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SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.
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COVID-19 , Humanos , Recém-Nascido , Biomarcadores Tumorais , COVID-19/epidemiologia , Ferritinas , Sistema Imunitário , Ferro , Pandemias , Estudos Prospectivos , SARS-CoV-2RESUMO
Given the need to improve the sensitivity of non-invasive methods to detect colorectal neoplasia, particularly adenomas, we compared a fecal test using a monoclonal antibody (Mab) raised against constituents of colonic adenomas designated Adnab-9 (Adenoma Antibody 9), recognizing an N-linked 87 kDa glycoprotein, to gFOBT, which is shown to reduce CRC mortality. p87 immunohistochemistry testing is significantly more sensitive (OR 3.64[CI 2.37-5.58]) than gFOBT (guaiac-based fecal occult blood test) for adenomas (<3 in number), advanced adenomas (OR 4.21[CI 2.47-7.15]), or a combination of the two (OR 3.35[CI 2.47-4.53]). p87 immunohistochemistry shows regional Paneth cell (PC) expression mainly in the right-sided colon and is significantly reduced in the ceca of African Americans (p < 0.0001). In a subset of patients, we obtained other body fluids such as urine, colonic effluent, and saliva. Urine tests (organ-specific neoantigen) showed a significant difference for advanced adenomas (p < 0.047). We conclude that fecal p87 testing is more sensitive than gFOBT and Adnab-9 and could be used to better direct the colonoscopy screening effort.
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Adenoma , Neoplasias Colorretais , Humanos , Guaiaco , Sangue Oculto , Programas de Rastreamento/métodos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/prevenção & controle , Colonoscopia/métodos , Adenoma/diagnóstico , Sensibilidade e Especificidade , Detecção Precoce de Câncer/métodosRESUMO
Background and Aims: It has been recently proposed to change the nomenclature of "chronic radiation proctitis" (CRP) to "radiation-associated vascular ectasia" on the basis that signs of inflammation are rarely observed. We herein present data supporting the idea that inflammation is a critical step that initiates the process that culminates in the characteristic changes of CRP. Methods: In support of inflammation in the pathogenesis of CRP, we review the pertinent literature and publish our new results, including the role of amifostine treatment and proinflammatory factors (p38 MAP kinase, VEGF, and CEACAM1). Results: Immunohistochemistry from anterior rectal wall biopsies obtained in a prospective pilot study demonstrates that expression of VEGF and the downstream vascular effector CEACAM1 were elevated before radiotherapy and declined with time. We also show that MAP Kinase p38 expression usually precede the radiation. Fibrosis scores increase from baseline at 9 and 18 months, while vascular scores decrease at 18 months. Conclusion: The proposed new nomenclature should be held in obeyance until more supportive data are presented. Possibly, the best way to view CRP is as a continuum that may take one of three forms, inflammation-predominant, vasculopathy-predominant, or mixed.
