Mammalian tumor-like organs. 1. The role of tumor-like normal organs and atypical tumor organs in the evolution of development (carcino-evo-devo)

Background Earlier I hypothesized that hereditary tumors might participate in the evolution of multicellular organisms. I formulated the hypothesis of evolution by tumor neofunctionalization, which suggested that the evolutionary role of hereditary tumors might consist in supplying evolving multicellular organisms with extra cell masses for the expression of evolutionarily novel genes and the origin of new cell types, tissues, and organs. A new theory—the carcino-evo-devo theory—has been developed based on this hypothesis. Main text My lab has confirmed several non-trivial predictions of this theory. Another non-trivial prediction is that evolutionarily new organs if they originated from hereditary tumors or tumor-like structures, should recapitulate some tumor features in their development. This paper reviews the tumor-like features of evolutionarily novel organs. It turns out that evolutionarily new organs such as the eutherian placenta, mammary gland, prostate, the infantile human brain, and hoods of goldfishes indeed have many features of tumors. I suggested calling normal organs, which have many tumor features, the tumor-like organs. Conclusion Tumor-like organs might originate from hereditary atypical tumor organs and represent the part of carcino-evo-devo relationships, i.e., coevolution of normal and neoplastic development. During subsequent evolution, tumor-like organs may lose the features of tumors and the high incidence of cancer and become normal organs without (or with almost no) tumor features.

The m6A methyltransferase METTL3 affects autophagy and progression of nasopharyngeal carcinoma by regulating the stability of lncRNA ZFAS1

Background Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the epithelial cells of the nasopharyngeal mucosa of the head and neck. The role of long non-coding RNA and RNA methylation in NPC has received increasing attention. Therefore, this study aims to investigate the mechanism of lncRNA ZFAS1 in NPC and its relationship with RNA methylation, providing evidence for targeted therapy of NPC. Methods Microarray arrays were used to screen the differentially expressed miRNAs in normal tissues and tumor tissues. QRT-PCR was used to quantify ZFAS1, miR-100-3p, ATG10, autophagy and epithelial-mesenchymal transition related genes. The interactive relationship between ZFAS1 and miR-100-3p was verified using dual-luciferase reporter gene assay and RIP assay. CCK-8, transwell and apoptosis were used to detect the occurrence of tumor cells after different treatments. The m6A modification test is used to verify the effect of METTL3 on ZFAS1. BALB/c mice and BALB/c nude mice are used to detect the effects of different treatments on tumor growth and immune escape in vivo. Results ZFAS1 is upregulated in tumor tissues and NPC cells. N (6)-methyladenosine (m6A) is highly enriched in ZFAS1 and enhances its RNA stability. ZFAS1 is used as an oncogenic lncRNA, which can promote NPC cell proliferation, migration and tumor growth. In terms of mechanism, ZFAS1 up-regulates the expression of ATG10 by competitively adsorbing miR-100-3p and regulates the level of autophagy by inhibiting the PI3K/Akt signaling pathway to promote the proliferation and migration of NPC cells. Conclusion In short, our study verified the cancer-promoting effect of ZFAS1 in NPC and explained part of the reason for its upregulation. In addition, we confirmed that ZFAS1 can regulate the autophagy level of NPC cells through the PI3K/AKT pathway through miR-100-3p/ATG10 to affect tumor progression.

BacMam virus-based surface display for HCV E2 glycoprotein induces strong cross-neutralizing antibodies and cellular immune responses in vaccinated mice

Background Despite recent advancements, limitations in the treatment and control of hepatitis C virus (HCV) infection reprioritized the studies for invention of an efficient HCV vaccine to elicit strong neutralizing antibodies (NAbs) and cellular responses. Methods Herein, we report molecular construction of a BacMam virus-based surface display for a subtype-1a HCV gpE2 (Bac-CMV-E2-gp64; Bac) that both expressed and displayed gpE2 in mammalian cells and bacouloviral envelope, respectively. Results Assessments by western blotting, Immunofluorescence and Immunogold-electron microscopy indicated the proper expression and incorporation in insect cell and baculovirus envelope, respectively. Mice immunized in three different prime-boost immunization groups of: Bac/Bac, Bac/Pro (bacoulovirus-derived gpE2) and Bac/DNA (plasmid DNA (pCDNA)-encoding gpE2) developed high levels of IgG and IFN-γ (highest for Bac/Bac group) indicating the induction of both humeral and cellular immune responses. Calculation of the IgG2a/IgG1 and IFN-γ/IL-4 ratios indicated a Th1 polarization of immune responses in the Bac/Bac and Bac/DNA groups but a balanced Th1-Th2 phenotype in the Bac/Pro group. Sera of the mice in the Bac/Bac group provided the highest percentage of cross-NAbs against a subtype-2a HCVcc (JFH1) compared to Bac/Pro and Bac/DNA groups (62% versus 41% and 6%). Conclusions Results indicated that BacMam virus-based surface display for gpE2 might act as both subunit and DNA vaccine and offers a promising strategy for development of HCV vaccine for concurrent induction of strong humoral and cellular immune responses.

