For many cancers a primary cause of poor survival is that they are detected at a late stage when therapies are less effective.Although screening methods exist to detect some types of cancer at an early stage,there are...For many cancers a primary cause of poor survival is that they are detected at a late stage when therapies are less effective.Although screening methods exist to detect some types of cancer at an early stage,there are currently no effective methods to screen for most types of cancer.Biomarkers have the potential to improve detection of early-stage cancers,risk stratification,and prediction of which pre-cancerous lesions are likely to progress and to make screening tests less invasive.Although thousands of research articles on biomarkers for early detection are published every year,few of these biomarkers have been validated and shown to be clinically useful.This reflects both the inherent difficulty in detecting early-stage cancers and a disconnect between the process of discovering biomarkers and their use in the clinic.To overcome this limitation the US National Cancer Institute created the Early Detection Research Network.It is a highly collaborative program that brings together biomarker discoverers,assay developers,and clinicians.It provides an infrastructure that is essential for developing and validating biomarkers and imaging methods for early cancer detection and has successfully completed several multicenter validation studies.展开更多
Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is curren...Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is currently unknown, although considerable progress has been made in determining the key players in this process. In this review, we present the current understanding of the molecular processes driving PCa metastasis to the bone.展开更多
BACKGROUND Calponin 3(CNN3)is an actin-binding protein expressed in smooth muscle and non-smooth muscle cells.It is required for cytoskeletal rearrangement and wound healing.AIM To dissect the role of CNN3 in carcinog...BACKGROUND Calponin 3(CNN3)is an actin-binding protein expressed in smooth muscle and non-smooth muscle cells.It is required for cytoskeletal rearrangement and wound healing.AIM To dissect the role of CNN3 in carcinogenesis with a focus on colon cancer.METHODS A total of 20 cancer cell lines(8 breast,11 colon,and HeLa cervical cancer cell as a positive control for mesenchymal phenotype)and 57 formalin-fixed,paraffinembedded sections from archived sporadic colorectal carcinomas were included in this study.CNN3 expression analysis by western blot or immunohistochemistry was followed by functional analyses.The CNN3 gene was silenced by specific small interfering RNA(commonly known as siRNA),followed by confirmation of the silencing efficiency by western blotting.Then,the silenced cells and control siRNA-transfected cells were analyzed for changes in epithelial and mesenchymal markers,invasion,and response to 5-fluoruracil treatment.We also performed proteomics analysis using a phospho-kinase array-based panel of 45 proteins.RESULTS CNN3 showed positive expression in 6/8 breast and 9/11 colon cancer lines and in HeLa cells.Interestingly,the colorectal adenocarcinoma line SW480 was negative,while the cell line developed from its matching lymph node metastasis(SW620)was positive for CNN3.CNN3 expression was fairly consistent with the metastatic phenotype in colon cancer because it was absent in one other colon cell line from a primary site and expressed in all others.We selected SW620 for subsequent functional analyses.CNN3-silenced SW620 cells showed a reduction in collagen invasion and loss of mesenchymal markers.CNN3 silencing caused an increase in the SW620 colon cancer cell sensitivity to 5-fluorouracil.Phosphokinase array-based proteomics analysis showed that CNN3 silencing in SW620 reduced extracellular signal-regulated kinase,β-Catenin,mutant p53,c-Jun,and heat shock protein 60 activities but increased that of checkpoint kinase 2.CNN3 was expressed in 20/57(35%)colon cancer cases as shown by immunohistochemistry.CNN3 was associated with a decrease in overall survival in colon cancer in silico.CONCLUSION These results show the involvement of CNN3 in lymph node metastasis and resistance to chemotherapy in colon cancer and suggest that significant oncogenic pathways are involved in these CNN3-related actions.展开更多
To characterize AXL receptor tyrosine kinase (AXL) expression in relationship to tumor protein P53 (TP53 gene, p53 protein) and its role in tumor invasion and response to therapy.METHODSWe used 14 cell lines, includin...To characterize AXL receptor tyrosine kinase (AXL) expression in relationship to tumor protein P53 (TP53 gene, p53 protein) and its role in tumor invasion and response to therapy.METHODSWe used 14 cell lines, including 3 isogenic pairs carrying mutant/knockout p53, to gain insight into the relationship between AXL and TP53. These included HCT116, HCT116.p53 mutant, RKO, and RKO.p53<sup>-/-</sup> lines (all from colon cancers) as well as breast cancer cell lines MCF7 and 1001 (MCF7-p53 mutant clone). HeLa cell line was used as a positive control for epithelial to mesenchymal transition (EMT). AXL expression was determined by Western blotting using rabbit monoclonal antibody clone C89E7. AXL siRNA silencing was performed and followed by collagen invasion assay. Cell viability analysis using the sulforhodamine B assay and the invasion assay were performed after exposure to chemotherapeutic agents (doxorubicin for breast cancer cells; 5FU or irinotecan for colon cancer cells).RESULTSWe showed that the introduction of p53 mutations or knockout increased expression levels of AXL in isogenic cells compared to the matching p53 wild-type parental cells. Overall, we found a trend for correlation between the potential EMT candidate AXL, p53 alterations, and EMT markers in colorectal and breast cancers. The expression of AXL in RKO cells, a rare colon cancer cell line with inactive Wnt signaling, suggests that the AXL oncogene might provide an alternative genetic pathway for colorectal carcinogenesis in the absence of Wnt signaling activation and TP53 mutation. AXL silencing in the TP53 mutant isogenic cell lines 1001, HCT116.p53 mutant and RKO.P53<sup>-/-</sup> was > 95% efficient and the silenced cells were less invasive compared to the parental TP53 wild-type cells. AXL silencing showed a subtle trend to restore colon cancer cell sensitivity to 5FU or irinotecan. Importantly, AXL expressing cells developed more invasive potential after exposure to chemotherapy compared to the AXL-silenced cells.CONCLUSIONAXL is influenced by p53 status and could cause the emergence of aggressive clones after exposure to chemotherapy. These findings could have applications in cancer management.展开更多
Prostate cancer (PCa) represents the most frequent urologic diagnosis in elderly males. We have previously shown that exposure of prostate to lipopolysaccharide (LPS) promotes cancer risk. We investigated the effect o...Prostate cancer (PCa) represents the most frequent urologic diagnosis in elderly males. We have previously shown that exposure of prostate to lipopolysaccharide (LPS) promotes cancer risk. We investigated the effect of non-selective cyclooxygenase (COX) inhibition on prostate inflammation-mediated cancer risk in vivo. The prostates of male rats were inoculated with E. coli as sources of inflammatory molecules (LPS) and were treated with COX inhibitor, aspirin 2 mg/Kg orally for 14 days or PBS. Oxidative stress was induced with two 2 mls of hydrogen peroxide orally twice daily or PBS for 14 days;they were either treated with COX inhibitor or PBS for another 14 days. Blood was collected and analyzed for acid phosphatase and PSA. Data showed presences of LPS in the prostate of the rats resulted in gradual increase in PSA when compared to control (P < 0.0001). However, COX inhibition resulted in statistically significant reduction in concentration of PSA level compared to control group (P < 0.0001). To understand if oxidative stress mechanism was involved in the inflammation mediated increase in PSA, data showed that rats exposed to H<sub>2</sub>O<sub>2</sub> had 2.5 fold increase in acid phosphatase (ACP) compared control (P < 0.0001), and by inhiting COX activity, a statistically significant reduction in ACP from 11.2 IU/L ± 0.67 to 5.7 IU/L ± 0.347 (P < 0.0034) was observed. Thus since increased in PSA was associated to cancer risk, our data suggested that inflammation mediated prostate cancer risk was reversible by Inhibition of COX Activity in rats.展开更多