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BACKGROUND: We evaluated the phenotype of sporadic gastric cancer based on HP status and binding of a tumor risk marker monoclonal, Adnab-9. METHODS: We compared a familial GC kindred with an extremely aggressive phenotype to HP-positive (HP+) and -negative (HP-) sporadic gastric adenocarcinoma (GC) patients in the same community to determine if similar phenotypes exist. This might facilitate gene discovery to understand the pathogenesis of aggressive GC phenotypes, particularly with publications implicating immune-related gene-based signatures, and the development of techniques to gauge the stance of the innate immune system (InImS), such as the FERAD ratio (blood ferritin:fecal Adnab-9 binding OD-background binding). Resection specimens for the sporadic and familial group were stained for HP and examined for intestinal metaplasia (IM) and immunostaining for Adnab-9. Familial kindred specimens were also tested for the E-cadherin mutation and APC (adenomatous polyposis coli). Survival was evaluated. RESULTS: Of 40 GC patients, 25% were HP+ with a greater proportion of intestinal metaplasia (IM) and gastric atrophy than the HP- group. The proband of the familial GC kindred, a 32-year-old mother with fatal GC, was survived by 13-year-old identical twins. Twin #1 was HP- with IM and Twin #2 was HP+. Both twins subsequently died of GC within two years. The twins did not have APC or E-cadherin mutations. The mean overall survival in the HP+ sporadic GC group was 2.47 ± 2.58 years and was 0.57 ± 0.60 years in the HP- group (p = 0.01). Survival in the kindred was 0.22 ± 0.24 years. Adnab-9 labeling was positive in fixed tissues of 50% of non-familial GC patients and in gastric tissue extract from Twin #2. The FERAD ratio was determined separately in six prospectively followed patient groups (n = 458) and was significantly lower in the gastric cancer patients (n = 10) and patients with stomach conditions predisposing them to GC (n = 214), compared to controls (n = 234 patients at increased risk for colorectal cancer but without cancer), suggesting a failure of the InImS. CONCLUSION: The HP+ sporadic GC group appears to proceed through a sequence of HP infection, IM and atrophy before cancer supervenes, and the HP- phenotype appear to omit this sequence. The familial cases may represent a subset with both features, but the natural history strongly resembles that of the HP- group. Two different paths of carcinogenesis may exist locally for sporadic GC. The InImS may also be implicated in prognosis. Identifying these patients will allow for treatment stratification and early diagnosis to improve GC survival.
Assuntos
Adenocarcinoma , Helicobacter pylori , Neoplasias Gástricas , Humanos , Adulto , Adolescente , Neoplasias Gástricas/genética , Adenocarcinoma/genética , Carcinogênese , Atrofia , CaderinasRESUMO
The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimetic (CFMs) compounds 4 and 5, and 4.6, a structurally related analog of CFM-4, are potent inhibitors of TNBC and NSCLC cells in vitro. Cell growth suppression by CFM-4 and -4.6 involved interaction and elevated expression of CARP-1/CCAR1 and Death Effector Domain (DED) containing DNA binding (DEDD)2 proteins. Apoptosis by these compounds also involved activation of pro-apoptotic stress-activated kinases p38 and JNK1/2, cleavage of PARP and loss of mitotic cyclin B1. Both the CFMs inhibited abilities of NSCLC and TNBC cells to migrate, invade, and form colonies in suspension, while disrupting tubule formation by the human umbilical vein endothelial cells (HUVECs). Nano-lipid formulation of CFM-4 (CFM-4 NLF) enhanced its serum bioavailability when compared with the free CFM-4. Oral administration of CFM-4 NLF reduced weights and volume of the xenografted tumors derived from A549 NSCLC and MDA-MB-231 TNBC cells. Although no gross tissue or histological toxicities were noticed, the immuno-histochemical analysis revealed increased CARP-1 and DNA fragmentation in tumors of the CFM-4 NLF-treated animals. In conclusion, while stimulation of pro-apoptotic CARP-1 and DEDD2 expression and their binding underscore a novel mechanism of apoptosis transduction by CFM compounds, our proof-of-concept xenograft studies demonstrate therapeutic potential of CFM-4 for TNBC and NSCLC.
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Proteínas Reguladoras de Apoptose/administração & dosagem , Proteínas Reguladoras de Apoptose/farmacocinética , Proteínas de Ciclo Celular/administração & dosagem , Proteínas de Ciclo Celular/farmacocinética , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/química , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/síntese química , Proteínas de Ciclo Celular/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Feminino , Camundongos , Camundongos Nus , Camundongos SCID , Nanopartículas/ultraestrutura , Neoplasias Experimentais/patologia , Resultado do TratamentoRESUMO
We hypothesize that ERRP (EGFR-related protein), a recently identified negative regulator of EGFR may modulate EGFR function in colorectal carcinogenesis. The expression of ERRP and EGFR in normal and neoplastic colorectal tissue was examined. ERRP was highly expressed in normal colonic mucosa and benign colorectal adenomas, but lower in colorectal cancer. Mean scores for ERRP expression decreased significantly across well differentiated, moderately well differentiated and poorly differentiated (P = 0.002) tumors, respectively. ERRP expression became more attenuated in polyps with increasing grades of dysplasia. In contrast, expression of EGFR was inversely related to ERRP in representative samples of normal and neoplastic tissues.
