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Nguyen, G. D. "Fast CRCs." IEEE Transactions on Computers 58, no. 10 (October 2009): 1321–31. http://dx.doi.org/10.1109/tc.2009.83.
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Gao, Jingfang, Hong Zhang, Gunnar Arbman, and Xiao-Feng Sun. "The Different Roles of hRAD50 in Microsatellite Stable and Unstable Colorectal Cancers." Disease Markers 24, no. 2 (2008): 127–34. http://dx.doi.org/10.1155/2008/724796.
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RAD50 protein is essential for DNA double-strand break repair and maintaining genomic integrity. In this study, we investigated the clinicopathological significance of hRAD50 expression and mutation in microsatellite stable (MSS) and unstable (MSI) colorectal cancers (CRCs). hRAD50 expression was examined in primary CRC (n=268), the corresponding distant (n=69) and adjacent normal mucosa (n=138), and lymph node metastasis (n=44) by immunohistochemistry. hRAD50 mutation was analyzed in 87 primary CRCs by PCR-SSCP-DNA sequencing. hRAD50 expression was increased in MSS primary CRCs, but not MSI ones, compared with distant/adjacent normal mucosa (p<0.05). There was no difference in the hRAD50 expression between primary and metastatic CRCs. The increased hRAD50 expression in MSS primary CRCs was related (p<0.05) or tended to be related (p=0.05) to early tumor stage, better differentiation, high inflammatory infiltration, p53 overexpression. Frameshift mutations of (A)9at coding region ofhRAD50were only found in MSI CRCs. Our results suggest that hRAD50 may play different roles in the development of MSS and MSI CRCs: increased hRAD50 expression in MSS CRCs may be a cellular response against tumor from further progression, whilehRAD50mutation may be involved in the development of MSI CRCs.
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Meijer, G. A. "What makes CRCs metastasise?" Gut 59, no. 9 (July 21, 2010): 1164–65. http://dx.doi.org/10.1136/gut.2010.212241.
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Das, Siddhartha, Leo Chen, and Winson Y. Cheung. "Temporal trends in colorectal cancer screening (CRCS)." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 356. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.356.
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356 Background: The rate of CRCS continues to be suboptimal. Our study objectives were to characterize temporal trends in CRCS in general and within specific subpopulations and identify clinical and system factors that pose barriers to CRCS. Methods: Data from respondents aged ≥50 years who were classified as average risk (no personal or family history of colorectal cancer) from the 2001 to 2009 California Health Interview Survey were analyzed. Up-to-date CRCS was defined as having had a sigmoidoscopy or colonoscopy within the past 10 years. Using multivariate regression analyses that adjusted for confounders, rates of CRCS over consecutive periods of 2 calendar years were determined. Stratified analyses that explored for effect modification based on gender, ethnicity, smoking history, educational attainment, income level, health insurance status, and urban vs. rural residence were conducted. Results: A total of 126,873 screening-eligible respondents was included: median age was 63 years (range 50-85); 50,303 (46%) were men, and 95,534 (63%) were white. In the entire cohort, only 73,589 (55%) reported up-to-date CRCS. Over time, there was a significant trend towards increased CRCS, ranging from 48% in 2001 to 61% in 2009 (p<0.01). After adjusting for confounding variables, this trend persisted with higher odds of up-to-date CRCS in more recent years (see Table). Specific characteristics were associated with decreased likelihood of CRCS: women (OR 0.63), low education (OR 0.72), poor income (OR 0.84), no insurance (OR 0.44), and rural residence (OR 0.93) (p<0.01 for all). Temporal increases in CRCS were most prominent in particular groups, such as women (OR 3.55 in 2009 vs. 2001) and the uninsured (OR 11.48 in 2009 vs. 2001) (p<0.01 for both). Conclusions: Although CRCS improved over time, there is still room for significant improvement. Temporal increases in CRCS were most substantial among women and the uninsured. Interventions used to improve CRCS in these groups should be harnessed and implemented within other minorities to enhance screening. [Table: see text]
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Shahidi, N. C., B. Homayoon, and W. Y. Cheung. "Causes of suboptimal colorectal cancer screening (CRCS) in U.S. immigrants." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 380. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.380.