Anal pruritus is a common anorectal symptom that can significantly impair a patient’s quality of life,including their mental health.It can be one of the most difficult proctological conditions to treat.Patients often...Anal pruritus is a common anorectal symptom that can significantly impair a patient’s quality of life,including their mental health.It can be one of the most difficult proctological conditions to treat.Patients often delay seeking medical attention,since it is an embarrassing but non-life-threatening situation.Pruritus ani can be associated with idiopathic and secondary causes,such as anorectal diseases,cancer(anal or colorectal),dermatological and sexually transmitted diseases,fungal infections and systemic diseases.If patients are referred for a colonoscopy,this can sometimes provide the first opportunity to evaluate the perianal area.Classifications of anal pruritus are based on the abnormalities of the perianal skin,one of the most commonly used being the Washington classi-fication.A proper digital anorectal examination is important,as well as an anoscopy to help to exclude anorectal diseases or suspicious masses.Endoscopists should be aware of the common etiologies,and classification of the perianal area abnormalities should be provided in the colonoscopy report.Information on treatment possibilities and follow-up can also be provided.The treatment normally consists of a triple approach:proper hygiene,elimination of irritants,and skin care and protection.Several topical therapies have been described as possible treatments,including steroids,capsaicin,tacrolimus and methylene blue intradermal injections.展开更多
AIM: To investigate Helicobacter pylori (H. pylori) CagA diversity and to evaluate the association between protein polymorphisms and the occurrence of gastric pathologies. METHODS: One hundred and twenty-two clinical ...AIM: To investigate Helicobacter pylori (H. pylori) CagA diversity and to evaluate the association between protein polymorphisms and the occurrence of gastric pathologies. METHODS: One hundred and twenty-two clinical isolates of H. pylori cultured from gastric biopsies obtained from Colombian patients with dyspepsia were included as study material. DNA extracted from isolates was used to determine cagA status, amplifying the C-terminal cagA gene region by polymerase chain reaction. One hundred and six strains with a single amplicon were sequenced and results were used to characterize the 3' variable region of the cagA gene. To establish the number and type of tyrosine phosphorylation motifs Glutamine acid-Proline-Isoleucine-Tyrosine-Alanine (EPI-YA) bioinformatic analysis using Amino Acid Sequence Analyzer-Amino Acid Sequence Analyzer software was conducted. Analysis of the association between the number of EPIYA motifs and the gastric pathology was performed using χ2 test and analysis of the presence of EPIYA-C motifs in relation to the pathology was made by logistic regression odds ratios. Comparisons among EPIYA types found and those reported in GenBank were performed using a proportion test in Statistix Analytical Software version 8.0. RESULTS: After amplification of the 3' of the cagA gene, 106 from 122 isolates presented a single amplicon and 16 showed multiple amplicons. As expected, diversity in the size of the cagA unique fragments among isolates was observed. The 106 strains that presented a single amplicon after 3' cagA amplification came from patients with gastritis (19 patients), atrophic gastritis (21), intestinal metaplasia (26), duodenal ulcer (22) and gastric cancer. DNA sequence analysis showed that the differences in size of 3' cagA unique fragments was attributable to the number of EPIYA motifs: 1.9% had two EPIYA motifs, 62.3% had three, 33.0% had four and 2.8% had five motifs. The majority of tested clinical strains (62.3%) were found to harbor the ABC combination of EPIYA motifs and a significant statistical difference was observed between the frequencies of ABCC tyrosine phosphorylation motifs and Western strains sequences deposited in GenBank. CONCLUSION: The present report describes a lack of association between H. pylori CagA-protein polymorphisms and pathogenesis. ABCC high frequency variations compared with Western-strains sequences deposited in GenBank require more investigation.展开更多
AIM: To evaluate the relation of cluster of differentiation 44 (CD44) expression with clinicopathological features of gastric adenocarcinoma, and also its effect on prognosis with an emphasis on the differences betwee...AIM: To evaluate the relation of cluster of differentiation 44 (CD44) expression with clinicopathological features of gastric adenocarcinoma, and also its effect on prognosis with an emphasis on the differences between intestinal and diffuse types. METHODS: From 2000 to 2006, 100 patients with gastric adenocarcinoma, who had undergone total or subtotal gastrectomy without any prior treatment, were studied. Haematoxylin & eosin (HE) staining was used for histological evaluation, including the type (Lauren's classifi cation) and grading of the tumor. The expression of CD44 in the gastric adenocarcinoma mucosa and the adjacent mucosa were determined by immunohistochemistry. The survival analysis was obtained using the Kaplan-Meier test. RESULTS: Of 100 patients, 74 (74%) patients were male. The tumors were categorized as intestinal type (78%) or diffuse type (22%). Sixty-five percent of patients were CD44-positive. CD44 expression was not detected in normal gastric mucosa. Rather, CD44 was more commonly expressed in the intestinal subtype (P = 0.002). A signifi cant relation was seen between the grade of tumor and the expression of CD44 (P = 0.014). The survival analysis showed a poor prognosis of patients with CD44-positive tumors (P = 0.008); and this was more prominent in the intestinal (P = 0.001) rather than diffuse type. CONCLUSION: Cell adhesion molecule CD44 is highly expressed in gastric adenocarcinoma. CD44 expression is correlated with a poor prognosis in patients with the intestinal type of gastric adenocarcinoma. CD44 can, therefore, be utilized as a prognostic marker for this group of patients.展开更多
BACKGROUND Colonoscopy attendance is a key quality parameter in colorectal cancer population screening programmes.Within these programmes,educative interventions with bidirectional contact carried out by trained perso...BACKGROUND Colonoscopy attendance is a key quality parameter in colorectal cancer population screening programmes.Within these programmes,educative interventions with bidirectional contact carried out by trained personnel have been proved to be an important tool for colonoscopy attendance improvement,and because of its huge clinical and economic impact,they have been widely implemented.However,outside of this population programmes,educative measures to improve colonoscopy attendance have been poorly studied and no navigation interventions are usually performed.AIM To investigate the clinical and economic impacts of an educational telephone intervention on colonoscopy attendance outside colorectal cancer screening programmes.METHODS This randomized controlled trial included consecutive patients referred to colonoscopy from primary care centres from November 2017 to May 2018.The intervention group(IG)received a telephone intervention,while the control group(CG)did not.Patients assigned to the IG received an educational telephone call 7 d before the colonoscopy appointment.The intervention was carried out by two nurses with deep endoscopic knowledge