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The Journal of Clinical Investigation Aug 2021BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and...
BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.MethodsHealthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.ResultsMedian VRC01 levels were quantifiable in serum (96.2 μg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).ConclusionIntravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.FundingNational Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
Topics: Adult; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; In Vitro Techniques; Infusions, Intravenous; Male; Middle Aged; Mucous Membrane; Rectum; Vagina; Young Adult
PubMed: 34166231
DOI: 10.1172/JCI146975 -
Expert Opinion on Biological Therapy Aug 2010There are currently over thirty million people infected with HIV and there are no vaccines available to prevent HIV infections or disease. The genitourinary, rectal and... (Review)
Review
IMPORTANCE OF THE FIELD
There are currently over thirty million people infected with HIV and there are no vaccines available to prevent HIV infections or disease. The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes. An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as a major means of protection against mucosal HIV transmission and AIDS.
WHAT THE READER WILL GAIN
Structure and cells that comprise the oral, vaginal and rectal mucosa pertaining to HIV transmission and vaccination strategies through each mucosal route to prevent mucosal and systemic infection will be discussed.
AREAS COVERED IN THIS REVIEW
Covering publications from 1980s through 2010, mucosal transmission of HIV and current and previous approaches to vaccinations are discussed.
TAKE HOME MESSAGE
Although oral transmission of HIV is far less common than vaginal and rectal transmissions, infections through this route do occur through oral sex as well as vertically from mother to child. Mucosal vaccination strategies against oral and other mucosal HIV transmissions are under intensive research but the lack of consensus on immune correlates of protection and lack of safe and effective mucosal adjuvants and delivery systems hamper progress towards a licensed vaccine.
Topics: AIDS Vaccines; Administration, Intravaginal; Administration, Oral; Administration, Rectal; Animals; Female; HIV Infections; Humans; Immunity, Mucosal; Intestinal Mucosa; Male; Mouth Mucosa; Mucous Membrane
PubMed: 20624114
DOI: 10.1517/14712598.2010.496776 -
The American Journal of Tropical... Apr 2023Environmental enteric dysfunction (EED) is a subclinical enteropathy prevalent in resource-limited settings, hypothesized to be a consequence of chronic exposure to...
Environmental enteric dysfunction (EED) is a subclinical enteropathy prevalent in resource-limited settings, hypothesized to be a consequence of chronic exposure to environmental enteropathogens, resulting in malnutrition, growth failure, neurocognitive delays, and oral vaccine failure. This study explored the duodenal and colonic tissues of children with EED, celiac disease, and other enteropathies using quantitative mucosal morphometry, histopathologic scoring indices, and machine learning-based image analysis from archival and prospective cohorts of children from Pakistan and the United States. We observed villus blunting as being more prominent in celiac disease than in EED, as shorter lengths of villi were observed in patients with celiac disease from Pakistan than in those from the United States, with median (interquartile range) lengths of 81 (73, 127) µm and 209 (188, 266) µm, respectively. Additionally, per the Marsh scoring method, celiac disease histologic severity was increased in the cohorts from Pakistan. Goblet cell depletion and increased intraepithelial lymphocytes were features of EED and celiac disease. Interestingly, the rectal tissue from cases with EED showed increased mononuclear inflammatory cells and intraepithelial lymphocytes in the crypts compared with controls. Increased neutrophils in the rectal crypt epithelium were also significantly associated with increased EED histologic severity scores in duodenal tissue. We observed an overlap between diseased and healthy duodenal tissue upon leveraging machine learning image analysis. We conclude that EED comprises a spectrum of inflammation in the duodenum, as previously described, and the rectal mucosa, warranting the examination of both anatomic regions in our efforts to understand and manage EED.
Topics: Humans; Child; Celiac Disease; Prospective Studies; Duodenum; Intestinal Diseases; Intestinal Mucosa; Machine Learning
PubMed: 36913924
DOI: 10.4269/ajtmh.22-0063 -
Gut Microbes 2021Ulcerative colitis (UC), a subtype of inflammatory bowel disease, is characterized by repetitive remission and relapse. Gut microbiome is critically involved in...
