Compared to natural selection, domestication implies a dramatic change in traits linked to fitness. A number of traits conferring fitness in the wild might be detri- mental under domestication, and domesticated species typically differ from their ancestors in a set of traits known as the domestication syndrome. Specifically, trade-offs between growth and reproduction are well established across the tree of life. According to allocation theory, selection for growth rate is expected to indirectly alter life-history reproductive traits, diverting resources from reproduc- tion to growth. Here we tested this hypothesis by examining the genetic change and correlated responses of reproductive traits as a result of selection for timber yield in the tree Pinus pinaster. Phenotypic selection was carried out in a natural population, and progenies from selected trees were compared with those of control trees in a common garden experiment. According to expectations, we detected a genetic change in important life-history traits due to selection. Specifi- cally, threshold sizes for reproduction were much higher and reproductive invest- ment relative to size significantly lower in the selected progenies just after a single artificial selection event. Our study helps to define the domestication syndrome in exploited forest trees and shows that changes affecting developmental pathways are relevant in domestication processes of long-lived plants.
For decades, fluoropyrimidines have been the mainstay of CRC chemotherapy (intravenous 5-FU plus leucovorin [LV] or oral capecitabine [Xeloda]). Since the turn of the century, two new cytotoxic agents have been introduced: a topoisomerase inhibitor named irinotecan (Campto) and oxaliplatin (Eloxatin), a third-generation platinum compound (32). Adjuvant treatment for six months after radical excision of colon cancer reduces the risk of relapse and enhances the chance for long-term survival. In stage III disease, there is a strong evidence base that supports adjuvant chemotherapy (6). A number of risk factors are taken into account in patient selection for adjuvant chemotherapy in stage II colon cancer. Factors that increase the risk of relapse include T4 disease, the presence of vessel invasion, <10 examined lymph nodes, poorly differentiated tumours and emergency surgery. Individuals with MSI-high are at lower risk of relapse, at least in stage II disease. The NSABP C07 study demonstrated that the addition of oxaliplatin to infusional 5-FU/LV resulted in a better five-year disease-free survival (DFS) (33). The MOSAIC trial stated that the absolute improvement in OS for high- risk stage II disease was 1.7% as opposed to 0.1% in low-risk stage II and 4.2% for stage III (34). In summary, adjuvant treatment with 5-FU/leucovorin reduced the relative risk for relapse in stage III disease with 30-40%. When adding oxaliplatin, the relative risk reduction is further increased by 19%. In stage II disease, the relative risk reduction is 20 % with 5- FU/LV and an additional 18% with oxaliplatin (6).
Por lo tanto, hay una necesidad de nuevos productos que se dirijan más específicamente a las bacterias asociadas al CCR. En este contexto, algunas moléculas han mostrado efectos prometedores en el CCR y otras enfermedades. Por ejemplo, un glicopolímero, antagonista del factor de virulencia FimH de E. coli, mostró una reducción en la adherencia de E. coli al epitelio intestinal, y por lo tanto a su capacidad de invasión en un modelo de ratón (Saus et al. 2019). Además, la exposición a una dosis baja de una enterotoxina recombinante BFT-2 (un importante factor de virulencia de B. fragilis) disminuyó la formación de tumores en un modelo de ratón (Saus et al. 2019). En varios estudios se ha evaluado el papel de un preparado antibiótico oral en la cirugía colorrectal electiva y se ha llegado a la conclusión de que existe un efecto protector potencialmente significativo de las complicaciones postoperatorias. Sin embargo, debido a la falta de especificidad y a la inducción de una disbiosis, se requieren más investigaciones para reducir el impacto del uso de antibióticos durante el tratamiento del cáncer. Es necesario abordar las perspectivas prometedoras de la coadministración de probióticos durante la terapia de antibióticos. Como alternativa, podrían considerarse estrategias muy específicas, como la fagoterapia (para atacar algunas bacterias intestinales) e incluso la administración de toxinas bacterianas pro- carcinógenas (Villéger et al. 2019). En modelos preclínicos, se ha demostrado que para atacar taxones bacterianos específicos, los bacteriófagos tienen una eficacia igual a la de los antibióticos, e incluso con una menor perturbación de las bacterias comensales (Helmink et al. 2019).