who were previously trained for a telephone educational intervention for colonoscopy.The impact on patient compliance with preparedness protocols related to bowel cleansing,antithrombotic management,and sedation scheduling was also evaluated.A second call was conducted to assess patient satisfaction.Intention-to-treat(ITT)and perprotocol(PP)analyses were performed.RESULTS A total of 738 and 746 patients were finally included in the IG and CG respectively.Six hundred thirteen(83%)patients were contacted in the IG.The non-attendance rate was lower in the IG,both in the ITT analysis(IG 8.4%vs CG 14.3%,P<0.001)and in the PP analysis(4.4%vs 14.3%,P<0.001).In a multivariable analysis,belonging to the control group increased the risk of nonattendance in both,the ITT analysis(OR 1.81,95%CI:1.27 to 2.58,P=0.001)and the PP analysis(OR 3.56,95%CI:2.25 to 5.64,P<0.001).There was also a significant difference in compliance with preparedness protocols[bowel cleansing:IG 61.7%vs CG 52.6%(P=0.001),antithrombotic management:IG 92.5%vs CG 62.8%(P=0.001),and sedation scheduling:IG 78.8%vs CG 0%(P≤0.001)].We observed a net benefit of €55600/year after the intervention.The information given before the procedure was rated as excellent by 26%(CG)and 51%(IG)of patients,P≤0.001.CONCLUSION Educational telephone nurse intervention improves attendance,protocol compliance and patient satisfaction in the non-screening colonoscopy setting and has a large economic impact,which supports its imple-mentation and maintenance over time.展开更多
BACKGROUND: Proliferation of hepatic stellate cells (HSCs) plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess ...BACKGROUND: Proliferation of hepatic stellate cells (HSCs) plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS: The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin (10, 50 and 100 μmol/L) for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS: Silibinin inhibits LX-2 cell proliferation in doseand time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin- inhibited proliferation of LX-2 cells. CONCLUSION: The anti-proliferative effect of silibinin on LX-2 human steUate cells is via the inhibition of the expres- sions of various cell cycle targets including p27, Akt and sir- tuin signaling.展开更多
Background: Previous studies have demonstrated inappropriate advice from health profes- sionals advocating therapeutic sun exposure during infancy and the post-partum period. This study examines the proportion of Aust...Background: Previous studies have demonstrated inappropriate advice from health profes- sionals advocating therapeutic sun exposure during infancy and the post-partum period. This study examines the proportion of Australian midwives and related hospital nursing staff who recommend therapeutic sun exposure during this period. Methods: Questionnaires were completed by 363 Australian nurses (57.2% response) responsible for nursing post-partum women in 11 maternity hospitals in Queensland (QLD) and the Australian Capital Territory (ACT). Results: Many nurses believed sun exposure was beneficial in treating: cracked nipples (QLD 41.3%, ACT 65.8%;p specified exposure time limits. Nursing staff from public hospitals in QLD, but not the ACT, were more likely than nurses from private hospitals to hold one or more such beliefs (p = 0.008). Approximately 40% of respondents thought people generally looked healthier with a suntan;79% of this group also held one or more risky beliefs about therapeutic sun exposure (p = 0.043). Conclusion: A high proportion of these nurses held risky beliefs about the beneficial uses of sunlight for post-partum women and their infants and made recommendations consistent with their beliefs. Professional education is needed to change the beliefs and practices of nursing staff about intentional sun exposure of women and their babies to reduce their long- term skin cancer risk, particularly as Australia has such a high prevalence of skin cancer.展开更多
Background:None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects.The aim of...Background:None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects.The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models.Methods:In order to achieve this goal,we included in the study one rat model(Yoshida AH‐130ascites hepatoma)and two mouse models(Lewis lung carcinoma and Colon26 carcinoma).The Animal cachexia score(ACASCO)includes five components:(a)body and muscle weight loss,(b)inflammation and metabolic disturbances,(c)physical performance,(d)anorexia,and(e)quality of life measured using discomfort symptoms and behavioral tests.Results:Using the ACASCO values,three cut‐off values were estimated by applying hierarchical cluster analysis.Four groups were originally described,one exactly below the observed mean,a second exactly over the mean,and two other groups adjusted to every cue(inferior and superior).The three cut‐off values were estimated through maximization of the classification function.This was accomplished by using a similarity matrix based on the metric properties of the variables and assuming multinormal distribution.The results show that the four groups were:no cachexia,mild cachexia,moderate cachexia and advanced cachexia.Conclusions:The results obtained allow us to conclude that the score could be very useful as an endpoint in pre‐clinical studies involving therapeutic strategies for cancer cachexia.The potential usefulness of ACASCO relates to the primary endpoint in pre‐clinical cancer cachexia drug evaluations.展开更多
CD40 ligation provides signals central to chronic lymphocytic leukemia (CLL) cell survival and proliferation. The release of soluble CD40 (sCD40) may impact on both these signals and CD40 targeted therapies. In this s...CD40 ligation provides signals central to chronic lymphocytic leukemia (CLL) cell survival and proliferation. The release of soluble CD40 (sCD40) may impact on both these signals and CD40 targeted therapies. In this study we investigated the prognostic significance of plasma sCD40 inuntreated CLL patients (n = 34). We report that 56% had levels higher than those of normal donors and that elevated levels were associated with significantly shorter treatment free (TFS) and overall survival. In bivariate analysis sCD40 remained a significant marker of TFS independent of Binet staging, CD38 positivity and lymphocyte count. RT-PCR analysis demonstrated that CLL cells expressed transcripts encoding putative sCD40. These results suggest sCD40 may play a role in CLL progression and that its function, prognostic significance and potential impact on antibody based therapies should be further investigated.展开更多
Lung cancer is the leading cause of cancer-related deaths in China,with over 690000 lung cancer deaths estimated in 2018.The mortality has increased about five-fold from the mid-1970s to the 2000s.Lung cancer lowdose ...Lung cancer is the leading cause of cancer-related deaths in China,with over 690000 lung cancer deaths estimated in 2018.The mortality has increased about five-fold from the mid-1970s to the 2000s.Lung cancer lowdose computerized tomography(LDCT)screening in smokers was shown to improve survival in the US National Lung Screening Trial,and more recently in the European NELSON trial.However,although the predominant risk factor,smoking contributes to a lower fraction of lung cancers in China than in the UK and USA.Therefore,it is necessary to establish Chinese-specific screening strategies.There have been 23 associated programmes completed or still ongoing in China since the 1980s,mainly after 2000;and one has recently been planned.Generally,their entry criteria are not smoking-stringent.Most of the Chinese programmes have reported preliminary results only,which demonstrated a different high-risk subpopulation of lung cancer in China.Evidence concerning LDCT screening implementation is based on results of randomized controlled trials outside China.LDCT screening programmes combining tobacco control would produce more benefits.Population recruitment(e.g.risk-based selection),screening protocol,nodule management and costeffectiveness are discussed in detail.In China,the high-risk subpopulation eligible for lung cancer screening has not as yet been confirmed,as all the risk parameters have not as yet been determined.Although evidence on best practice for implementation of lung cancer screening has been accumulating in other countries,further research in China is urgently required,as China is now facing a lung cancer epidemic.展开更多