Ulcerative colitis (UC), a subtype of inflammatory bowel disease, is characterized by repetitive remission and relapse. Gut microbiome is critically involved in pathogenesis of UC. The shifts in microbiome profile during disease remission remain under-investigated. Recent studies revealed that UC pathogenesis is likely to originate in the mucosal barrier. Therefore, we investigated the effectiveness of mucosal tissue microbiomes to differentiate patients with subclinical UC from healthy individuals. The microbiomes of cecal and rectal biopsies and feces were characterized from 13 healthy individuals and 45 patients with subclinical UC. Total genomic DNA was extracted from the samples, and their microbial communities determined using next-generation sequencing. We found that changes in relative abundance of subclinical UC were marked by a decrease in Proteobacteria and an increase in Bacteroidetes phyla in microbiome derived from rectal tissues but not cecal tissue nor feces. Only in the microbiome of rectal tissue had significantly higher community richness and evenness in subclinical UC patients than controls. Twenty-seven operational taxonomic units were enriched in subclinical UC cohort with majority of the taxa from the Firmicutes phylum. Inference of putative microbial functional pathways from rectal biopsy microbiome suggested a differential increase in interleukin-17 signaling and T-helper cell differentiation pathways. Rectal biopsy tissue was suggested to be more suitable than fecal samples for microbiome assays to distinguish patients with subclinical UC from healthy adults. Assessment of the rectal biopsy microbiome may offer clinical insight into UC disease progression and predict relapse of the diseases.
Topics: Adult; Cecum; Colitis, Ulcerative; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Male; Middle Aged; Rectum
PubMed: 33525983
DOI: 10.1080/19490976.2020.1832856 -
Journal of Cancer Research and... Apr 2023This study aimed to estimate the fitting parameters of sigmoidal dose-response (SDR) curve of radiation-induced acute rectal mucositis in pelvic cancer patients treated...
PURPOSE
This study aimed to estimate the fitting parameters of sigmoidal dose-response (SDR) curve of radiation-induced acute rectal mucositis in pelvic cancer patients treated with Intensity Modulated Radiation Therapy (IMRT) for the calculation of normal tissue complication probability (NTCP).
MATERIALS AND METHODS
Thirty cervical cancer patients were enrolled to model the SDR curve for rectal mucositis. The patients were evaluated weekly for acute radiation-induced (ARI) rectal mucositis toxicity and their scoring was performed as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The radiobiological parameters, namely n, m, TD50, and γ50 were calculated from the fitted SDR curve obtained from the clinical data of cervical cancer patients.
RESULTS
ARI toxicity for rectal mucosa in carcinoma of cervical cancer patients was calculated for the endpoint rectal mucositis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade 1 and Grade 2 rectal mucositis were found to be 0.328, 0.047, 25.44 ± 1.21 (confidence interval [CI]: 95%), and 8.36 and 0.13, 0.07, 38.06 ± 2.94 (CI: 95%), and 5.15, respectively.
CONCLUSION
This study presents the fitting parameters for NTCP calculation of Grade 1 and Grade 2 ARI rectal toxicity for the endpoint of rectal mucositis. The provided nomograms of volume versus complication and dose versus complication for different grades of rectal mucositis help radiation oncologists to decide the limiting dose to reduce the acute toxicities.
Topics: Female; Humans; Uterine Cervical Neoplasms; Radiotherapy Dosage; Mucositis; Rectum; Radiotherapy, Intensity-Modulated; Radiation Injuries
PubMed: 37147948
DOI: 10.4103/jcrt.jcrt_879_21 -
Wiadomosci Lekarskie (Warsaw, Poland :... 2021The aim: To determine whether the pig could be used as biomodel for study and reconstruction of rectal pathology for development the new approaches for prevention and...
OBJECTIVE
The aim: To determine whether the pig could be used as biomodel for study and reconstruction of rectal pathology for development the new approaches for prevention and treatment of rectal diseases.
PATIENTS AND METHODS
Materials and methods: For the research the rectum of 8 vietnamese pot-bellied pigs were used. Via macro- and microscopy the structure of mucosa coat of the pig`s and human`s rectum was compared.
RESULTS
Results: Mucosa coat`s peculiarities of pig`s and human`s rectum in comparative aspect are described in this article. With the help of traditional methods, known as macroscopy the structure of the pig`s rectal mucosa was study and compared wih macrostructure of human`s rectum. The microstucture of pig`s rectal mucosa was study due to histological method too. The macro- and microscopy demonstrated that structure of pig`s and human`s rectal mucosa are similar and includes same structural components.
CONCLUSION
Conclusions: Thus, the research proved that pigs can be used as biomodels in biomedical research for creating various new methods and applications in approaching the prevention and treatment of rectal pathology in humans.
Topics: Animals; Humans; Intestinal Mucosa; Rectal Diseases; Rectum; Swine
PubMed: 34459777
DOI: No ID Found -
International Journal of Clinical and... 2012Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal... (Comparative Study)
Comparative Study Review
Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas.
Topics: Combined Modality Therapy; Female; Genital Neoplasms, Female; Head and Neck Neoplasms; Humans; Male; Melanocytes; Melanoma; Mouth Neoplasms; Mucous Membrane; Paranasal Sinus Neoplasms; Rectal Neoplasms; Skin Neoplasms; Survival Rate
PubMed: 23071856
DOI: No ID Found -
International Journal of Obesity (2005) Feb 2022Obesity increases colorectal cancer (CRC) risk. However, the effects of weight loss on CRC risk are unclear. Epigenetic mechanisms involving microRNAs that lead to...