El tratamiento del CCR incluye la utilización de distintas estrategias terapéuticas, en función del estadío tumoral. Aproximadamente el 40% de los casos de CCR en estadíos I o II pueden ser curados únicamente con cirugía, sin tratamiento quimio o radioterapéutico (88). Los pacientes diagnosticados con estadío III son candidatos para recibir quimioterapia adjuvante después de la resección quirúrgica, mientras que los pacientes diagnosticados en estadío IV (con metástasis) normalmente reciben quimioterapia antes de la posible resección quirúrgica (88). Para tratar a los pacientes con CCR en estadíos III y IV, hoy en día se utiliza quimioterapia combinada de diferentes drogas, como: 5-fluorouracil, leucovorin y oxaliplatin (FOLFOX); 5- fluorouracil, leucovorin e irinotecan (FOLFIRI); y capecitabine (la forma oral del 5- fluorouracil, también conocido como Xeloda®) más oxaliplatin (XELOX); puesto que se ha observado que incrementa la supervivencia desde 6 meses a 18-20 meses (89-95).
breast cancerand CRC. Their findings showed HRT reduced CRC risk by 40% and the combined oral contraceptive pill (OCP) reduced CRC risk by 20% (Rossouw et al., 2002, Rossouw et al., 2013, Roehm, 2015). Studies have shown differences between HRT formulations (oestrogen-progestin versus oestrogen only therapy) and protection against CRC. These findings have not been consistent as to which formulation may offer the most protection against CRC, but none appear to have found any increase in CRC risk. The reason for these inconsistencies with HRT formulations is unclear but may relate to duration of treatment within the study (Hildebrand et al., 2009, Johnson et al., 2009, Dinger et al., 2007). However, the WHI trial did note women diagnosed with CRC whilst using oestrogen plus progestin therapy had higher tumour grades, suggesting HRT had a possible role in CRC progression (Chlebowski et al., 2004). HRT may initially offer a protection against CRC, but once established promote tumour proliferation. Alternatively, HRT side effects may mask/simulate CRC symptoms delaying presentation and diagnosis. However, the finding of advanced CRC with HRT treatment in the WHI trial has not been replicated and could instead be related to study design (Prentice et al., 2009).
Goldberg et al (1989) used iso- tretinoin to treat a pair of identical twins with vasal cell nevus syndrome (a precurssor of basal cell carcinoma). The twins received isotretinoin 0.4 milligram/kilogram/day orally for 1 year. After 1 year, both patients had a significant decrease in the number of new lesions. At this time, the dosage was lowered to 0.2 milligram/kilogram/day in one of the twins (twin A). Four years later the twins were evaluated and twin B had developed only 12 new basal cell carcinomas, while twin A developed almost four times as many new lesions. The authors concluded that isotretinoin was a useful adjunct in the treatment of patients with basal cell nevus syndrome. Also, the dosage of 0.2 milligram/kilogram/day isotretinoin was significantly less chemoprotective than the 0.4 milligram/ kilogram/day dose. Kessler et al (1987) administered isotretinoin to 25 patients with extensive MYCOSIS FUNGOIDES (T-cell lymphoma). The first 16 patients received isotretinoin 2 milligrams/kilogram/day. Subsequent
Participants 1238 cases of incident CRC, which developed after enrolment into the cohort, were matched with 1238 controls for age, sex, centre, follow- up time, time of blood collection and fasting status. Main outcome measures Serum concentrations were quantitatively determined by colorimetric and turbidimetric methods. Dietary and lifestyle data were obtained from questionnaires. Conditional logistic regression models were used to estimate incidence rate ratios (RRs) and 95% CIs which were adjusted for height, weight, smoking habits, physical activity, education, consumption of fruit, vegetables, meat, fish, alcohol, fibre and energy. Results After adjustments, the concentrations of HDL and apoA were inversely associated with the risk of colon cancer (RR for 1 SD increase of 16.6 mg/dl in HDL and 32.0 mg/dl in apoA of 0.78 (95% CI 0.68 to 0.89) and 0.82 (95% CI 0.72 to 0.94), respectively). No association was observed with the risk of rectal cancer. Additional adjustment for biomarkers of systemic inflammation, insulin resistance and oxidative stress or exclusion of the first 2 years of follow-up did not influence the association between HDL and risk of colon cancer.