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380 Background: Research shows that CRCS in U.S. immigrants is low, but causes for this poor uptake are unclear. Our aims were to 1) compare CRCS among U.S. born citizens (USB), naturalized citizens (NAC) and non-citizens (NOC), 2) evaluate clinical factors associated with CRCS, and 3) explore health system barriers to CRCS for immigrants. Methods: Screening eligible patients were identified from the 2007 California Health Interview Survey. CRCS was defined as a fecal occult blood test within 1 year, a sigmoidoscopy within 5 years or a colonoscopy within 10 years. Using logistic regression, we determined the effect of immigrant status and other clinical factors on CRCS. We devised a 3-point composite scoring system based on survey responses to questions about health system barriers (where 0=worst and 3=best). Stratified analyses based on residence (urban vs rural), healthcare coverage (insured vs uninsured), English proficiency (good vs. poor), and composite score were conducted to assess their relationship with CRCS. Results: We identified 30,434 respondents: USB 83%, NAC 13%, NOC 4%; mean age 66, 65, 61 years; male 39%, 41%, 48%; white 85%, 38%, 29%, respectively. Only 67% of USB, 61% of NAC and 46% of NOC underwent CRCS (p<0.001). Old age, male, high income earners, non-smokers, being married and those who visited their physicians frequently were more likely to receive CRCS (all p<0.05). When compared to USB, NAC and NOC were associated with decreased odds of CRCS (OR 0.88, 95%CI 0.73-1.05 and OR 0.67, 95%CI 0.52-0.87, respectively; global p=0.009). Stratified analyses revealed that the association between immigrants and decreased CRCS was more evident for immigrants who lived in rural areas, lacked insurance, or those who were not proficient in English (Table). Immigrants with a composite score ≤2 also reported worse CRCS. Conclusions: CRCS remains suboptimal, especially in new U.S. immigrants. Inferior healthcare access and language barriers are potential drivers of this disparity. Addressing these system issues for immigrants may promote CRCS in this population. [Table: see text] No significant financial relationships to disclose.
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Rigter, Lisanne S., Petur Snaebjornsson, Efraim H. Rosenberg, Peggy N. Atmodimedjo, Berthe M. Aleman, Jelle ten Hoeve, Willemina R. Geurts-Giele, et al. "Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment." Gut 67, no. 3 (November 8, 2016): 447–55. http://dx.doi.org/10.1136/gutjnl-2016-312608.
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ObjectiveHodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.Design54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111).ResultsKRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome.ConclusionsWe have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.
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Akimoto, Naohiko, Takahiro Fujimori, Hiroyuki Mitomi, Kazuhito Ichikawa, Shigeki Tomita, Atsushi Tatsuguchi, Shunji Fujimori, Zenya Naito, and Choitsu Sakamoto. "Micropapillary Pattern at the Invasive Front and Its Association with Unresectable Colorectal Carcinomas." Disease Markers 35 (2013): 451–55. http://dx.doi.org/10.1155/2013/851623.