BACKGROUND/OBJECTIVES
Obesity increases colorectal cancer (CRC) risk. However, the effects of weight loss on CRC risk are unclear. Epigenetic mechanisms involving microRNAs that lead to dysregulated gene expression may mediate the effects of obesity and weight loss on CRC risk. We examined the effects of obesity and weight loss following Roux-en-Y gastric bypass (RYGB) on microRNA expression in the human rectal mucosa.
SUBJECTS/METHODS
We collected rectal mucosal biopsies from obese patients (n = 22) listed for RYGB and age- and sex-matched healthy non-obese Controls (n = 20), at baseline and six months post-surgery. We quantified microRNA expression in rectal mucosal biopsies using Next Generation Sequencing and bioinformatics analysis to investigate the likely functional consequences of these epigenetic changes.
RESULTS
Compared with non-obese individuals, obese individuals showed differential expression of 112 microRNAs (p < 0.05). At six-months post-RYGB, when mean body mass had fallen by 27 kg, 60 microRNAs were differentially expressed, compared with baseline (p < 0.05). The expression of 36 microRNAs differed significantly between both i) obese and non-obese individuals and ii) obese individuals pre- and post-RYGB. Quantitative polymerase chain reaction (qPCR) demonstrated that expression of miR-31 and miR-215 was significantly (p < 0.05) higher, 143-fold and 15-fold respectively, in obese than in non-obese individuals. Weight loss, following RYGB, reduced expression of miR-31 and miR-215 to levels comparable with Controls. These differentially expressed microRNAs are implicated in pathways linked with inflammation, obesity and cancer.
CONCLUSION
Our findings show, for the first time, that obesity is associated with dysregulated microRNA expression in the human rectal mucosa. Further, surgically-induced weight loss may normalise microRNA expression in this tissue.
Topics: Adult; Colorectal Neoplasms; England; Female; Gastric Bypass; Humans; Male; MicroRNAs; Middle Aged; Mucous Membrane; Obesity; Rectum; Statistics, Nonparametric
PubMed: 34716428
DOI: 10.1038/s41366-021-01005-y -
Cellular & Molecular Immunology Feb 2006Ulcerative colitis (UC) is an inflammatory disease of the rectal and colonic mucosa and seems to result from a complex series of interactions between susceptibility... (Review)
Review
Ulcerative colitis (UC) is an inflammatory disease of the rectal and colonic mucosa and seems to result from a complex series of interactions between susceptibility genes, the environment and the immune system. Various components of the mucosal immune system are implicated in the immunopathogenesis of UC. Evidence from animal models also suggests that an altered immune response to the commensal microflora of the host plays a central role in the development of UC. So in this review, we elucidate the cells and molecules which are implicated in the immunopathogenesis of the disease from four aspects: antigens in the intestine, dendritic cells, toll like receptors and NF-kappaB in the UC.
Topics: Animals; Colitis, Ulcerative; Colon; Dendritic Cells; Humans; Immunity, Mucosal; Intestinal Mucosa; Mice; NF-kappa B; Toll-Like Receptors
PubMed: 16549047
DOI: No ID Found -
Frontiers in Immunology 2022Young men who have sex with men (YMSM) represent a particularly high-risk group for HIV acquisition in the US, despite similarly reported rates of sexual activity as...
Young men who have sex with men (YMSM) represent a particularly high-risk group for HIV acquisition in the US, despite similarly reported rates of sexual activity as older, adult MSM (AMSM). Increased rates of HIV infection among YMSM compared to AMSM could be partially attributable to differences within the rectal mucosal (RM) immune environment associated with earlier sexual debut and less lifetime exposure to receptive anal intercourse. Using an explant HIV challenge model, we found that rectal tissues from YMSM supported higher levels of p24 at peak viral replication timepoints compared to AMSM. Among YMSM, the RM was characterized by increased CD4+ T cell proliferation, as well as lower frequencies of tissue resident CD8+ T cells and pro-inflammatory cytokine producing CD4+ and CD8+ T cells. In addition, the microbiome composition of YMSM was enriched for anaerobic taxa that have previously been associated with HIV acquisition risk, including , and . These distinct immunologic and microbiome characteristics were found to be associated with higher HIV replication following challenge of rectal explants, suggesting the RM microenvironment of YMSM may be uniquely conducive to HIV infection.
Topics: Adult; Male; Humans; Homosexuality, Male; HIV Infections; Sexual and Gender Minorities; Sexual Behavior; Mucous Membrane
PubMed: 36341414
DOI: 10.3389/fimmu.2022.972170