Jornadas Académicas de Salud 2021 / Las Jornadas Académicas en Salud 2021 tienen como propósito promover la actualización de los profesionales de la salud de diversas especialidades, enfatizando la atención interprofesional centrada en el paciente.

Colorectal Cancer (CRC) is one of the most common cancers worldwide. Although various genetic and environmental mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remain largely unknown. Transmembrane and Immunoglobulin Domain Containing-1 (TMIGD1) is a newly identified candidate tumor suppressor that is mainly expressed in the kidneys and intestines. However, whether TMIGD1 is involved in the tumorigenesis of CRC is not currently known. The main objective of this project was to investigate the effects of the loss of TMIGD1 on intestinal morphology and cellular differentiation in wildtype and knockout mice. Our findings illustrate that the loss of TMIGD1 causes intestinal adenomas and disrupts intestinal brush border formation in mouse models. Furthermore, our research shows that the loss of TMIGD1 in mice affects cellular maturation and intestinal epithelium differentiation. We also demonstrate that TMIGD1 is downregulated in human CRC tissue. Taken together, our results reveal that the loss of TMIGD1 in mouse colonic epithelium results in impaired intestinal epithelium brush border formation, junctional polarity, and development of colonic adenoma. / 2021-06-04T00:00:00Z

Indiana University-Purdue University Indianapolis (IUPUI) / The nuclear factor κB (NF-κB) plays pivotal roles in inflammatory and immune responses and in cancer. Therefore, understanding its regulation holds great promise for disease therapy. Using validation-based insertional mutagenesis (VBIM), a powerful technique established by us, we discovered armadillo repeat containing protein 4 (ARMC4) as a novel negative regulator of NF-κB in colorectal cancer (CRC). ARMC4 is a rarely studied protein only known to date for its role in primary ciliary dyskinesia (PCD) and mouse spermatogenesis. Thus, my work reveals a completely new facet of ARMC4 function that has never been reported before. We showed that ARMC4 overexpression downregulated the expression of NF-κB-dependent genes, many of which are related to cancer. Additionally, compared to the vector control group, overexpression of ARMC4 in HEK293 cells or CRC HT29, DLD1, and HCT116 cells dramatically reduced NF-κB activity, cellular proliferation, anchorage-independent growth, and migratory ability in vitro, and unsurprisingly, significantly decreased xenograft tumor growth in vivo. In contrast, shARMC4 knockdown cells showed quite opposite effect. Furthermore, co-immunoprecipitation (Co-IP) experiment confirmed that ARMC4 may form a complex with the p65 subunit of NF-κB. Importantly, immunohistochemistry (IHC) data exhibited much lower ARMC4 expression level in CRC patient tumor tissues compared to normal tissues, indicating that ARMC4 may function as a tumor suppressor in CRC. To conclude, my important findings for the first time uncovered the negative regulatory function of ARMC4 in NF-κB signaling, and present ARMC4 as an innovative therapeutic target in CRC treatment. / 2022-05-06

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand, 2008

a variety of South African Hospitals: a retrospective study Purpose: To examine the number of lymph nodes present in specimens submitted for histological examination from a variety of South African hospitals; the identification of factors that influence nodal yield and node positivity; determining whether oncological clearance is improved based on the number of nodes examined in high volume centers versus low volume centres; the establishment of guidelines on where surgery for colorectal cancer should ideally be performed. Patients and methods: Pathology reports of resected specimens of colorectal adenocarcinoma in the database of the National Health Laboratory Service Johannesburg laboratory from 2000 to 2005, were examined for patient demographics, referring hospital, tumour specific features of T-stage, degree of differentiation, lymphovascular invasion and adenocarcinoma subtype (mucinous versus non-mucinous), number of lymph nodes identified, number of nodes positive and whether preoperative radiotherapy was administered. Hospitals were grouped into four groups of Charlotte Maxeke Johannesburg Academic Hospital, Helen Joseph Hospital, private hospitals and non-academic public hospitals. Patients were grouped according to the number of lymph nodes retrieved into the following groups: not recorded, no nodes identified,1-7 nodes identified, 8-12 nodes, 13-18 nodes, and greater than 18 nodes identified. Additionally, patients were subdivided into those with nodal metastasis and those without, and into colon and rectal cancer respectively. Multivariate analysis was performed via StatSoft, Inc. (2008) STATISTICA (data analysis software system), version 8.0 on the different lymph node groups versus the abovementioned covariates. Results: Of the 365 patients identified, the mean number of lymph nodes examined per resected specimen was 8.9 (±6.2SD), with significant differences noted between the different resection subtypes (p < 0.001). No statistically significant difference in mean number of nodes identified could be seen between the various hospitals. Alarmingly, in the group of patients where no metastatic nodes could be identified, the recommendation of 12 or more nodes examined per specimen was upheld in only 29% of cases. Factors associated with positive lymph nodes in this study include T-stage, degree of differentiation and lymphovascular invasion by the tumour. No significant benefit in terms of finding metastasis nodes could be demonstrated by examining more than 18 nodes. Conclusions and recommendations: This study highlights a substandard nodal assessment in colorectal cancer specimens overall, including the academic hospitals. More than 70% of node negative patients in this series may have been understaged. Close liaison between the surgeon and examining pathologist is recommended. In the presence of the identified high risk factors for nodal involvement and a substandard nodal assessment, additional measures i.e. fat clearance and immunohistochemistry need employment. A prospective study assessing quality of surgery is necessary, as is the creation of a central database to improve overall quality of cancer care.

The author deals with two groups of patients diagnosed with colorectal cancer and compared patients with this diagnosis are treated and monitored a second group in which this newly diagnosed disease.