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Unresectable colorectal carcinomas (CRCs) as considered incurable even if the primary tumors and the metastatic ones can undergo resection are correlated with poor prognosis. We evaluated the association between micropapillary pattern at the invasive front and unresectable CRCs. Thirty-four out of 264 (12.9%) CRC patients with stages III and IV were unresectable cases. The patients with unresectable CRCs had significantly worse survival than those with resectable CRCs (). Micropapillary pattern was evident in 12 (4.5%) out of 264 cases. This pattern was observed in 6 of 34 (17.6%) unresectable CRCs and in 6 of 230 (2.6%) resectable cases (). Unresectable CRCs revealed more frequently deeper invasion (odds ratio (OR), 1.175; 95% confidence interval (CI), 1.113–1.241), lymph node metastasis (OR, 2.356; 95% CI, 1.132–4.905), and presence of micropapillary pattern at the invasive front (OR, 8.000; 95% CI, 2.415–26.504) as compared to resectable cases. By multivariable logistic regression analysis, only micropapillary pattern was shown to be an independent predictor of unresectable CRCs (OR, 9.451; 95% CI, 2.468–36.196; ). In conclusion, micropapillary pattern at the invasive front is associated with unresectable CRCs, and detection of it could help identify unresectable CRC cases.
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Kim, Jung Ho, Mi-Kyoung Seo, Ji Ae Lee, Seung-Yeon Yoo, Hyeon Jeong Oh, Hyundeok Kang, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang, and Sangwoo Kim. "Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers." Journal for ImmunoTherapy of Cancer 9, no. 12 (December 2021): e003414. http://dx.doi.org/10.1136/jitc-2021-003414.
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BackgroundColorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.MethodsWe conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.ResultsWe found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.ConclusionsMSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.
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Homayoon, B., N. C. Shahidi, and W. Y. Cheung. "The impact of Asian race on colorectal cancer screening (CRCS)." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 381. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.381.
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381 Background: While research shows that African Americans and Hispanics frequently receive less CRCS than Whites, few studies have focused on CRCS among Asians. The aims of the current analysis were to 1) compare CRCS between Asians and Whites in a large U.S. population, 2) evaluate for other clinical predictors of CRCS, and 3) examine the impact of health insurance coverage, place of birth and English proficiency on potential racial disparities. Methods: From the 2007 California Health Interview Survey, we identified all Asian (N=2,108) and White (N=23,237) average-risk respondents aged ≥50 years who were eligible for CRCS. Logistic regression was performed to evaluate for differences in CRCS between Asians and Whites. We used stratified and interaction analyses to examine whether associations between race and CRCS were modified by insurance status (insured vs uninsured), birthplace (U.S. vs non-U.S.) or language skills (good vs poor English), while controlling for other confounders. Results: Baseline characteristics were similar between Asians and Whites: mean age was 64 years in both groups; 45% and 47% were male; and 47% and 50% were employed, respectively. Only 58% of Asians and 66% of Whites reported undergoing up-to-date CRCS (p<0.001). In multivariate analyses, female gender and those living in rural areas were less likely to receive CRCS (OR 0.84, 95%CI 0.76-0.93, p=0.001 and OR 0.88, 95%CI 0.81-0.98, p=0.015, respectively).When compared to Whites, Asians also had decreased odds of CRCS (OR 0.82, 95%CI 0.71-0.95, p=0.008), even after adjusting for confounders such as education and income. Stratified analyses revealed that this disparity existed mainly in the insured (OR 0.83, 95%CI 0.72-0.96, p=0.014), but not in the uninsured (OR 0.94, 95%CI 0.43-2.06, p=0.873). The relationship between race and CRCS was not modified by place of birth or English proficiency. Conclusions: Despite its ability to reduce mortality, CRCS is suboptimal in our U.S. population-based cohort of Asians when compared to Whites. The racial disparity was more evident within the insured subset, suggesting that factors unrelated to healthcare access, such as patient preference, physician discretion or patient-physician rapport, may be more important drivers of CRCS among Asians. No significant financial relationships to disclose.
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Urabe, Y., S. Tanaka, Y. Saito, M. Igarashi, T. Watanabe, and K. Sugihara. "Impact of revisions of the JSCCR guidelines on the treatment of T1 colorectal carcinomas in Japan." Zeitschrift für Gastroenterologie 53, no. 04 (April 2015): 291–301. http://dx.doi.org/10.1055/s-0034-1385764.
