects of vitamin D supplementation on plasma vitamin D levels, inflammatory and antioxidant biomarkers and factors associated with cell proliferation, differentiation, damage, and apoptosis will be investigated stratified by variations in VDR genotype. The present study will be conducted on breast cancer survivors referred to the Shohadaye Tajrish hospital and its associated clinics. One hundred ninety-eight breast cancer survivors will receive 4000 IU of vitamin D3 daily for 12 weeks. VDR Fok1, ApaI, TaqI, BsmI, and Cdx-2 genotype will be determined at the end of the study and responses to vitamin D supplements (inflammatory, antioxidant, cell proliferation, differentiation, damage, and apoptosis biomarkers) will be compared between the three subgroups of each VDR polymorphism as well as different VDR haplotype categories.DiscussionGenetic variation is a fundamental factor influencing individuals’ divergent responses to diet, nutritional status, metabolic response, and diet-related health disorders. Furthermore, studies of gene and environment interactions will provide a precise and accurate assessments of individuals’ dietary requirements by considering both the genetic and environmental aspects simultaneously. The results of the current study, to some extent, will highlight the discrepancies existing in the findings of different studies regarding vitamin D, VDR, and cancer by considering both the genetic and environmental aspects simultaneously. If responses to vitamin D supplementation could be modified by VDR SNPs, determining the distribution of VDR polymorphisms in both breast cancer survivors and healthy populations will provide a new insight into the vitamin D requirements of individuals to prevent cancer and its related mortality based on their genotypes.Trial registration This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153

Intra-Anal Imiquimod Cream against Human Papillomavirus Infection in Men Who Have Sex with Men Living with HIV: A Single-Arm, Open-Label Pilot Study.

Men who have sex with men (MSM) living with HIV have a high prevalence and incidence of anal high-risk human papillomavirus (hrHPV) and anal cancer. We conducted an open-label, single-arm pilot study to examine the tolerability of imiquimod cream among MSM aged ≥18 years, living with HIV, who tested positive for anal hrHPV at Melbourne Sexual Health Centre between April 2018 and June 2020. We instructed men to apply 6.25 mg imiquimod intra-anally and peri-anally 3 doses per week for 16 weeks (period 1) and then one dose per week for a further 48 weeks (period 2). Twenty-seven MSM enrolled in period 1 and 24 (86%) applied at least 50% of doses. All men reported adverse events (AEs), including 39.5% grade 1, 39.5% grade 2, and 21% grade 3 AEs on at least one occasion. Eighteen MSM (67%) temporarily stopped using imiquimod during period 1, most commonly due to local AEs (n = 11) such as irritation and itching. Eighteen MSM continued in period 2 and all applied at least 50% of doses with no treatment-limiting AEs reported. Imiquimod 3 doses per week caused local AEs in most men and was not well tolerated. In contrast, once-a-week application was well tolerated over 48-weeks with no treatment-limiting AEs.

Global patterns of breast cancer incidence and mortality: A population-based cancer registry data analysis from 2000 to 2020.

BackgroundBreast cancer is the most commonly diagnosed cancer and leading cause of cancer death among women worldwide but has patterns and trends which vary in different countries. This study aimed to evaluate the global patterns of breast cancer incidence and mortality and analyze its temporal trends for breast cancer prevention and control.MethodsBreast cancer incidence and mortality data in 2020 were obtained from the GLOBOCAN online database. Continued data from the Cancer Incidence in Five Continents Time Trends, the International Agency for Research on cancer mortality and China National Central Cancer Registry were used to analyze the time trends from 2000 to 2015 through Joinpoint regression, and annual average percent changes of breast cancer incidence and mortality were calculated. Association between Human Development Index and breast cancer incidence and mortality were estimated by linear regression.ResultsThere were approximately 2.3 million new breast cancer cases and 685,000 breast cancer deaths worldwide in 2020. Its incidence and mortality varied among countries, with the age‐standardized incidence ranging from the highest of 112.3 per 100,000 population in Belgium to the lowest of 35.8 per 100,000 population in Iran, and the age‐standardized mortality from the highest of 41.0 per 100,000 population in Fiji to the lowest of 6.4 per 100,000 population in South Korea. The peak age of breast cancer in some Asian and African countries were over 10 years earlier than in European or American countries. As for the trends of breast cancer, the age‐standardized incidence rates significantly increased in China and South Korea but decreased in the United States of America (USA) during 2000‐2012. Meanwhile, the age‐standardized mortality rates significantly increased in China and South Korea but decreased in the United Kingdom, the USA, and Australia during 2000 and 2015.ConclusionsThe global burden of breast cancer is rising fast and varies greatly among countries. The incidence and mortality rates of breast cancer increased rapidly in China and South Korea but decreased in the USA. Increased health awareness, effective prevention strategies, and improved access to medical treatment are extremely important to curb the snowballing breast cancer burden, especially in the most affected countries.