The degradation of Rap1GAP via E6AP-mediated ubiquitin-proteasome pathway is associated with HPV16/18-infection in cervical cancer cells

Background Cervical cancers are closely associated with persistent high-risk human papillomaviruses (HR HPV) infection. The main mechanism involves the targeting of tumor suppressors, such as p53 and pRB, for degradation by HR HPV-encoded oncoproteins, thereby leading to tumorigenesis. Rap1GAP, a tumor suppressor gene, is down-regulated in many cancers. Previous studies have revealed that down-regulation of Rap1GAP is correlated with HPV16/18 infection in cervical cancer. However, the molecular mechanism remains unclear. In this study, we aimed to address the degradation pathway of Rap1GAP in HPV-positive cervical cancer cells. Methods HPV-positive (HeLa and SiHa) and negative (C33A) cervical cancer cells were used to analyze the pathways of Rap1GAP degradation. MG132 (carbobenzoxy-leucyl-leucyl-leucine) was used to inhibit protein degradation by proteasome. Co-immunoprecipitation (co-IP) was used to detect the interaction between Rap1GAP and E6AP. siRNA for E6AP was used to silence the expression of E6AP. Rapamycin was used to induce cell autophagy. Western blotting was used to check the levels of proteins. Results Following treatment with MG132, the levels of Rap1GAP were increased in the HR HPV-positive HeLa and SiHa cells, but not in the HPV-negative C33A cells. Co-immunoprecipitation assay revealed ubiquitinated Rap1GAP protein in HeLa and SiHa cells, but not in C33A cells. E6-associated protein (E6AP) mediated the ubiquitination of Rap1GAP by binding to it in HeLa and SiHa cells, but not in C33A cells. However, the levels of Rap1GAP were decreased in HeLa and SiHa cells after knocking down E6AP by siRNA. Silencing of E6AP did not affect the levels of Rap1GAP in C33A cells. Autophagy marker p62 was decreased and LC3 II/LC3 I was increased after knocking down E6AP in HeLa cells, but not in C33A cells. The levels of Rap1GAP were decreased after treating the cells with rapamycin to induce cell autophagy in HeLa and C33A cells. Conclusion Rap1GAP may be degraded by autophagy in cervical cancer cells, but HPV infection can switch the degradation pathway from autophagy to E6AP-mediated ubiquitin-proteasome degradation. E6AP may be a key component of the switch.

The effectiveness of a model-based health education program on genital warts preventive behaviors: a quasi-experimental study

Background Genital warts (GWs) are highly prevalent among Iranian women. GWs are not only highly infectious but are also followed by severe adverse effects, including the development of cervical cancer. Therefore, the present study aimed to explore the effect of an educational intervention based on the health belief model (HBM) on the adoption of GWs preventive behaviors by married women in Bandar Abbas, a city in the south of Iran. Methods A quasi-experimental intervention was conducted between 2019 and 2020 among 150 women participants (75 as the intervention and 75 as the control group). The sampling method was multi-stage clustering. The required data was collected using a reliable and valid tripartite questionnaire which explored demographic information, awareness, and HBM constructs. A total number of 15 educational sessions were held, each 90 min long. The control group received only one 90-min session. The final follow-up was completed three months after the intervention in November 2020. Results The two research groups had no statistically significant differences in terms of awareness, perceived susceptibility, severity, benefits, barriers, and self-efficacy before the intervention (in the pre-test) (p > .05). After the educational intervention, the two groups showed statistically significant differences in all constructs except for the perceived benefits (p < .001). In the intervention group, in the pretest (before the intervention), the behavior score was 2.77 ± 2.59, which was increased to 3.73 ± .52 after the intervention (p < .001). In the control group, however, the difference was not statistically significant (p = 0.227). Conclusion The present findings showed that the educational intervention based on the HBM can improve the prevalence of GWs preventive behaviors in women. This education should be provided by experts at regular intervals in all healthcare centers.