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Abstract Purpose: In 1977, the Japanese Society for Cancer of the Colon and Rectum (JSCCR) published the first edition of the general guidelines that described how to record clinical and histopathological findings of colorectal carcinomas (CRCs) and how to treat these cancers, and since then, the guidelines were revised several times. The aim of this study was to examine the impact of the revisions of the JSCCR guidelines on the treatment of submucosal CRCs (T1-CRCs) in Japanese clinical settings. Methods: Questionnaires were sent to all 391 member institutions of the JSCCR. The questionnaires consisted of 2 parts: details of the institutions and treatment strategies for T1-CRCs. Results: 73 (19 %) institutions responded to the survey. The number of treated T1-CRCs has increased year by year, and the rate of endoscopic resection for T1-CRCs has significantly increased with revisions of the guidelines (1417 [47 %] of 2985 T1-CRCs in 2003 – 2005, 2110 [50 %] of 4212 in 2006 – 2008, and 2546 [54 %] of 4686 in 2009 – 2011, P<.05). Conclusion: The revisions of the JSCCR guidelines have influenced the treatment of T1-CRCs in Japanese clinical settings. There is room to revise the criteria for curative endoscopic resection to avoid unnecessary surgeries.
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Sitepu, Bintang Petrus. "PEMBERDAYAAN TBM MELALUI DANA BANTUAN DIREKTORAT PENDIDIKAN MASYARAKAT." Perspektif Ilmu Pendidikan 25, no. XVI (April 30, 2012): 73–94. http://dx.doi.org/10.21009/pip.251.7.
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Community Reading Centers (CRC) play an important role in developing the community to become a reading and learning society. The Indonesian Government, therefore, encourages the development of CRCs by providing financial assistance or grant to selected CRCs. The problem rised in this research is how the grant influences TBM’s development. This research aims at describing the development of CRCs which had received the grant. The research was done in four districts in Banten Provinces as from June through November 2011 coffering seven CRCs. Applying qualitative paradigm, the research collected data using observation, interview, and study document techniques. The data were analyze qualitatively to draw conclusions and suggestions. The research findings show that the development of CRCs received the grant is not as expected. Based on the findings the research suggest the concerned institutions to intensify monitoring and supervision on the CRCs.
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Gofine, Miriam, Ora Paltiel, Orly Manor, Arnon Cohen, Einat Elran, Liora Valinsky, Eran Matz, and Dena Hirschfield Jaffe. "Demographic, medical, and behavioral factors associated with colorectal cancer screening and diagnostic colonoscopy in Israel." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 557. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.557.
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557 Background: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide and second leading cause of cancer death in Israel. Israel's universal health care system funds CRC screening (CRCS) (fecal occult blood testing or colonoscopy) for all adults aged 50-74. CRCS adherence is influenced by numerous factors including patient characteristics. In addition to screening asymptomatic individuals, those with anemia may have undiagnosed CRC and require aggressive case finding. This study’s goals were: 1) To compare the socio-demographic, health status, and health behavior characteristics of the eligible Israeli population who underwent any versus no CRCS (2009-2012); 2) To examine the relationship between anemia severity and CRCS likelihood; 3) To determine whether anemia status predicts time-to-CRCS. Methods: National retrospective cohort study of Israeli adults aged 51-71 on 1.1.2009 using electronic medical records from all 4 Israeli HMOs (n=1,009,898) over a 4-year period. Results: Differences in CRCS adherence were observed by patient characteristics. For example, ever-smokers comprised 17.9% of the screened population and 24.9% of the non-screened population (p<0.001). Increasing anemia severity was positively associated with any CRCS performance, especially colonoscopy. For example, severely anemic individuals (hemoglobin <10 g/dL for men, <8 g/dL for women) were significantly more likely to receive colonoscopy than those who were not anemic (OR = 3.23; 95% CI, 2.58-4.27). Anemia somewhat expedites CRCS. For example, 8.9% of those with anemia and 7.6% of those without anemia performed any CRCS within 30 days of hemoglobin level recording (p<0.001). Conclusions: Full CRCS adherence is not yet optimized in Israel. Particular attention directed at those at-risk for CRCS non-adherence may decrease CRC mortality. Although lower hemoglobin somewhat expedites colonoscopy performance, few individuals with anemia actually undergo colonoscopy. Further analysis accounting for confounding and effect modification is crucial for a more complete understanding of these relationships.