Intermittent fasting in the prevention and treatment of cancer.

Chronic caloric restriction (CR) has powerful anticarcinogenic actions in both preclinical and clinical studies but may be difficult to sustain. As an alternative to CR, there has been growing interest in intermittent fasting (IF) in both the scientific and lay community as a result of promising study results, mainly in experimental animal models. According to a survey by the International Food Information Council Foundation, IF has become the most popular diet in the last year, and patients with cancer are seeking advice from oncologists about its beneficial effects for cancer prevention and treatment. However, as discussed in this review, results from IF studies in rodents are controversial and suggest potential detrimental effects in certain oncologic conditions. The effects of IF on human cancer incidence and prognosis remain unknown because of a lack of high-quality randomized clinical trials. Preliminary studies suggest that prolonged fasting in some patients who have cancer is safe and potentially capable of decreasing chemotherapy-related toxicity and tumor growth. However, because additional trials are needed to elucidate the risks and benefits of fasting for patients with cancer, the authors would not currently recommend patients undergoing active cancer treatment partake in IF outside the context of a clinical trial. IF may be considered in adults seeking cancer-prevention benefits through means of weight management, but whether IF itself affects cancer-related metabolic and molecular pathways remains unanswered.

Biological insights into the piericidin family of microbial metabolites.

Extensively produced by members of the genus Streptomyces, piericidins are a large family of microbial metabolites, which consist of main skeleton of 4-pyridinol with methylated polyketide side chain. Nonetheless, these metabolites show differences in their bioactive potentials against micro-organisms, insects and tumour cells. Due to its close structural similarity with coenzyme Q, piericidins also possess an inhibitory activity against NADH dehydrogenase as well as Photosystem II. This review studied the latest research progress of piericidins, covering the chemical structure and physical properties of newly identified members, bioactivities, biosynthetic pathway with gene clusters and future prospect. With the increasing incidence of drug-resistant human pathogen strains and cancers, this review aimed to provide clues for the development of either new potential antibiotics or anti-tumour agents.

Prevalence and characteristics of mouse mammary tumor virus-like virus associated breast cancer in China

BackgroundDespite extensive molecular epidemiological studies, the prevalence and characteristics of Mouse Mammary Tumor Virus-Like Virus (MMTV-LV) in Chinese women breast cancer are still unclear. Besides, the prevalence of MMTV-LV in women breast cancer tissue varies in different countries and its dependent factors remain inconclusive.MethodsIn the first part of the study, a case-control study was performed. 119 breast cancer samples (84 from Northern China and 35 from Southern China) and 50 breast fibroadenoma specimens were collected from Chinese women patients. MMTV-like env sequence and the homology to MMTV env gene were analysed by semi-nested polymerase chain reaction (PCR). We also explored the association of MMTV-LV prevalence with sample sources (Southern and Northern China) and patients’ clinicopathological characteristics. To investigate the dependent factors of the prevalence of MMTV-LV in breast cancer worldwide, a meta-analysis was conducted in the second part of the study.ResultsWe found that the prevalence of MMTV-LV was much higher in breast cancer tissues (17.65%) than that in breast fibroadenoma specimens (4.00%) (P < 0.05). MMTV-LV prevalence in Chinese women breast cancer tissues was significantly different between Southern China (5.71%) and Northern China (22.62%) (P < 0.05). The prevalence of MMTV-LV also associates significantly with expression of HER2, but shows no significant correlation with other parameters. In the meta-analysis, we found that MMTV-LV prevalence in breast cancer tissue was dependent on the distribution of M. domesticus mouse (M. d), M. musculus mouse (M.m) and M.castaneus mouse (M.c) worldwide (P < 0.05).ConclusionThe distribution of house mice may be a crucial environmental factor that explains the geographic differences in human breast cancer incidence. Our findings may provide a potential avenue of prevention, diagnosis and treatment for breast cancer.

