Understanding the interplay of colorectal cancer awareness and attitudes among Palestinians: a national cross-sectional study.

BACKGROUND: In Palestine, colorectal cancer (CRC) is the second most common cause of cancer-related mortality after lung cancer. No studies have examined the relationship between CRC awareness and attitudes. This study aimed to investigate the interplay between CRC awareness and attitudes among the Palestinian population. METHODS: A nationwide cross-sectional survey was carried out between July 2019 and March 2020. Convenience sampling was used to collect data from hospitals, primary healthcare facilities, and public areas in 11 governorates. Modified, translated-into-Arabic versions of the validated Bowel Cancer Awareness Measure and Cancer Awareness Measure-Mythical Causes Scale were utilized to assess the awareness of CRC signs/symptoms, risk factors, and causation myths. The cumulative awareness score for each domain was computed and stratified into tertiles. The top tertile denoted 'high' awareness, while the remaining two tertiles denoted 'low' awareness. RESULTS: The final analysis included 4,623 participants; of whom, 3115 (67.4%) reported positive attitudes toward CRC. In total, 1,849 participants (40.0%) had high awareness of CRC signs/symptoms. There was no association between displaying a high awareness of CRC signs/symptoms and having positive attitudes toward CRC. A total of 1,840 participants (38.9%) showed high awareness of CRC risk factors. Participants with high CRC risk factor awareness were more likely to display positive attitudes toward CRC (OR = 1.22, 95% CI: 1.07-1.39). Only 219 participants (4.7%) had high awareness of CRC causation myths. Participants with high awareness of CRC causation myths were more likely to exhibit positive attitudes toward CRC (OR = 2.48, 95% CI: 1.71-3.58). CONCLUSION: A high awareness level of CRC risk factors and causation myths was associated with a greater likelihood of demonstrating positive attitudes toward CRC in terms of perceived susceptibility, importance of early detection, and consequences of developing the disease. Future educational interventions should focus on raising public awareness about CRC, with a particular emphasis on risk factors and causation myths, to maximize the potential for shaping favorable attitudes toward the disease.

Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer.

Cancer comes in second place on the list of causes of death worldwide. In 2018, the 5-year prevalence of breast cancer (BC), prostate cancer (PC), and colorectal cancer (CRC) were 30%, 12.3%, and 10.9%, respectively. Cannabinoids are chemicals derived from the Cannabis sativa plant; the most investigated cannabinoids are cannabinol, delta 9-tetrahydrocannabinol (Δ9-THC), and cannabidiol. In humans, the endogenous endocannabinoid system consists of endocannabinoids, cannabinoids receptors (CBs), and enzymes that degrade the endocannabinoids. In this review, we will review the most recent literature for evidence that discusses the role of cannabis in the treatment of the three types of neoplasms mentioned. Studies have proved that BC cells express CB receptors; many in-vivo studies showed that cannabinoids cause apoptosis and inhibit proliferation and migration. Also, researchers found that treating BC mice with THC and JWH-133 (CB2 receptor agonist) slowed the tumor growth. Regarding CRC, cannabidiol was found to decrease the viability of chemotherapy-resistant CRC cells and inhibit metastasis by antagonizing the G-protein-coupled receptor 55 (GPR55; a novel cannabinoid receptor) necessary for metastasis. Moreover, cannabidiol had anti-angiogenetic effects by reducing the expression of vascular endothelial growth factor (VEGF) in addition to anti-inflammatory effects. Finally, studies demonstrated that PC cells highly express CB1 and CB2 receptors and that cannabinoids are capable of inhibiting the release of exosomes and microvesicles related to cancer progression. Cannabinoids also have antiproliferative, anti-invasive, anti-fibroblastic, cell cycle arrest, and proapoptotic effects on PC cells.

Myths and Common Misbeliefs About Colorectal Cancer Causation in Palestine: A National Cross-Sectional Study.

PURPOSE: To explore public awareness of myths around colorectal cancer (CRC) causation in Palestine and to examine factors associated with good awareness. MATERIALS AND METHODS: Convenience sampling was used to recruit adult Palestinians from governmental hospitals, primary health care centers, and public spaces. Recognizing 13 myths around CRC causation was assessed using a translated-into-Arabic version of the Cancer Awareness Measure-Mythical Causes Scale. Awareness level was determined based on the number of CRC mythical causes recognized: poor (0-4), fair (5-9), and good (10-13). Multivariable logistic regression was used to examine the association between sociodemographic characteristics and displaying good awareness. It adjusted for age group, sex, education, occupation, monthly income, residence, marital status, having chronic diseases, being a vegetarian, knowing someone with cancer, and site of data collection. RESULTS: Of 5,254 participants approached, 4,877 agreed to participate (response rate, 92.3%). A total of 4,623 questionnaires were included in the final analysis: 2,700 from the West Bank and Jerusalem (WBJ) and 1,923 from the Gaza Strip. Only 219 participants (4.7%) demonstrated good awareness of myths around CRC causation. WBJ participants were twice more likely than those from the Gaza Strip to display good recognition (5.9% v 3.1%). Male sex, living in the WBJ, and visiting hospitals were all associated with an increase in the likelihood of displaying good awareness. Conversely, knowing someone with cancer was associated with a decrease in the likelihood of displaying good awareness. Having a physical trauma was the most recognized CRC causation myth (n = 2,752, 59.5%), whereas eating food containing additives was the least (n = 456, 9.8%). CONCLUSION: Only 4.7% displayed good ability to recognize myths around CRC causation. Future educational interventions are needed to help the public distinguish the evidence-based versus mythical causes of CRC.