Infectious diseases as a cause of death among cancer patients: a trend analysis and population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results database

Background Infectious diseases are a major cause of morbidity and mortality among cancer patients. We aimed to determine the incidence of infectious diseases as a cause of death among cancer patients and analyze the trends and risk factors associated with mortality. Methods In total, 151,440 cancer patients who died from infectious diseases in the US diagnosed between 1973 and 2014 from the Surveillance, Epidemiology, and End Results program were enrolled. A trend analysis of annual cancer deaths caused by infectious diseases was conducted. Cox proportional hazards model and survival decision tree model were performed. Result The most common infectious diseases were pneumonia and influenza (n = 72,133), parasitic and other infectious (n = 47,310) diseases, and septicemia (n = 31,119). The patients’ mean age was 66.33 years; majority of them were male (62%). The overall incidence from 1973 to 2014 showed an insignificant decrease (annual percentage change = − 0.3, 95% confidence interval [CI] = − 2.2–1.7, P = 0.8). Parasitic and other infectious diseases, including HIV (standardized incidence ratio [SIR] = 1.77, 95% CI = 1.69–1.84), had the highest incidence, followed by septicemia (SIR = 0.84, 95% CI = 0.81–0.88), tuberculosis (SIR = 0.72, 95% CI = 0.51–0.99), and pneumonia (SIR = 0.63, 95% CI = 0.61–0.64). Based on the Cox regression analysis, old black male patients with intrahepatic tumor or acute leukemia of different grades, except the well-differentiated grade, had the highest risk of dying from infectious diseases. Conclusion Infectious diseases remain the major cause of morbidity and mortality among cancer patients. Early recognition of risk factors and timely intervention may help mitigate the negative consequences on patients’ quality of life and prognosis, improving the prognosis and preventing early death from infection, which is preventable in most cases.

Evaluating the presence of Mycoplasma hyorhinis, Fusobacterium nucleatum, and Helicobacter pylori in biopsies of patients with gastric cancer

Background Gastric cancer is the third leading cause of cancer-related deaths worldwide and has been associated with infections that may promote tumour progression. Accordingly, we analysed the presence of Mollicutes, Mycoplasma hyorhinis, Fusobacterium nucleatum and Helicobacter pylori in gastric cancer tissues and evaluated their correlation with clinicopathological factors. Methods Using a commercial kit, DNA were extracted from 120 gastric samples embedded in paraffin: 80 from patients with gastric cancer and 40 from cancer free patients, dating from 2006 to 2016. Mollicutes and H. pylori were detected by PCR; F. nucleatum and M. hyorhinis were detected by qPCR, together with immunohistochemistry for the latter bacteria. Results Mollicutes were detected in the case and control groups (12% and 2.5%) and correlated with the papillary histologic pattern (P = 0.003), likely due to cell transformation promoted by Mollicutes. M. hyorhinis was detected in the case and control group but was not considered a cancer risk factor. H. pylori was detected at higher loads in the case compared to the control group (8% and 22%, P = 0.008) and correlated with metastasis (P = 0.024), lymphatic invasion (P = 0.033), tumour of diffused type (P = 0.028), and histopathological grading G1/G2 (P = 0.008). F. nucleatum was the most abundant bacteria in the case group, but was also detected in the control group (26% and 2.5%). It increased the cancer risk factor (P = 0.045, OR = 10.562, CI95% = 1.057–105.521), and correlated with old age (P = 0.030) and tumour size (P = 0.053). Bacterial abundance was significantly different between groups (P = 0.001). Conclusion Our findings could improve the control and promote our understanding of opportunistic bacteria and their relevance to malignant phenotypes.