The author in his doctoral thesis, proposed primers and conditions optimized design Quantitative PCR for determining the gene expression of MMP-7, TIMP-1, MMP-2 and TIMP- second Revealed the presence of gene expression of GAPDH TIMP-1 and TIMP-2 in cancer line HT-29 SW480 and SW620. Noted the high level expression of MMP-7 in line HT-29th Expression of the 2-3 orders of magnitude higher than the lines SW480 and SW620. MRNA expression of MMP-2 in line HT-29 noticed. MRNA expression of MMP-2 by the detected lines SW480 and SW620. He found that determining absolute and relative expression in tumor lines is ekvivalentní. significantly higher mRNA expression of MMP-7, TIMP-1, MMP-2 and TIMP-2 in tumor tissue compared to normal tissue. It can be used in therapy. Noticed the presence of correlation of gene expression MMP-7, TIMP-1, MMP-2 and TIMP-2 with survival and DFI. He showed that a higher stage cancer correlated with a higher median momery MMP-2/TIMP-2. 7, Noticed the difference in gene expression between TS, TP and DPD in control and tumor tissue. Scored marginally significant increase in TS expression in colon tumors compared to tumors rectosigmoid and rectum. This finding can be used in treatment decisions. scored marginally significant correlation between the expression of TS and DPD. This finding can be...

The level of MMP-7, TIMP-1 and MMP-2 mRNA expression was significantly higher in the tumour tissue of colorectal carcinoma than in normal colorectal tissue. It could be possible to inhibit matrix metalloproteinases activity using appropriate antibodies, which could have therapeutic effect on tumour tissue and its vicinity. Some of the preparations are being tested (Bay 12-9566 /Bayer/, BB94 /British Biotechnology/). We have not proved correlation between expression of these genes and disease stage and diagnosis. We have succeeded to prove that if the surgical principles for colon resection performed due to colorectal carcinoma are observed, the resection line does not show any signs of the presence of tumour cells - mRNA for CEA is not present. The level of mRNA for TIMP-1 is present in the resection line at lower levels than in tumour tissue, and this is due to the role that TIMP- 1 plays in the colon. Its level increases not only in all tumour diseases, but also in inflammatory diseases of the colon. The question whether the expression of mRNA for TIMP-1 is also increased outside the resection line and therefore it is a reaction of the colon as an organ will be subject to further research, as will be a potential comparison with samples of colon unaffected by tumour or inflammation. Although the...

Colorectal cancers (CRCs) rely heavily on host-derived structures to support tumour development and maintain growth. The tumour microenvironment (TME) includes contributions from underlying vascular endothelial cells to maintain nutrient and oxygen availability, as well as a delicate interplay with effector and suppressor immune cells to ensure effective immune evasion. Despite previous attempts to target these TME components through direct, individual therapeutic interventions targeting pro-angiogenic signaling and blocking immune suppression, in many cases the CRC TME remains supportive of tumour growth. Here, I have identified a loci-specific Autism Spectrum Disorder-linked 16p11.2 microdeletion, that demonstrates a negative impact on tumour growth. Initially, I show that a constitutive 16p11.2 deficiency (16p11.2df) alters tumour growth, although has no impact on tumourigenesis. Moreover, I demonstrate that a 16p11.2df in host- derived structures of the TME but not tumour cells is sufficient to slow tumour growth. Further, I demonstrate that vascular networks are altered in tumours derived from a 16p11.2df TME. While I present systemic alterations to the immunological landscape of 16p11.2df individuals at the transcriptional level, there is no detectable alteration in cytotoxic immune cell infiltration into 16p11.2df-derived tumours despite increased expression of T cell activating cytokines. In addition to altered growth characteristics, tumours derived from 16p11.2df mice show an enrichment in apoptosis of tumour cells, despite no change in proliferation. These findings suggest the potential for a 16p11.2df-mediated induction of tumour dormancy, through which volumetric tumour growth is slowed. Together, this study demonstrates the need for further investigation of the 16p11.2 microdeletion as a critical regulator of tumour growth.

Following colonoscopic polypectomy, US Multisociety Task Force (USMSTF) guidelines stratify patients based on risk of subsequent advanced neoplasia (AN) using number, size, and histology of resected polyps, but have only moderate sensitivity and specificity. We hypothesized that a state-of-the-art statistical prediction model might improve identification of patients at high risk of future AN and address these challenges. Data were pooled from seven prospective studies which had follow-up ascertainment of metachronous AN within 3-5 years of baseline polypectomy (combined n = 8,228). Pooled data were randomly split into training (n = 5,483) and validation (n = 2,745) sets. A prognostic model was developed using best practices. Two risk cut-points were identified in the training data which achieved a 10 percentage point improvement in sensitivity and specificity, respectively, over current USMSTF guidelines. Clinical benefit of USMSTF versus model-based risk stratification was then estimated using validation data. The final model included polyp location, prior polyp history, patient age, and number, size and histology of resected polyps. The first risk cut-point improved sensitivity but with loss of specificity. The second risk cut-point improved specificity without loss of sensitivity (specificity 46.2 % model vs. 42.1 % guidelines, p < 0.001; sensitivity 75.8 % model vs. 74.0 % guidelines, p = 0.64). Estimated AUC was 65 % (95 % CI: 62-69 %). This model-based approach allows flexibility in trading sensitivity and specificity, which can optimize colonoscopy over- versus underuse rates. Only modest improvements in prognostic power are possible using currently available clinical data. Research considering additional factors such as adenoma detection rate for risk prediction appears warranted.