Role of Bacteria in the Incidence of Common GIT Cancers: The Dialectical Role of Integrated Bacterial DNA in Human Carcinogenesis.

Despite the wide medical knowledge about the direct role of many viruses in the pathogenesis of certain cancers, there is still ambiguity and hazy vision about the direct role of bacteria in cancer incidence. Understanding the role of bacteria in carcinogenesis is no longer a scientific luxury, but it has become an urgent and extremely important necessity to realize the pathogenesis of cancer caused by oncogenic bacteria as an attempt to overcome the oncogenic mechanisms exhibited by these oncogenic bacteria. This review shed the light on the indirect role of the host’s inflammatory and immunological responses in the pathogenesis of bacteria-induced cancer. Also, this review discussed the indirect role of the bacterial toxins and virulence factors in the induction of common gastrointestinal cancers, such as gallbladder cancer (GBC), colorectal cancer (CRC), and gastric cancer (GC). Finally, this review dealt with the debate about the possibility of bacterial DNA integration into the human genome and cancer incidence.

Pharmaceutical Pollution and Disposal of Expired, Unused, and Unwanted Medicines in the Brazilian Context.

The occurrence of pharmaceuticals in the environment is an everyday recognized concern worldwide, and drugs as environmental contaminants have been detected in water and soil systems, posing risks to humans and wildlife. The presence of drugs in wastewater, groundwater, and even drinking water occurs in several countries, including Brazil, where the pharmaceutical market is expanding over the years. The adverse, harmful effects of pharmaceuticals in the environment range from the spreading of antimicrobial resistance and species survival to the interference with reproduction and increased cancer incidence in humans. Therefore, it is demanding to count on proper legislation to prevent these pollutants from entering the distinct environment compartments. In some developed countries, laws, directives, programs, and initiatives regarding drug disposal reach a mature status. In Brazil, federal laws dealing with drug residues’ management are recent, with flaws that might facilitate non-compliance with drug pollution issues. Besides, pharmacies and drugstores are not obligated to collect unneeded household medicines, while particular State laws aim to ordinate the disposal of drug residues regionally. In this review, we consider the current knowledge about pharmaceutical (drug) pollution, the recommendation and regulations on the disposal of useless medicines in some countries, and in the context of the expanding pharmaceutical market in Brazil. The awareness of emerging contaminants in the environment, besides the joint effort of authorities, consumers, and the general public nationwide, will be required to avoid pharmaceutical/drug pollution and achieve an eco-friendly environment and a sustainable society.

Worldwide trend in human papillomavirus-attributable cancer incidence rates between 1990 and 2012 and Bayesian projection to 2030.

There is a paucity of global comparative trend analyses of all human papillomavirus (HPV)-attributable cancers. In addition, most analyses by international sources only describe past trends; few studies have projected the future trend of HPV-attributable cancers. Data were used from the Cancer Incidence in Five Continents (CI5plus) database that contains annual incidence by cancer site, age, and sex, as well as corresponding populations. Age-standardized HPV-attributable cancer incidence rates were calculated and plotted from 1990 through 2012. A Bayesian age-period-cohort model was used to project the HPV-attributable cancer incidence rates of each country up to 2030. A significant but small decreasing trend worldwide in the HPV-attributable cancer incidence rate was observed with an average annual percent change (AAPC) of -0.3 (95% CI, -0.6 to -0.1). Notably, Uganda had a consistently increasing trend of HPV-attributable cancer incidence rate, with an AAPC of 1.7 (95% CI, 0.6-2.9). U-shaped trends were observed in some high-income countries because of a recent increase in oral cavity and oropharyngeal cancers. Most countries experience a decreasing or stable trend in HPV-attributable cancers incidence rates between 1990 and 2030. However, Japan, the United Kingdom, the Netherlands, Italy, Costa Rica, and Uganda will have an increasing trend during the projection period. Analyses revealed favorable downward trends in HPV-attributable cancer incidence rates in most of the included countries. However, the persistently increasing trend in HPV-attributable cancer incidence rates in Uganda and the recent increase in oral cavity and oropharyngeal cancer incidence rates in some high-income countries may present a new challenge for global HPV-attributable cancer prevention. Analyses revealed favorable downward trends in human papillomavirus (HPV)-attributable cancer incidence rates in most of the included countries. However, the persistently increasing trend in HPV-attributable cancer incidence rates in Uganda and the recent increase in oral cavity and oropharyngeal cancer incidence rates in some high-income countries may present a new challenge for global HPV-attributable cancer prevention.