Fecal incontinence is a common condition that can significantly impact patients’quality of life.Obstetric anal sphincter injury and anorectal surgeries are common etiologies.Endoanal ultrasound and anorectal manometr...Fecal incontinence is a common condition that can significantly impact patients’quality of life.Obstetric anal sphincter injury and anorectal surgeries are common etiologies.Endoanal ultrasound and anorectal manometry are important diagnostic tools for evaluating patients.There are various treatment options,including diet,lifestyle modifications,drugs,biofeedback therapy,tibial and sacral nerve neuromodulation therapy,and surgery.In this editorial,we will discuss current controversies and novel approaches to fecal incontinence.Screening for asymptomatic anal sphincter defects after obstetric anal sphincter injury and in patients with inflammatory bowel disease is not generally recommended,but may be helpful in selected patients.The Garg incontinence score is a new score that includes the assessment of solid,liquid,flatus,mucous,stress and urge fecal incontinence.Novel tests such as translumbosacral anorectal magnetic stimulation and novel therapies such as translumbosacral neuromodulation therapy are promising diagnostic and treatment options,for both fecal incontinence and neuropathy.Home biofeedback therapy can overcome some limitations of the office-based therapy.Skeletal muscle-derived cell implantation of the external anal sphincter has been further studied as a possible treatment option.Sacral neuromodulation may be useful in scleroderma,congenital fecal incontinence and inflammatory bowel disease but merits further study.展开更多
Aim:The transcription factor RIP140(receptor interacting protein of 140 kDa)is involved in intestinal tumorigenesis.It plays a role in the control of microsatellite instability(MSI),through the regulation of MSH2 and ...Aim:The transcription factor RIP140(receptor interacting protein of 140 kDa)is involved in intestinal tumorigenesis.It plays a role in the control of microsatellite instability(MSI),through the regulation of MSH2 and MSH6 gene expression.The aim of this study was to explore its effect on the expression of POLK,the gene encoding the specialized translesion synthesis(TLS)DNA polymeraseκknown to perform accurate DNA synthesis at microsatellites.Methods:Different mouse models and engineered human colorectal cancer(CRC)cell lines were used to analyze by RT-qPCR,while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression.Published DNA microarray datasets were reanalyzed.The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined.Results:RIP140 positively regulates,at the transcriptional level,the expression of the POLK gene,and this effect involves,at least partly,the p53 tumor suppressor.In different cohorts of CRC biopsies(with or without MSI),a strong positive correlation was observed between RIP140 and POLK gene expression.In connection with its effect on POLK levels and the TLS function of this polymerase,the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene.Finally,the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK,thus strengthening the functional link between the two genes in human CRC.Conclusion:The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability,and more generally to the control of genome integrity.展开更多
Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy targets.Here,our goal was to expand our previous ranking analysis of survi...Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy targets.Here,our goal was to expand our previous ranking analysis of survival-associated genes in various solid tumors to include colon cancer specimens with available transcriptomic and clinical data.A Gene Expression Omnibus search was performed to identify available datasets with clinical data and raw gene expression measurements.A combined database was set up and integrated into our Kaplan-Meier plotter,making it possible to identify genes with expression changes linked to altered survival.As a demonstration of the utility of the platform,the most powerful genes linked to overall survival in colon cancer were identified using uni-and multivariate Cox regression analysis.The combined colon cancer database includes 2,137 tumor samples from 17 independent cohorts.The most significant genes associated with relapse-free survival with a false discovery rate below 1%in colon cancer carcinoma were RBPMS(hazard rate[HR]=2.52),TIMP1(HR=2.44),and COL4A2(HR=2.36).The three strongest genes associated with shorter survival in stage II colon cancer include CSF1R(HR=2.86),FLNA(HR=2.88),and TPBG(HR=2.65).In summary,a new integrated database for colon cancer is presented.A colon cancer analysis subsystem was integrated into our Kaplan-Meier plotter that can be used to mine the entire database(https://www.kmplot.com).The portal has the potential to be employed for the identification and prioritization of promising biomarkers and therapeutic target candidates in multiple solid tumors including,among others,breast,lung,ovarian,gastric,pancreatic,and colon cancers.展开更多
Three-dimensional(3D)bioprinting,an additive manufacturing based technique of biomaterials fabrication,is an innovative and auspicious strategy in medical and pharmaceutical fields.The ability of producing regenerativ...Three-dimensional(3D)bioprinting,an additive manufacturing based technique of biomaterials fabrication,is an innovative and auspicious strategy in medical and pharmaceutical fields.The ability of producing regenerative tissues and organs has made this technology a pioneer to the creation of artificial multi-cellular tissues/organs.A broad variety of biomaterials is currently being utilized in 3D bioprinting as well as multiple techniques employed by researchers.In this review,we demonstrate the most common and novel biomaterials in 3D bioprinting technology further with introducing the related techniques that are commonly taking into account by researchers.In addition,an attempt has been accomplished to hand over the most relevant application of 3D bioprinting techniques such as tissue regeneration,cancer investigations,etc.by presenting the most important works.The main aim of this review paper is to emphasis on strengths and limitations of existence biomaterials and 3D bioprinting techniques in order to carry out a comparison through them.展开更多
文摘For many cancers a primary cause of poor survival is that they are detected at a late stage when therapies are less effective.Although screening methods exist to detect some types of cancer at an early stage,there are currently no effective methods to screen for most types of cancer.Biomarkers have the potential to improve detection of early-stage cancers,risk stratification,and prediction of which pre-cancerous lesions are likely to progress and to make screening tests less invasive.Although thousands of research articles on biomarkers for early detection are published every year,few of these biomarkers have been validated and shown to be clinically useful.This reflects both the inherent difficulty in detecting early-stage cancers and a disconnect between the process of discovering biomarkers and their use in the clinic.To overcome this limitation the US National Cancer Institute created the Early Detection Research Network.It is a highly collaborative program that brings together biomarker discoverers,assay developers,and clinicians.It provides an infrastructure that is essential for developing and validating biomarkers and imaging methods for early cancer detection and has successfully completed several multicenter validation studies.