Perceived barriers to early presentation and symptom-specific time to seek medical advice for possible colorectal cancer symptoms among Palestinians.

This study explored the anticipated time to seek medical advice for possible colorectal cancer (CRC) signs/symptoms and its association with CRC symptom awareness. In addition, it examined perceived barriers that may delay seeking medical advice. Palestinian adults were recruited from hospitals, primary healthcare centers, and public spaces in 11 governorates. A modified, translated-into-Arabic version of the validated Bowel Cancer Awareness Measure was used. The questionnaire comprised three sections: sociodemographics, assessment of CRC symptom awareness and time to seek medical advice, and barriers to early presentation. A total of 4623 participants were included. The proportion that reported seeking immediate medical advice for possible CRC signs/symptoms with blood or mass ranged from 47.1% for 'blood in stools' to 59.5% for 'bleeding from back passage'. Less than half of the participants reported immediate seeking of medical advice for non-specific symptoms (ranging from 5.4% for 'loss of appetite' to 42.0% for 'anemia') and other gastrointestinal symptoms (ranging from 7.7% for 'feeling persistently full' to 35.7% for 'change in bowel habits'). Good CRC symptom awareness was associated with higher likelihood of seeking medical advice within a week from recognizing a CRC symptom. About 13.0% reported a delay to visit their doctor after recognizing a CRC symptom. The most reported barriers were practical with 'would try some herbs first' (50.9%) as the leading barrier. CRC symptoms with blood or mass prompted earlier help seeking. Participants with good CRC awareness were more likely to seek medical advice within a week.

Human Colon Cancer-Derived Clostridioides difficile Strains Drive Colonic Tumorigenesis in Mice.

Defining the complex role of the microbiome in colorectal cancer and the discovery of novel, protumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of colorectal cancer patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and protumorigenic mucosal immune responses marked by the infiltration of activated myeloid cells and IL17-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of colorectal cancer in patients. SIGNIFICANCE: Colorectal cancer is a leading cause of cancer and cancer-related deaths worldwide, with a multifactorial etiology that likely includes procarcinogenic bacteria. Using human colon cancer specimens, culturing, and murine models, we demonstrate that chronic infection with the enteric pathogen C. difficile is a previously unrecognized contributor to colonic tumorigenesis. See related commentary by Jain and Dudeja, p. 1838. This article is highlighted in the In This Issue feature, p. 1825.

Murine fecal microbiota transfer models selectively colonize human microbes and reveal transcriptional programs associated with response to neoadjuvant checkpoint inhibitors.

Human gut microbial species found to associate with clinical responses to immune checkpoint inhibitors (ICIs) are often tested in mice using fecal microbiota transfer (FMT), wherein tumor responses in recipient mice may recapitulate human responses to ICI treatment. However, many FMT studies have reported only limited methodological description, details of murine cohorts, and statistical methods. To investigate the reproducibility and robustness of gut microbial species that impact ICI responses, we performed human to germ-free mouse FMT using fecal samples from patients with non-small cell lung cancer who had a pathological response or nonresponse after neoadjuvant ICI treatment. R-FMT mice yielded greater anti-tumor responses in combination with anti-PD-L1 treatment compared to NR-FMT, although the magnitude varied depending on mouse cell line, sex, and individual experiment. Detailed investigation of post-FMT mouse microbiota using 16S rRNA amplicon sequencing, with models to classify and correct for biological variables, revealed a shared presence of the most highly abundant taxa between the human inocula and mice, though low abundance human taxa colonized mice more variably after FMT. Multiple Clostridium species also correlated with tumor outcome in individual anti-PD-L1-treated R-FMT mice. RNAseq analysis revealed differential expression of T and NK cell-related pathways in responding tumors, irrespective of FMT source, with enrichment of these cell types confirmed by immunohistochemistry. This study identifies several human gut microbial species that may play a role in clinical responses to ICIs and suggests attention to biological variables is needed to improve reproducibility and limit variability across experimental murine cohorts.

Stress-induced alternative splice forms of MDM2 and MDMX modulate the p53-pathway in distinct ways.