A Skin Cancer Prophylaxis Study in Hairless Mice Using Methylene Blue, Riboflavin, and Methyl Aminolevulinate as Photosensitizing Agents in Photodynamic Therapy.

The high incidence of sunlight-induced human skin cancers reveals a need for more effective photosensitizing agents. In this study, we compared the efficacy of prophylactic photodynamic therapy (PDT) when methylene blue (MB), riboflavin (RF), or methyl aminolevulinate (MAL) were used as photosensitizers. All mice in four groups of female C3.Cg/TifBomTac hairless immunocompetent mice (N = 100) were irradiated with three standard erythema doses of solar-simulated ultraviolet radiation (UVR) thrice weekly. Three groups received 2 × 2 prophylactic PDT treatments (days 45 + 52 and 90 + 97). The PDT treatments consisted of topical administration of 16% MAL, 20% MB, or 20% RF, and subsequent illumination that matched the photosensitizers’ absorption spectra. Control mice received no PDT. We recorded when the first, second, and third skin tumors developed. The pattern of tumor development after MB-PDT or RF-PDT was similar to that observed in irradiated control mice (p > 0.05). However, the median times until the first, second, and third skin tumors developed in mice given MAL-PDT were significantly delayed, compared with control mice (256, 265, and 272 vs. 215, 222, and 230 days, respectively; p < 0.001). Only MAL-PDT was an effective prophylactic treatment against UVR-induced skin tumors in hairless mice.

Role of Notch, IL-1 and leptin expression in colorectal cancer.

An increasing number of studies have shown that angiogenesis has an important role in the progression of cancer. The growth of a new network of blood vessels is crucial for tumor growth and metastasis, which is promoted by several proangiogenic factors. Leptin, an essential adipokine that is secreted from fat tissue, is one of these pro-angiogenic factors. It has been shown that the inhibition of leptin-induced angiogenesis resulted in decreased levels of vascular endothelial growth factor (VEGF)/VEGFR2, hypoxia inducible factor (HIF) 1α, NF-κB, IL-1 and Notch and reduced the tumor growth in breast cancer. Leptin induces angiogenesis in breast cancer either by upregulating VEGFR2 in endothelial cells or by increasing VEGF/VEGFR2 expression through the Notch, IL-1 and leptin crosstalk outcome (NILCO) pathway. NILCO is a novel mechanism that interacts with proinflammatory and proangiogenic signals, which are critical for cell proliferation and angiogenesis in cancer. Several studies have shown that components of NILCO may affect human cancer incidence and progression. However, to the best of our knowledge, the interactions between Notch, IL-1 and leptin in human colorectal cancer have not been yet studied at the molecular level. The aim of the present study was to investigate the expression levels of genes related to the NILCO pathway in human colorectal cancer specimens. The current results demonstrated that leptin, leptin receptor (ObR) b, Notch-1, Notch-4, IL-1α, IL-1β, IL-1R, IL-6, JAK-2, STAT-1, STAT-3, VEGFA, VEGFR1, VEGFR2, TNF-α and NF-κB mRNA expression levels in the cancer tissue were increased compared with the normal tissue. No significant changes in the mRNA expression levels of Jagged-1, HIF-1α and TNF receptor 1 were observed. Western blotting revealed that the protein expression levels of IκB were increased in the cancer tissue compared with normal tissue, whereas HIF-1α and phosphorylated STAT-1 levels were decreased. IL-6 and VEGFA plasma concentrations were statistically raised and the leptin plasma concentration was also raised, although significantly, patients with cancer compared with control individuals. Together, the present findings indicated that Notch, IL-1 and leptin may serve a crucial role in the development of colorectal cancer.