文摘Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is currently unknown, although considerable progress has been made in determining the key players in this process. In this review, we present the current understanding of the molecular processes driving PCa metastasis to the bone.
文摘BACKGROUND Calponin 3(CNN3)is an actin-binding protein expressed in smooth muscle and non-smooth muscle cells.It is required for cytoskeletal rearrangement and wound healing.AIM To dissect the role of CNN3 in carcinogenesis with a focus on colon cancer.METHODS A total of 20 cancer cell lines(8 breast,11 colon,and HeLa cervical cancer cell as a positive control for mesenchymal phenotype)and 57 formalin-fixed,paraffinembedded sections from archived sporadic colorectal carcinomas were included in this study.CNN3 expression analysis by western blot or immunohistochemistry was followed by functional analyses.The CNN3 gene was silenced by specific small interfering RNA(commonly known as siRNA),followed by confirmation of the silencing efficiency by western blotting.Then,the silenced cells and control siRNA-transfected cells were analyzed for changes in epithelial and mesenchymal markers,invasion,and response to 5-fluoruracil treatment.We also performed proteomics analysis using a phospho-kinase array-based panel of 45 proteins.RESULTS CNN3 showed positive expression in 6/8 breast and 9/11 colon cancer lines and in HeLa cells.Interestingly,the colorectal adenocarcinoma line SW480 was negative,while the cell line developed from its matching lymph node metastasis(SW620)was positive for CNN3.CNN3 expression was fairly consistent with the metastatic phenotype in colon cancer because it was absent in one other colon cell line from a primary site and expressed in all others.We selected SW620 for subsequent functional analyses.CNN3-silenced SW620 cells showed a reduction in collagen invasion and loss of mesenchymal markers.CNN3 silencing caused an increase in the SW620 colon cancer cell sensitivity to 5-fluorouracil.Phosphokinase array-based proteomics analysis showed that CNN3 silencing in SW620 reduced extracellular signal-regulated kinase,β-Catenin,mutant p53,c-Jun,and heat shock protein 60 activities but increased that of checkpoint kinase 2.CNN3 was expressed in 20/57(35%)colon cancer cases as shown by immunohistochemistry.CNN3 was associated with a decrease in overall survival in colon cancer in silico.CONCLUSION These results show the involvement of CNN3 in lymph node metastasis and resistance to chemotherapy in colon cancer and suggest that significant oncogenic pathways are involved in these CNN3-related actions.
基金Supported by Terry Fox Foundation for Cancer Research
文摘To characterize AXL receptor tyrosine kinase (AXL) expression in relationship to tumor protein P53 (TP53 gene, p53 protein) and its role in tumor invasion and response to therapy.METHODSWe used 14 cell lines, including 3 isogenic pairs carrying mutant/knockout p53, to gain insight into the relationship between AXL and TP53. These included HCT116, HCT116.p53 mutant, RKO, and RKO.p53<sup>-/-</sup> lines (all from colon cancers) as well as breast cancer cell lines MCF7 and 1001 (MCF7-p53 mutant clone). HeLa cell line was used as a positive control for epithelial to mesenchymal transition (EMT). AXL expression was determined by Western blotting using rabbit monoclonal antibody clone C89E7. AXL siRNA silencing was performed and followed by collagen invasion assay. Cell viability analysis using the sulforhodamine B assay and the invasion assay were performed after exposure to chemotherapeutic agents (doxorubicin for breast cancer cells; 5FU or irinotecan for colon cancer cells).RESULTSWe showed that the introduction of p53 mutations or knockout increased expression levels of AXL in isogenic cells compared to the matching p53 wild-type parental cells. Overall, we found a trend for correlation between the potential EMT candidate AXL, p53 alterations, and EMT markers in colorectal and breast cancers. The expression of AXL in RKO cells, a rare colon cancer cell line with inactive Wnt signaling, suggests that the AXL oncogene might provide an alternative genetic pathway for colorectal carcinogenesis in the absence of Wnt signaling activation and TP53 mutation. AXL silencing in the TP53 mutant isogenic cell lines 1001, HCT116.p53 mutant and RKO.P53<sup>-/-</sup> was > 95% efficient and the silenced cells were less invasive compared to the parental TP53 wild-type cells. AXL silencing showed a subtle trend to restore colon cancer cell sensitivity to 5FU or irinotecan. Importantly, AXL expressing cells developed more invasive potential after exposure to chemotherapy compared to the AXL-silenced cells.CONCLUSIONAXL is influenced by p53 status and could cause the emergence of aggressive clones after exposure to chemotherapy. These findings could have applications in cancer management.