Low frequency of HPV positivity in breast tumors among patients from south-central Poland

Background Some studies suggest that Human Papilloma Virus (HPV) infection is important factor in carcinogenesis of breast tumors. This study’ objective was to analyze HPV prevalence in breast cancers of patients from south-central Poland. Materials and methods The study was performed based on archival paraffin embebbed and formalin fixed blocks in the group of 383 patients with breast cancer. HPV prevalence and its genotype were assessed, respectively by: nested PCR (with two groups of primers: PGMY09/PGMY11 and GP5+/GP6+), quantitative PCR (qPCR). Tumors were classified as HPV positive in case of at least one positive result in nested PCR and positive results in genotyping procedure. For all HPV positive tissues P16 immunostaining was applied in order to confirm active viral infection. Results In the group of 383 breast cancers, HPV positivity was found in 17 samples (4.4%) in nested PCR. All these samples were subjected to HPV genotyping. This analysis revealed presence of HPV type 16 into two tumors (0.5%). In these two cancers, P16 overexpression was reported. Conclusion In breast tumors of patients from south-central Poland in Poland, HPV positivity is demonstrated in very low percentage of cases.

Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis

Background Previous studies hypothesized that androgen deprivation therapy (ADT) may reduce severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infectivity. However, it is unknown whether there is an association between ADT and a higher survival in prostate cancer patients with COVID-19. Methods We performed a retrospective analysis of prostate cancer (PC) patients hospitalized to treat COVID-19 in Brazil’s public health system. We compared patients with the active use of ADT versus those with non-active ADT, past use. We constructed propensity score models of patients in active versus non-active use of ADT. All variables were used to derive propensity score estimation in both models. In the first model we performed a pair-matched propensity score model between those under active and non-active use of ADT. To the second model we initially performed a multivariate backward elimination process to select variables to a final inverse-weight adjusted with double robust estimation model. Results We analyzed 199 PC patients with COVID-19 that received ADT. In total, 52.3% (95/199) of our patients were less than 75 years old, 78.4% (156/199) were on active ADT, and most were using a GnRH analog (80.1%; 125/156). Most of patients were in palliative treatment (89.9%; 179/199). Also, 63.3% of our cohort died from COVID-19. Forty-eight patients under active ADT were pair matched against 48 controls (non-active ADT). All patients (199) were analyzed in the double robust model. ADT active use were not protective factor in both inverse-weight based propensity score (OR 0.70, 95% CI 0.38–1.31, P = 0.263), and pair-matched propensity score (OR 0.67, 95% CI 0.27–1.63, P = 0.374) models. We noticed a significant imbalance in the propensity score of patients in active and those in non-active ADT, with important reductions in the differences after the adjustments. Conclusions The active use of ADT was not associated with a reduced risk of death in patients with COVID-19.

Healthcare resource utilization and costs associated with anogenital warts in Morocco

Background Human papillomavirus (HPV), primarily genotypes 6 and 11, cause the majority of cases of anogenital warts (AGW). Although benign, AGW are associated with a substantial economic and psychosocial burden. Several vaccines have been developed to prevent HPV. The objective of this study was to describe the epidemiology and healthcare resource utilization of AGW in Morocco, as well as the associated costs of treatment from the public healthcare perspective. Methods This was a descriptive analysis of questionnaire data obtained via a Delphi panel. The panel consisted of 9 physicians practicing in public hospitals in Morocco (4 dermatologists and 5 obstetricians/gynecologists). The questionnaire collected data on physician and practice characteristics, diagnostic tests and procedures, treatments, and follow-up (including recurrence) of patients with AGW. Questionnaire items on which ≥ 70% of respondents agreed were considered as having consensus. Costs associated with diagnosis, treatment, and follow-up were calculated in Moroccan dirham (MAD) and converted to euros (€) based on official national price lists for public hospitals and the HCRU estimates from the questionnaire. Results The physician-estimated prevalence of AGW in Morocco was 1.6%-2.6% in women and 2.0%-5.3% in men. A mean (median) of 6.4 (4) patients per month per physician sought medical attention for AGW. Simple observation was the most common diagnostic method for AGW in both men and women, and excision was the most prescribed therapy (75%), requiring a mean of 2 visits. Recurrence occurred in approximately 27% of patients. The cost per case of managing AGW, including recurrence, was estimated at 2182–2872 MAD (€207–272) for women and 2170–2450 MAD (€206–233) for men. The total annual cost of medical consultations for AGW in Morocco ranged from 3,271,877 MAD to 4,253,703 MAD (€310,828–404,102). Conclusions Expert consensus indicates that AGW represent a significant burden to the Moroccan public healthcare system. These data can inform policy makers regarding this vaccine-preventable disease.