Descriptive analysis was performed through frequency distribution tables. For the overall survival (OS) analysis, the follow-up period was defined as the time elapsed between the date of diagnosis and the date of death or last contact. Survival curves were estimated using the Kaplan-Meier method and differences among curves within different variables were established with the log-rank test. Prognostic factors were identified through Cox regression model. A level of p<0,05 was considered significant. The statistical package SPSS 12.0 (IBM SPSS Statistics for Windows, Version 19.0. Armonk,NY: IBM Corp) was used for the data analysis.
The status of CRC in a patient spans the spectrum from benign adenoma or polyp to malignant carcinoma. This disease progression involves several mechanisms, the most notably being over-proliferation, loss of apoptotic regulation, acquisition of an invasive phenotype, increased angiogenesis, and maintenance of CSCs (Figure 1 ). This progression typically involves upregulation of numerous oncogenes, as well as downregulation of important tumor suppressor genes. The first association between miRNAs and CRC was identified by Michael et al. in 2003, who found decreased levels of miR-143 and miR-145 in CRC tissue compared to healthy tissue [ 6 ]. miRNAs may take on an oncogenic or tumor-suppressive role in their regulation of pathways leading to cancer formation. Oncogenic miRNAs, termed oncomiRs, typically target and downregulate endogenous tumor-suppressor genes. Tumor-suppressive miRNAs, on the other hand, play an important role in downregulating genes associated with growth and metastasis. The upregulation of oncomiRs and the downregulation of tumor-suppressive miRNAs therefore have profound effects on the development of cancer. An overview of current miRNAs associated with CRC is depicted in Tables 1 – 3 .
Regarding parenteral delivery, o/w microemulsions have been largely tested as depots of hydrophobic drugs when administered subcutaneously or intramuscularly. A similar role can be played by w/o microemulsions encapsulating hydrophilic drugs. Intravenous administration of hydrophobic antitumoral, antimicrobial and antiinflamatory drugs has been shown to be also notably facilitated when formulated as o/w microemulsions . Microemulsions enable the preparation of liquid formulations (with the drug totally solubilized in the droplets) avoiding the use of ethoxylated castor oil (Cremophor ® EL) which is commonly employed to prepare injectable solutions of hydrophobic therapeutic agents. Additionally, if PEGylated surfactants are used, microemulsions show high physical stability in plasma and great resistance to leaching of drugs through the oil phase, which in turn facilitates a sustained re1ease of the drug in the blood stream [50-52]. The small size of the microemulsion droplets ensures that the probability of emboli formation in the blood is insignificant and, if the surface is neutral or anionic, a prolonged blood circulation time can be achieved . All together these features make microemulsions attractive for passive targeting of drugs towards tissues showing enhanced capillary permeability, such as those affected by inflammatory, infectious or tumoral processes. Sizes between 10 and 100 nm (which are the typical ones of microemulsion droplets) have been pointed out as the optimum for exploiting the enhanced permeability and retention (EPR) effect . Selective extravasation of drug- loaded droplets can allow for greater accumulation of the drug in the sites of the body where it is required. Therefore, therapeutic efficacy is improved while total systemic dose can be notably diminished . For example, phospholipid- based microemulsions loaded with all-trans-retinoic acid have been proved to be suitable for treatment of patients with acute promyelocytic leukemia . Although much less investigated than other nanocarriers, microemulsion droplets could be al so susceptible of decoration with ligands able to recognize specific cells, enabling active targeting as recently demonstrated for nanoemulsions . Moreover, microemulsions droplets are suitable starting cores for functionalization with diagnostic agents (magnetic resonance imaging (MRI), X-ray computed tomography (CT) imaging) and may lead to theranostic systems .