文摘Prostate cancer (PCa) represents the most frequent urologic diagnosis in elderly males. We have previously shown that exposure of prostate to lipopolysaccharide (LPS) promotes cancer risk. We investigated the effect of non-selective cyclooxygenase (COX) inhibition on prostate inflammation-mediated cancer risk in vivo. The prostates of male rats were inoculated with E. coli as sources of inflammatory molecules (LPS) and were treated with COX inhibitor, aspirin 2 mg/Kg orally for 14 days or PBS. Oxidative stress was induced with two 2 mls of hydrogen peroxide orally twice daily or PBS for 14 days;they were either treated with COX inhibitor or PBS for another 14 days. Blood was collected and analyzed for acid phosphatase and PSA. Data showed presences of LPS in the prostate of the rats resulted in gradual increase in PSA when compared to control (P < 0.0001). However, COX inhibition resulted in statistically significant reduction in concentration of PSA level compared to control group (P < 0.0001). To understand if oxidative stress mechanism was involved in the inflammation mediated increase in PSA, data showed that rats exposed to H<sub>2</sub>O<sub>2</sub> had 2.5 fold increase in acid phosphatase (ACP) compared control (P < 0.0001), and by inhiting COX activity, a statistically significant reduction in ACP from 11.2 IU/L ± 0.67 to 5.7 IU/L ± 0.347 (P < 0.0034) was observed. Thus since increased in PSA was associated to cancer risk, our data suggested that inflammation mediated prostate cancer risk was reversible by Inhibition of COX Activity in rats.
文摘Anal pruritus is a common anorectal symptom that can significantly impair a patient’s quality of life,including their mental health.It can be one of the most difficult proctological conditions to treat.Patients often delay seeking medical attention,since it is an embarrassing but non-life-threatening situation.Pruritus ani can be associated with idiopathic and secondary causes,such as anorectal diseases,cancer(anal or colorectal),dermatological and sexually transmitted diseases,fungal infections and systemic diseases.If patients are referred for a colonoscopy,this can sometimes provide the first opportunity to evaluate the perianal area.Classifications of anal pruritus are based on the abnormalities of the perianal skin,one of the most commonly used being the Washington classi-fication.A proper digital anorectal examination is important,as well as an anoscopy to help to exclude anorectal diseases or suspicious masses.Endoscopists should be aware of the common etiologies,and classification of the perianal area abnormalities should be provided in the colonoscopy report.Information on treatment possibilities and follow-up can also be provided.The treatment normally consists of a triple approach:proper hygiene,elimination of irritants,and skin care and protection.Several topical therapies have been described as possible treatments,including steroids,capsaicin,tacrolimus and methylene blue intradermal injections.
基金Supported by Sciences Faculty,Los Andes University,Bogotá,Colombia and National Cancer Institute,Bogotá,Colombia,Grant No.41030310-28 (to Bravo MM)
文摘AIM: To investigate Helicobacter pylori (H. pylori) CagA diversity and to evaluate the association between protein polymorphisms and the occurrence of gastric pathologies. METHODS: One hundred and twenty-two clinical isolates of H. pylori cultured from gastric biopsies obtained from Colombian patients with dyspepsia were included as study material. DNA extracted from isolates was used to determine cagA status, amplifying the C-terminal cagA gene region by polymerase chain reaction. One hundred and six strains with a single amplicon were sequenced and results were used to characterize the 3' variable region of the cagA gene. To establish the number and type of tyrosine phosphorylation motifs Glutamine acid-Proline-Isoleucine-Tyrosine-Alanine (EPI-YA) bioinformatic analysis using Amino Acid Sequence Analyzer-Amino Acid Sequence Analyzer software was conducted. Analysis of the association between the number of EPIYA motifs and the gastric pathology was performed using χ2 test and analysis of the presence of EPIYA-C motifs in relation to the pathology was made by logistic regression odds ratios. Comparisons among EPIYA types found and those reported in GenBank were performed using a proportion test in Statistix Analytical Software version 8.0. RESULTS: After amplification of the 3' of the cagA gene, 106 from 122 isolates presented a single amplicon and 16 showed multiple amplicons. As expected, diversity in the size of the cagA unique fragments among isolates was observed. The 106 strains that presented a single amplicon after 3' cagA amplification came from patients with gastritis (19 patients), atrophic gastritis (21), intestinal metaplasia (26), duodenal ulcer (22) and gastric cancer. DNA sequence analysis showed that the differences in size of 3' cagA unique fragments was attributable to the number of EPIYA motifs: 1.9% had two EPIYA motifs, 62.3% had three, 33.0% had four and 2.8% had five motifs. The majority of tested clinical strains (62.3%) were found to harbor the ABC combination of EPIYA motifs and a significant statistical difference was observed between the frequencies of ABCC tyrosine phosphorylation motifs and Western strains sequences deposited in GenBank. CONCLUSION: The present report describes a lack of association between H. pylori CagA-protein polymorphisms and pathogenesis. ABCC high frequency variations compared with Western-strains sequences deposited in GenBank require more investigation.
基金Supported by A research grant offered by Mashhad University of Medical Sciences, No. 85017
文摘AIM: To evaluate the relation of cluster of differentiation 44 (CD44) expression with clinicopathological features of gastric adenocarcinoma, and also its effect on prognosis with an emphasis on the differences between intestinal and diffuse types. METHODS: From 2000 to 2006, 100 patients with gastric adenocarcinoma, who had undergone total or subtotal gastrectomy without any prior treatment, were studied. Haematoxylin & eosin (HE) staining was used for histological evaluation, including the type (Lauren's classifi cation) and grading of the tumor. The expression of CD44 in the gastric adenocarcinoma mucosa and the adjacent mucosa were determined by immunohistochemistry. The survival analysis was obtained using the Kaplan-Meier test. RESULTS: Of 100 patients, 74 (74%) patients were male. The tumors were categorized as intestinal type (78%) or diffuse type (22%). Sixty-five percent of patients were CD44-positive. CD44 expression was not detected in normal gastric mucosa. Rather, CD44 was more commonly expressed in the intestinal subtype (P = 0.002). A signifi cant relation was seen between the grade of tumor and the expression of CD44 (P = 0.014). The survival analysis showed a poor prognosis of patients with CD44-positive tumors (P = 0.008); and this was more prominent in the intestinal (P = 0.001) rather than diffuse type. CONCLUSION: Cell adhesion molecule CD44 is highly expressed in gastric adenocarcinoma. CD44 expression is correlated with a poor prognosis in patients with the intestinal type of gastric adenocarcinoma. CD44 can, therefore, be utilized as a prognostic marker for this group of patients.