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Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/biossíntese , Adenoma/genética , Diferenciação Celular , Colo/fisiologia , Pólipos do Colo/genética , Fator de Crescimento Epidérmico , Receptores ErbB , Humanos , Proteínas OncogênicasRESUMO
AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells (CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and Helicobacter pylori (H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old (young) with 22 mo (aged) old Fischer-344 rats. For human studies, gastric biopsies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells. RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia. CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.
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Patients with the hamartomatous polyposis Peutz-Jeghers and familial juvenile polyposis syndromes are predisposed to colorectal cancer but lack early genetic alterations found in adenomatous premalignant lesions. We studied hamartomatous polyps for the expression of an early preneoplastic colorectal neoplasia risk marker also found in familial adenomatous polyposis patients. Retrospective, genetic, and hospital archival tissue immunohistochemistry using Adnab-9, a premalignant marker often found in Paneth-like cells (PCs), was performed on sections of polyps from eight patients with Peutz-Jeghers syndrome, eight patients with familial juvenile polyposis, and 36 hyperplastic polyp control sections. Anti-alpha-defensin 5 (AD5), a universal PC marker, was also used to label a subgroup of sections. Hamartomatous polyposis patients also underwent specific genetic analysis. Eighty-nine percent of Peutz-Jeghers syndrome polyps labeled with Adnab-9 compared with 63% for AD5; 88% of familial juvenile polyposis sections also labeled with Adnab-9. Of the 36 hyperplastic polyp sections, only four (11%) labeled with Adnab-9 and one (3%) with AD5. Adnab-9 labeling of PCs in the epithelial elements of hamartomatous colonic lesions of hereditary hamartomatous syndrome patients reflects the predisposition to colorectal cancer, further justifying early intervention strategies.
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Polipose Adenomatosa do Colo/patologia , Anticorpos Monoclonais , Biomarcadores Tumorais , Colo/patologia , Pólipos do Colo/patologia , Síndrome de Peutz-Jeghers/patologia , Quinases Proteína-Quinases Ativadas por AMP , Polipose Adenomatosa do Colo/genética , Adolescente , Adulto , Idoso , Pré-Escolar , Pólipos do Colo/genética , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Processos Neoplásicos , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/genética , alfa-Defensinas/metabolismoRESUMO
Since significant neoplasia after initial colonoscopy is low, we conducted this pilot study to compare the predictive role for colorectal neoplasia recurrence of anti-DCC with that of Adnab-9 binding to colonic effluent of high-risk patients. DCC and Adnab-9 effluent ELISA were performed at baseline colonoscopies. The results of follow-up colonoscopies were reviewed. To ensure specificity, immunohistochemistry and Western blot was performed with anti-DCC and for Adnab-9 where optimal fixation times were also evaluated. Mean follow-up was 2.6 years. Of 21 patients, 6 of 10 who progressed to CRN and 2 of 11 who did not had a positive Adnab-9 ELISA result (P=0.08). Despite an initial good correlation with Adnab-9 ELISA results in a smaller dataset, we were unable to obtain consistent subsequent DCC immunohistochemistry or Western blot data using antibody from two different sources. However, the original dataset of Adnab-9 results was reproducible on repetition of the ELISA with a larger set of samples that included this initial dataset and optimal fixation time was 20 min. We conclude that Adnab-9 appears to be a promising prognostic marker for neoplasia in the high-risk population. Industry standards need to be developed for DCC monoclonal antibodies that may have similar utility.