One of the most important risk factors for colorectalcancer is having a family history of the disease. First-degree relatives of persons diagnosed with colorectalcancer are, on average, at an approximately two-fold increased risk of colorectalcancer compared with those without a family history (familial relative risk) (1). An estimated 3% to 5% of colorectal cancers are caused by high-risk mutations in the identified major colorectalcancer susceptibility genes(2): DNA mismatch repair (MMR) genes(3) and constitutional 3’ end deletions of EPCAM(4, 5) implicated in Lynch syndrome; the adenomatous polyposis coli (APC) gene implicated in familial adenomatous polyposis(6-8); and the MUTYH gene implicated in colorectal polyps and subsequently cancer (MUTYH-associated polyposis)(9). Current estimates of MMR gene mutation carriers in the general population, inferred from the prevalence of mutations in cases and the risk of colorectalcancer for carriers, range widely from approximately 1 in 300 to 1 in 3,000 depending on differing assumptions and genes (10- 16). With the availability of cost-effective sequencing technologies, improved precision in estimates of mutation prevalence would be useful for devising cost-effective genetic testing protocols.
Background : Hereditary nonpolyposis colorectalcancer (HNPCC) accounts for 3 to 5% of all colorectalcancer (CC). It is an autosomal dominant syndrome with 80% of penetrance for this disease. Aim: To analyze the pedigree and surgical treatment of HNPCC. Patients and methods: We retrospectively analyzed our database of CC selecting pa- tients with HNPCC according to clinical criteria (Amsterdam II). We characterized our patient’s pedigrees with telephonic interviews. Results: From 1111 patients operated on with CC we identi- fied 13 (1.17%) with HNPCC. The mean age at diagnosis was 41.6 years (range: 23-75). Sixty two percent presented in International Union Against Cancer (UICC) stages I or II and none in stage IV. Seventy one percent of tumors were proximal to splenic flexure. In 5 patients the diagnosis of HNPCC was made postoperatively, after diagnosis of CC in their relatives. In all but one of the 8 patients with preoperative diagnosis of HNPCC, we performed a total colectomy. From the remain- ing 6 patients with partial colectomy, 2 developed metachronic CC. Two patients died of cancer. From 101 persons in the 4 families, 25 have developed neoplasia: 18 CC, 3 endometrial cancerand 4 other tumors. Twenty eight relatives were eligible for colonoscopic screening, but only 21% of them have been screened appropriately. Conclusions: Preoperative diagnosis should change the surgical treatment of HNPCC, preventing metachronic disease. Primary colonoscopic screen- ing allowed us to diagnose CC in early stages, nonetheless most of eligible relatives have not fol- lowed recommended frequency for colonoscopy (Rev Méd Chile 2004; 132: 539-47).