基金Supported by Hospital del Mar,Parc de Salut Mar.
文摘BACKGROUND Colonoscopy attendance is a key quality parameter in colorectal cancer population screening programmes.Within these programmes,educative interventions with bidirectional contact carried out by trained personnel have been proved to be an important tool for colonoscopy attendance improvement,and because of its huge clinical and economic impact,they have been widely implemented.However,outside of this population programmes,educative measures to improve colonoscopy attendance have been poorly studied and no navigation interventions are usually performed.AIM To investigate the clinical and economic impacts of an educational telephone intervention on colonoscopy attendance outside colorectal cancer screening programmes.METHODS This randomized controlled trial included consecutive patients referred to colonoscopy from primary care centres from November 2017 to May 2018.The intervention group(IG)received a telephone intervention,while the control group(CG)did not.Patients assigned to the IG received an educational telephone call 7 d before the colonoscopy appointment.The intervention was carried out by two nurses with deep endoscopic knowledge who were previously trained for a telephone educational intervention for colonoscopy.The impact on patient compliance with preparedness protocols related to bowel cleansing,antithrombotic management,and sedation scheduling was also evaluated.A second call was conducted to assess patient satisfaction.Intention-to-treat(ITT)and perprotocol(PP)analyses were performed.RESULTS A total of 738 and 746 patients were finally included in the IG and CG respectively.Six hundred thirteen(83%)patients were contacted in the IG.The non-attendance rate was lower in the IG,both in the ITT analysis(IG 8.4%vs CG 14.3%,P<0.001)and in the PP analysis(4.4%vs 14.3%,P<0.001).In a multivariable analysis,belonging to the control group increased the risk of nonattendance in both,the ITT analysis(OR 1.81,95%CI:1.27 to 2.58,P=0.001)and the PP analysis(OR 3.56,95%CI:2.25 to 5.64,P<0.001).There was also a significant difference in compliance with preparedness protocols[bowel cleansing:IG 61.7%vs CG 52.6%(P=0.001),antithrombotic management:IG 92.5%vs CG 62.8%(P=0.001),and sedation scheduling:IG 78.8%vs CG 0%(P≤0.001)].We observed a net benefit of €55600/year after the intervention.The information given before the procedure was rated as excellent by 26%(CG)and 51%(IG)of patients,P≤0.001.CONCLUSION Educational telephone nurse intervention improves attendance,protocol compliance and patient satisfaction in the non-screening colonoscopy setting and has a large economic impact,which supports its imple-mentation and maintenance over time.
文摘BACKGROUND: Proliferation of hepatic stellate cells (HSCs) plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS: The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin (10, 50 and 100 μmol/L) for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS: Silibinin inhibits LX-2 cell proliferation in doseand time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin- inhibited proliferation of LX-2 cells. CONCLUSION: The anti-proliferative effect of silibinin on LX-2 human steUate cells is via the inhibition of the expres- sions of various cell cycle targets including p27, Akt and sir- tuin signaling.
文摘Background: Previous studies have demonstrated inappropriate advice from health profes- sionals advocating therapeutic sun exposure during infancy and the post-partum period. This study examines the proportion of Australian midwives and related hospital nursing staff who recommend therapeutic sun exposure during this period. Methods: Questionnaires were completed by 363 Australian nurses (57.2% response) responsible for nursing post-partum women in 11 maternity hospitals in Queensland (QLD) and the Australian Capital Territory (ACT). Results: Many nurses believed sun exposure was beneficial in treating: cracked nipples (QLD 41.3%, ACT 65.8%;p specified exposure time limits. Nursing staff from public hospitals in QLD, but not the ACT, were more likely than nurses from private hospitals to hold one or more such beliefs (p = 0.008). Approximately 40% of respondents thought people generally looked healthier with a suntan;79% of this group also held one or more risky beliefs about therapeutic sun exposure (p = 0.043). Conclusion: A high proportion of these nurses held risky beliefs about the beneficial uses of sunlight for post-partum women and their infants and made recommendations consistent with their beliefs. Professional education is needed to change the beliefs and practices of nursing staff about intentional sun exposure of women and their babies to reduce their long- term skin cancer risk, particularly as Australia has such a high prevalence of skin cancer.
基金Ministerio de Ciencia y Tecnología , Spain, Grant/Award Number: SAF-26091-2011
文摘Background:None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects.The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models.Methods:In order to achieve this goal,we included in the study one rat model(Yoshida AH‐130ascites hepatoma)and two mouse models(Lewis lung carcinoma and Colon26 carcinoma).The Animal cachexia score(ACASCO)includes five components:(a)body and muscle weight loss,(b)inflammation and metabolic disturbances,(c)physical performance,(d)anorexia,and(e)quality of life measured using discomfort symptoms and behavioral tests.Results:Using the ACASCO values,three cut‐off values were estimated by applying hierarchical cluster analysis.Four groups were originally described,one exactly below the observed mean,a second exactly over the mean,and two other groups adjusted to every cue(inferior and superior).The three cut‐off values were estimated through maximization of the classification function.This was accomplished by using a similarity matrix based on the metric properties of the variables and assuming multinormal distribution.The results show that the four groups were:no cachexia,mild cachexia,moderate cachexia and advanced cachexia.Conclusions:The results obtained allow us to conclude that the score could be very useful as an endpoint in pre‐clinical studies involving therapeutic strategies for cancer cachexia.The potential usefulness of ACASCO relates to the primary endpoint in pre‐clinical cancer cachexia drug evaluations.
文摘CD40 ligation provides signals central to chronic lymphocytic leukemia (CLL) cell survival and proliferation. The release of soluble CD40 (sCD40) may impact on both these signals and CD40 targeted therapies. In this study we investigated the prognostic significance of plasma sCD40 inuntreated CLL patients (n = 34). We report that 56% had levels higher than those of normal donors and that elevated levels were associated with significantly shorter treatment free (TFS) and overall survival. In bivariate analysis sCD40 remained a significant marker of TFS independent of Binet staging, CD38 positivity and lymphocyte count. RT-PCR analysis demonstrated that CLL cells expressed transcripts encoding putative sCD40. These results suggest sCD40 may play a role in CLL progression and that its function, prognostic significance and potential impact on antibody based therapies should be further investigated.