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Thomas, P. "Cooperative Research Centres as effective institutions for contemporary models for achieving innovation in primary industry." Animal Production Science 50, no. 6 (2010): 424. http://dx.doi.org/10.1071/an10004.
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The creation of a formal organisational structure that brings together the specific needs of particular industries, with the expertise and research capacity available through recognised research providers, has an underlying and undeniable logic. Cooperative Research Centres (CRCs) provide this formal structure and are generally strongly focussed on carrying out applied outcome-driven research to improve productivity through innovation. Despite this strong commercial focus and record of scientific-output CRCs, there is general recognition that adoption of research from CRCs can be improved. The present paper focuses on primary industry CRCs and discusses the applicability of contemporary innovation concepts, which have evolved through the process of industrialisation and socialisation of science, and their application for improving innovation within primary industry CRCs. Specifically considered are 4th and 5th generation innovation concepts that promote ideas within ‘Open Innovation’ and ‘Knowledge Creation’ as a means of improving innovation within the primary industry CRCs organisational structure.
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FENG, Yu, Lin RAO, and Jie QIAO. "Investigation and analysis of the status of clinical research coordinators." Pharmaceutical Care and Research 20, no. 5 (October 31, 2020): 350–54. http://dx.doi.org/10.5428/pcar20200507.
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Objective： To investigate the current status of clinical research coordinators（CRCs） in Fudan University Shanghai Cancer Center，so as to optimize the current management mode and improve the quality of drug clinical trials.Methods： A survey was made among 104 CRCs in the hospital by using a self-made questionnaire，which included professional background，problems facing CRCs and their opinions or suggestions concerning the current management mode.Finally，the study made a descriptive statistical analysis of the obtained results.Results and Conclusion： Most of the CRCs in the hospital had an educational background of above undergraduate course in related medical science，over 80% of them had service years of less than 3 years，and less than 50% of them used to undertake clinical trials independently before they took up their posts in the hospital.The majority of the CRCs had a love for their profession and a sense of accomplishment，but only 20% of them had a sense of home-coming and approval.The feelings of heavy workload and dissatisfaction with salary widely existed among CRCs.Poor cooperation between subjects and pharmacy intravenous admixture service（PIVAS） and CRCs occasionally occurred in work.CRCs put forward a series of suggestions on the current CRCs management mode in the hospital.Such measures as setting up CRCs access threshold，raising salary，enriching training contents，reforming the work system of PIVAS，enhancing the sense of responsibility of clinical researchers，and holding regular informal discussions should be taken to intensify the construction of the CRCs team both professionally and from the aspect of team stability in the long run.
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FENG, Yu, Lin RAO, and Jie QIAO. "Investigation and analysis of the status of clinical research coordinators." Pharmaceutical Care and Research 20, no. 5 (October 31, 2020): 350–54. http://dx.doi.org/10.5428/pcar20200507.