MDM2 and MDMX are the chief negative regulators of the tumor-suppressor protein p53 and are essential for maintaining homeostasis within the cell. In response to genotoxic stress and also in several cancer types, MDM2 and MDMX are alternatively spliced. The splice variants MDM2-ALT1 and MDMX-ALT2 lack the p53-binding domain and are incapable of negatively regulating p53. However, they retain the RING domain that facilitates dimerization of the full-length MDM proteins. Concordantly, MDM2-ALT1 has been shown to lead to the stabilization of p53 through its interaction with and inactivation of full-length MDM2. The impact of MDM2-ALT1 expression on the p53 pathway and the nature of its interaction with MDMX remain unclear. Also, the role of the architecturally similar MDMX-ALT2 and its influence of the MDM2-MDMX-p53 axis are yet to be elucidated. We show here that MDM2-ALT1 is capable of binding full-length MDMX as well as full-length MDM2. Additionally, we demonstrate that MDMX-ALT2 is able to dimerize with both full-length MDMX and MDM2 and that the expression of MDM2-ALT1 and MDMX-ALT2 leads to the upregulation of p53 protein, and also of its downstream target p21. Moreover, MDM2-ALT1 expression causes cell cycle arrest in the G1 phase in a p53 and p21 dependent manner, which is consistent with the increased levels of p21. Finally we present evidence that MDM2-ALT1 and MDMX-ALT2 expression can activate subtly distinct subsets of p53-transcriptional targets implying that these splice variants can modulate the p53 tumor suppressor pathway in unique ways. In summary, our study shows that the stress-inducible alternative splice forms MDM2-ALT1 and MDMX-ALT2 are important modifiers of the p53 pathway and present a potential mechanism to tailor the p53-mediated cellular stress response.

The splicing factor FUBP1 is required for the efficient splicing of oncogene MDM2 pre-mRNA.

Alternative splicing of the oncogene MDM2 is a phenomenon that occurs in cells in response to genotoxic stress and is also a hallmark of several cancer types with important implications in carcinogenesis. However, the mechanisms regulating this splicing event remain unclear. Previously, we uncovered the importance of intron 11 in MDM2 that affects the splicing of a damage-responsive MDM2 minigene. Here, we have identified discrete cis regulatory elements within intron 11 and report the binding of FUBP1 (Far Upstream element-Binding Protein 1) to these elements and the role it plays in MDM2 splicing. Best known for its oncogenic role as a transcription factor in the context of c-MYC, FUBP1 was recently described as a splicing regulator with splicing repressive functions. In the case of MDM2, we describe FUBP1 as a positive splicing regulatory factor. We observed that blocking the function of FUBP1 in in vitro splicing reactions caused a decrease in splicing efficiency of the introns of the MDM2 minigene. Moreover, knockdown of FUBP1 in cells induced the formation of MDM2-ALT1, a stress-induced splice variant of MDM2, even under normal conditions. These results indicate that FUBP1 is also a strong positive splicing regulator that facilitates efficient splicing of the MDM2 pre-mRNA by binding its introns. These findings are the first report describing the regulation of alternative splicing of MDM2 mediated by the oncogenic factor FUBP1.

Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma.

Pediatric rhabdomyosarcoma (RMS) is a morphologically and genetically heterogeneous malignancy commonly classified into three histologic subtypes, namely, alveolar, embryonal, and anaplastic. An issue that continues to challenge effective RMS patient prognosis is the dearth of molecular markers predictive of disease stage irrespective of tumor subtype. Our study involving a panel of 70 RMS tumors has identified specific alternative splice variants of the oncogenes Murine Double Minute 2 (MDM2) and MDM4 as potential biomarkers for RMS. Our results have demonstrated the strong association of genotoxic-stress inducible splice forms MDM2-ALT1 (91.6% Intergroup Rhabdomyosarcoma Study Group stage 4 tumors) and MDM4-ALT2 (90.9% MDM4-ALT2-positive T2 stage tumors) with high-risk metastatic RMS. Moreover, MDM2-ALT1-positive metastatic tumors belonged to both the alveolar (50%) and embryonal (41.6%) subtypes, making this the first known molecular marker for high-grade metastatic disease across the most common RMS subtypes. Furthermore, our results show that MDM2-ALT1 expression can function by directly contribute to metastatic behavior and promote the invasion of RMS cells through a matrigel-coated membrane. Additionally, expression of both MDM2-ALT1 and MDM4-ALT2 increased anchorage-independent cell-growth in soft agar assays. Intriguingly, we observed a unique coordination in the splicing of MDM2-ALT1 and MDM4-ALT2 in approximately 24% of tumor samples in a manner similar to genotoxic stress response in cell lines. To further explore splicing network alterations with possible relevance to RMS disease, we used an exon microarray approach to examine stress-inducible splicing in an RMS cell line (Rh30) and observed striking parallels between stress-responsive alternative splicing and constitutive splicing in RMS tumors.