基金We give our special appreciation to Robert Carlton for proofreading the manuscript.YIC is funded by China Scholarship Council(CSC201706240094)West China-Liverpool Clinician-Scientist Leadership Scholarship.MPAD is funded by the Roy Castle Lung Cancer Foundation+3 种基金This work is also supported by 1.3.5 Project for Disciplines of Excellence,West China Hospital.Sichuan University(ZYJC18001)the National Key Development Plan for Precision Medicine Research(2017YFC0910004)the Transformation Projects of Sci-Tech Achievements of Sichuan Province(2016CZYD0001)the Sci-Tech Support Program of Science and Technology Department of Sichuan Province(2016SZ0073).
文摘Lung cancer is the leading cause of cancer-related deaths in China,with over 690000 lung cancer deaths estimated in 2018.The mortality has increased about five-fold from the mid-1970s to the 2000s.Lung cancer lowdose computerized tomography(LDCT)screening in smokers was shown to improve survival in the US National Lung Screening Trial,and more recently in the European NELSON trial.However,although the predominant risk factor,smoking contributes to a lower fraction of lung cancers in China than in the UK and USA.Therefore,it is necessary to establish Chinese-specific screening strategies.There have been 23 associated programmes completed or still ongoing in China since the 1980s,mainly after 2000;and one has recently been planned.Generally,their entry criteria are not smoking-stringent.Most of the Chinese programmes have reported preliminary results only,which demonstrated a different high-risk subpopulation of lung cancer in China.Evidence concerning LDCT screening implementation is based on results of randomized controlled trials outside China.LDCT screening programmes combining tobacco control would produce more benefits.Population recruitment(e.g.risk-based selection),screening protocol,nodule management and costeffectiveness are discussed in detail.In China,the high-risk subpopulation eligible for lung cancer screening has not as yet been confirmed,as all the risk parameters have not as yet been determined.Although evidence on best practice for implementation of lung cancer screening has been accumulating in other countries,further research in China is urgently required,as China is now facing a lung cancer epidemic.
文摘Fecal incontinence is a common condition that can significantly impact patients’quality of life.Obstetric anal sphincter injury and anorectal surgeries are common etiologies.Endoanal ultrasound and anorectal manometry are important diagnostic tools for evaluating patients.There are various treatment options,including diet,lifestyle modifications,drugs,biofeedback therapy,tibial and sacral nerve neuromodulation therapy,and surgery.In this editorial,we will discuss current controversies and novel approaches to fecal incontinence.Screening for asymptomatic anal sphincter defects after obstetric anal sphincter injury and in patients with inflammatory bowel disease is not generally recommended,but may be helpful in selected patients.The Garg incontinence score is a new score that includes the assessment of solid,liquid,flatus,mucous,stress and urge fecal incontinence.Novel tests such as translumbosacral anorectal magnetic stimulation and novel therapies such as translumbosacral neuromodulation therapy are promising diagnostic and treatment options,for both fecal incontinence and neuropathy.Home biofeedback therapy can overcome some limitations of the office-based therapy.Skeletal muscle-derived cell implantation of the external anal sphincter has been further studied as a possible treatment option.Sacral neuromodulation may be useful in scleroderma,congenital fecal incontinence and inflammatory bowel disease but merits further study.
文摘Aim:The transcription factor RIP140(receptor interacting protein of 140 kDa)is involved in intestinal tumorigenesis.It plays a role in the control of microsatellite instability(MSI),through the regulation of MSH2 and MSH6 gene expression.The aim of this study was to explore its effect on the expression of POLK,the gene encoding the specialized translesion synthesis(TLS)DNA polymeraseκknown to perform accurate DNA synthesis at microsatellites.Methods:Different mouse models and engineered human colorectal cancer(CRC)cell lines were used to analyze by RT-qPCR,while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression.Published DNA microarray datasets were reanalyzed.The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined.Results:RIP140 positively regulates,at the transcriptional level,the expression of the POLK gene,and this effect involves,at least partly,the p53 tumor suppressor.In different cohorts of CRC biopsies(with or without MSI),a strong positive correlation was observed between RIP140 and POLK gene expression.In connection with its effect on POLK levels and the TLS function of this polymerase,the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene.Finally,the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK,thus strengthening the functional link between the two genes in human CRC.Conclusion:The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability,and more generally to the control of genome integrity.
基金National Research,Development and Innovation Office(PharmaLab,RRF-2.3.1-21-2022-00015).
文摘Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy targets.Here,our goal was to expand our previous ranking analysis of survival-associated genes in various solid tumors to include colon cancer specimens with available transcriptomic and clinical data.A Gene Expression Omnibus search was performed to identify available datasets with clinical data and raw gene expression measurements.A combined database was set up and integrated into our Kaplan-Meier plotter,making it possible to identify genes with expression changes linked to altered survival.As a demonstration of the utility of the platform,the most powerful genes linked to overall survival in colon cancer were identified using uni-and multivariate Cox regression analysis.The combined colon cancer database includes 2,137 tumor samples from 17 independent cohorts.The most significant genes associated with relapse-free survival with a false discovery rate below 1%in colon cancer carcinoma were RBPMS(hazard rate[HR]=2.52),TIMP1(HR=2.44),and COL4A2(HR=2.36).The three strongest genes associated with shorter survival in stage II colon cancer include CSF1R(HR=2.86),FLNA(HR=2.88),and TPBG(HR=2.65).In summary,a new integrated database for colon cancer is presented.A colon cancer analysis subsystem was integrated into our Kaplan-Meier plotter that can be used to mine the entire database(https://www.kmplot.com).The portal has the potential to be employed for the identification and prioritization of promising biomarkers and therapeutic target candidates in multiple solid tumors including,among others,breast,lung,ovarian,gastric,pancreatic,and colon cancers.
文摘Three-dimensional(3D)bioprinting,an additive manufacturing based technique of biomaterials fabrication,is an innovative and auspicious strategy in medical and pharmaceutical fields.The ability of producing regenerative tissues and organs has made this technology a pioneer to the creation of artificial multi-cellular tissues/organs.A broad variety of biomaterials is currently being utilized in 3D bioprinting as well as multiple techniques employed by researchers.In this review,we demonstrate the most common and novel biomaterials in 3D bioprinting technology further with introducing the related techniques that are commonly taking into account by researchers.In addition,an attempt has been accomplished to hand over the most relevant application of 3D bioprinting techniques such as tissue regeneration,cancer investigations,etc.by presenting the most important works.The main aim of this review paper is to emphasis on strengths and limitations of existence biomaterials and 3D bioprinting techniques in order to carry out a comparison through them.