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Adenoma/diagnóstico , Adenoma/metabolismo , Antígenos Glicosídicos Associados a Tumores/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Receptores de Superfície Celular/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenoma/genética , Idoso , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos Glicosídicos Associados a Tumores/genética , Antígenos Glicosídicos Associados a Tumores/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Colonoscopia , Neoplasias Colorretais/genética , Receptor DCC , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Projetos Piloto , Valor Preditivo dos Testes , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologiaRESUMO
We sought a correlation between site and morphology of colonic polyps by labeling with neoplastic and general Paneth cell markers, monoclonal antibodies Adnab-9 and anti-alpha-defensin 5, respectively. Proportions labeled by Adnab-9 and anti-alpha-defensin 5 were, respectively, 42 and 85% for adenomas, 39 and 63% for early tubular adenomas, 41 and 44% for serrated, 34 and 20% for mixed, and 11 versus 2.7% for hyperplastic polyps. Compared with hyperplastic polyps, the proportion of other polyps labeled by Adnab-9 or anti-alpha-defensin 5 was higher but this difference was more significant for distal (P = 0.008 for Adnab-9 and P = 0.0001 for anti-alpha-defensin 5) than proximal (P = 0.645 and P = 0.154, respectively) polyps. While increased labeling of all proximal polyps compared to distal ones mirrored the colonic distribution of Paneth cells, distal adenomas tended to have a higher proportion labeled by Adnab-9, suggesting that Adnab-9 labels Paneth cells associated with increased neoplastic potential.
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Pólipos Adenomatosos/patologia , Anticorpos Monoclonais , Neoplasias do Colo/patologia , Pólipos do Colo/patologia , alfa-Defensinas/imunologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica/métodos , Celulas de Paneth/patologia , Método Simples-Cego , Coloração e RotulagemAssuntos
Dor Abdominal/etiologia , Colo/patologia , Perfuração Intestinal/patologia , Dor Abdominal/diagnóstico , Dor Abdominal/cirurgia , Artéria Braquial/cirurgia , Colo/cirurgia , Humanos , Doença Iatrogênica , Perfuração Intestinal/cirurgia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Trombectomia/efeitos adversosRESUMO
BACKGROUND & AIMS: Distal colonic adenomas found on flexible sigmoidoscopy are associated with proximal neoplasias, thus requiring a complete colonoscopic examination, but data regarding the association of distal mixed polyps with proximal neoplasia are lacking. We conducted this study to elucidate the significance of distal mixed colonic polyps in predicting proximal neoplasia. METHODS: We retrospectively analyzed data from patients who underwent a flexible sigmoidoscopic examination for colorectal cancer screening and a follow-up colonoscopic examination because of distal colonic polyps. Distal index polyps were classified by a pathologist as early tubular adenoma (ETA), serrated, or true mixed categories. Index polyps also were immunostained with a monoclonal antibody, Adnab-9, a marker for the colorectal adenoma carcinoma sequence. RESULTS: In 636 patients with distal index polyps, 6% were malignant, 55% were adenomas, 13% were ETAs, 6% were serrated, 4% were true mixed, and 17% were hyperplastic. Compared with distal hyperplastic index polyps, distal malignant polyps (P = 0.0006) and adenomas (P = 0.001) were associated with a significantly increased number of synchronous proximal neoplasia, but the small distal mixed, serrated, or ETA did not predict the increased incidence of proximal neoplasia. Large distal polyps of each category were significantly associated with an increased number of synchronous proximal neoplasias. In support of these findings, immunostaining of distal polyps with Adnab-9 showed predictability for proximal neoplasia only in the adenoma category (P < 0.05). CONCLUSIONS: Small ETAs, serrated, or mixed polyps found on flexible sigmoidoscopic examination do not increase the probability of synchronous proximal neoplasia.