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Objective： To investigate the current status of clinical research coordinators（CRCs） in Fudan University Shanghai Cancer Center，so as to optimize the current management mode and improve the quality of drug clinical trials.Methods： A survey was made among 104 CRCs in the hospital by using a self-made questionnaire，which included professional background，problems facing CRCs and their opinions or suggestions concerning the current management mode.Finally，the study made a descriptive statistical analysis of the obtained results.Results and Conclusion： Most of the CRCs in the hospital had an educational background of above undergraduate course in related medical science，over 80% of them had service years of less than 3 years，and less than 50% of them used to undertake clinical trials independently before they took up their posts in the hospital.The majority of the CRCs had a love for their profession and a sense of accomplishment，but only 20% of them had a sense of home-coming and approval.The feelings of heavy workload and dissatisfaction with salary widely existed among CRCs.Poor cooperation between subjects and pharmacy intravenous admixture service（PIVAS） and CRCs occasionally occurred in work.CRCs put forward a series of suggestions on the current CRCs management mode in the hospital.Such measures as setting up CRCs access threshold，raising salary，enriching training contents，reforming the work system of PIVAS，enhancing the sense of responsibility of clinical researchers，and holding regular informal discussions should be taken to intensify the construction of the CRCs team both professionally and from the aspect of team stability in the long run.
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Hussain, Tahir, Fawad Khan, Ashfaque H. Bokhari, and Sumaira Saleem Akhtar. "Classification of Kantowski–Sachs metric via conformal Ricci collineations." International Journal of Geometric Methods in Modern Physics 15, no. 01 (December 19, 2017): 1850006. http://dx.doi.org/10.1142/s0219887818500068.
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In this paper, we present a classification of the Kantowski–Sachs spacetime metric according to its conformal Ricci collineations (CRCs). Solving the CRC equations, it is shown that the Kantowski–Sachs metric admits 15-dimensional Lie algebra of CRCs when its Ricci tensor is non-degenerate and an infinite dimensional group of CRCs when the Ricci tensor is degenerate. Some examples of Kantowski–Sachs metric admitting nontrivial CRCs are presented and their physical interpretation is provided.
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Manz, Salomon M., Marco Losa, Ralph Fritsch, and Michael Scharl. "Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer." Therapeutic Advances in Gastroenterology 14 (January 2021): 175628482110020. http://dx.doi.org/10.1177/17562848211002018.
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Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity – in terms of progression free survival (PFS) and objective response rate (ORR) – in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration’s approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a “cold” to “hot” tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs.
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Holland, Roberto, Sueli Satomi Murata, Monica Nunes da Silva, Eloi Dezan Junior, Valdir de Souza, and Pedro Felício Estrada Bernabé. "Influence of the sealer and a plug in coronal leakage after post space preparation." Journal of Applied Oral Science 12, no. 3 (September 2004): 223–26. http://dx.doi.org/10.1590/s1678-77572004000300012.
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The subject of this paper was to conduct an in vitro study of the coronal leakage after root canal filling and post space preparation. One hundred single-rooted human teeth had their crowns removed and the canals prepared and filled by the lateral condensation technique with gutta-percha points and the sealers CRCS and Endofill (a Grossman cement). After post space preparation, the remainder of the filling was protected or not with 1mm of a plug of the following materials: Coltosol, Super Bonder (cyanoacrylate-ester), CRCS and Endofill. After 24 hours in saline, the specimens were immersed in a 2% methylene blue solution in a vacuum environment for 24 hours. The teeth were then sectioned longitudinally, leakage was evaluated linearly and the obtained data were submitted to the Kruskal-Wallis test. The results with the two sealers studied were similar between themselves and worse (p<0.01) than the groups with a protector plug. The statistical analysis ordered the experimental groups from the best to the worst in the following way: a - Endofill-Super Bonder, CRCS-Super Bonder, CRCS-CRCS; b - Endofill-Endofill; c - Endofill-Coltosol, CRCS-Coltosol; d - Endofill, CRCS.
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Shanmugam, Chandrakumar, Venkat R. Katkoori, Nirag C. Jhala, William E. Grizzle, Gene P. Siegal, and Upender Manne. "p53 Nuclear Accumulation and Bcl-2 Expression in Contiguous Adenomatous Components of Colorectal Adenocarcinomas Predict Aggressive Tumor Behavior." Journal of Histochemistry & Cytochemistry 56, no. 3 (November 12, 2007): 305–12. http://dx.doi.org/10.1369/jhc.7a7362.2007.