Special attention should be paid to the fact that two of the previously commented basic ways of alteration in colorectal tumors, the MSI and CIMP pathways, are related to epigenetic modifications, indicating the important role of the malfunction of epigenetic mechanisms in the development and clinical behavior of colorectal tumors. Epigenetic marks occur widely across the genome and extensively regulate the expression of the multitude of genes. The disposition and dosage of these epigenetic marks are strictly controlled in normal non-neoplastic cells but, in cancer cells, their deregulation opens the door to the expression or silencing of oncogenes and tumor suppressor genes, respectively. Therefore, the altered epigenome is a hallmark for many tumors, including colorectalcancer, and constitutes an important cause of heterogeneity. In fact, although the most studied and the major epigenetic events which are believed to play critical roles in colorectalcancer are CpG island methylation and histone modifications , there are multiple ways for epigenetic modification, including nucleosomal occupancy and remodeling, chromatin looping, and noncoding RNAs . Consequently, epigenomic modifications represent an attractive target for epidemiological analysis, molecular pathology, therapeutic response evaluation, and drug design [17–19]. However, like the analysis of other molecular traits, the study of epigenome can be remarkably challenging due to the variability existing not only between individuals but also between and within tumors. Therefore, future development of powerful technologies to analyze the epigenomic landscape together with novel tools to integrate this information with other molecular data could help to advance the diagnosis, management, and treatment of patients.
Background: Among colorectalcancer hereditary variants, two syndromes show a predisposition to the disease based on germline mutations: Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis ColorectalCancer (HNPCC). Aim: To screen mutations in FAP and HNPCC families in Chile. Materials and Methods: Two FAP and one HNPCC families were studied. The APC gene (for FAP patients) and the MLH1 gene (for HNPCC patients), were screened for mutations on genomic DNA. The molecular analysis was performed through polymerase chain reaction, Single Strand Conformer Polymorphism (SSCP) and DNA sequencing. Mutations were defined as changes in the DNA sequence leading into a stop codon and a truncated protein. Results: In the two FAP families the analysis revealed a mutation consisting in the deletion of five nucleotides named c.3927_3931delAAAGA. The genetic study of the HNPCC family demonstrated the insertion of one adenine in codon 168 of exon 6, named c.504insA. Discussion: Germ-line mutations were identified in the three families. The relevance of these studies in a better knowledge of cancer susceptibility, and the possibility of identifying in relatives in risk by molecular diagnosis (Rev Méd Chile 2006; 134: 841-8).
We studied the prevalence of three SNPs within CAV1 in our study population. The rationale for this study was that some authors found caveolin-1 overexpressed in experi- mental colon adenocarcinoma and its expression in human colon cancer cell lines directly correlates with their growth rate (11). Some studies with tissues from human prostate, breast and colon adenocarcinoma also showed over- expression of CAV1 (15,16). In contrast, previous reports using xenographs in nude mice showed that tumor formation in vivo resulted in the selection of cells with lower basal levels of caveolin-1 (10). Moreover, 7q31.1 is a frequently deleted region in different carcinomas, and tumor suppressor activity in vitro was reported (40,41). Thus, CAV1 has been considered a tumor suppressor gene (13). With this ante- cedents, it seemed necessary to circumvent the experimental designs and perform a genomic approach to elucidate the role of CAV1 in CRC. Following this approach, we were not Table IV. Endocohort analysis of the CRC series.
Interestingly, our study found that higher sTNF-RII levels were not associated with worse outcome among patients who reported regular aspirin use, although the P-value for interaction between sTNF-RII and aspirin was not significant, possibly because of reduced power in exploratory subgroup analyses. Ample clinical data (Algra and Rothwell, 2012) suggest that initiation of aspirin after CRC diagnosis may be beneficial in reducing mortality, particularly among older patients (Lai and Liao, 2013) and COX-2- overexpressing (Chan et al, 2009) or PIK3CA-mutated tumours (Liao et al, 2012; Langley and Rothwell, 2013). Moreover, treatment with COX inhibitors leads to inhibition of TNF-a- induced COX-2 expression and decreased proliferation of CRC cells (Ricchi et al, 1997; Paik et al, 2000), thus lending biologic plausibility to our findings. Currently, a large, randomised
Please cite this article in press as: Santos SC, Barbosa LE. Crohn’s disease: risk factor for colorectalcancer. J Coloproctol (Rio J). 2016.
ileocolic location, 30% suffer from an isolated ileal disease,
and 30% are affected only in the colon. Approximately 5–10%
of patients exhibit associated lesions of the upper gastroin-