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For subsets of colorectal adenocarcinoma (CRC) patients, nuclear accumulation of p53 (p53nac) and Bcl-2 expression are prognostic indicators. To understand their role in the progression of CRC we evaluated 90 CRCs and their contiguous adenomatous components (CAdCs) for immunohistochemical expression of these markers. In general, p53nac and Bcl-2 expression was significantly increased when comparing normal colonic epithelia to CAdCs and CRCs. Thirteen (14%) CAdCs that demonstrated p53nac continued to express p53nac in their contiguous CRCs. A similar trend was observed in Bcl-2 expression in that the majority of CAdCs expressing Bcl-2 continued to express it in their matching CRCs (39/44). Patients whose CAdCs and their contiguous CRCs demonstrate p53nac had shorter median survival (35.9 months) than those patients whose CAdCs and CRCs did not (80.56 months). However, patients whose CAdCs had p53nac and lacked Bcl-2 expression had the lowest median survival (15.74 months) when compared with patients whose CAdCs did not demonstrate p53nac but had increased expression of Bcl-2 (71.77 months). These findings suggest that in those adenomas that demonstrate p53nac but lack Bcl-2 expression, their contiguous CRCs are more likely to be aggressive as they progress.
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Khan, Fawad, Tahir Hussain, Ashfaque Hussain Bokhari, and Sumaira Saleem Akhtar. "Non-static spherically symmetric spacetimes and their conformal Ricci collineations." Arabian Journal of Mathematics 9, no. 2 (March 4, 2019): 393–400. http://dx.doi.org/10.1007/s40065-019-0249-5.
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Abstract For a perfect fluid matter, we present a study of conformal Ricci collineations (CRCs) of non-static spherically symmetric spacetimes. For non-degenerate Ricci tenor, a vector field generating CRCs is found subject to certain integrability conditions. These conditions are then solved in various cases by imposing certain restrictions on the Ricci tensor components. It is found that non-static spherically symmetric spacetimes admit 5, 6 or 15 CRCs. In the degenerate case, it is concluded that such spacetimes always admit infinite number of CRCs.
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Inamura, Kentaro. "Colorectal Cancers: An Update on Their Molecular Pathology." Cancers 10, no. 1 (January 20, 2018): 26. http://dx.doi.org/10.3390/cancers10010026.
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Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. This heterogeneity slows the development of molecular-targeted therapy as a form of precision medicine. Recent data regarding comprehensive molecular characterizations and molecular pathological examinations of CRCs have increased our understanding of the genomic and epigenomic landscapes of CRCs, which has enabled CRCs to be reclassified into biologically and clinically meaningful subtypes. The increased knowledge of the molecular pathological epidemiology of CRCs has permitted their evolution from a vaguely understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes, a development that will allow the implementation of personalized therapies and better management of patients with CRC. This review provides a perspective regarding recent developments in our knowledge of the molecular and epidemiological landscapes of CRCs, including results of comprehensive molecular characterizations obtained from high-throughput analyses and the latest developments regarding their molecular pathologies, immunological biomarkers, and associated gut microbiome. Advances in our understanding of potential personalized therapies for molecularly specific subtypes are also reviewed.
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Barros-Bailey, Mary, and Jodi L. Saunders. "Labor Market Surveys: Importance to and Preparedness of Certified Rehabilitation Counselors." Rehabilitation Research, Policy, and Education 27, no. 2 (2013): 74–88. http://dx.doi.org/10.1891/2168-6653.27.2.74.
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The purpose of this study was to explore certified rehabilitation counselors’ (CRCs’) importance of and preparedness in the labor market survey (LMS) competency through data collected by theKnowledge Validation Inventory-Revised(KVI-R) instrument used by the Commission on Rehabilitation Counselor Certification’s (CRCC) 2011 role and function study (CCRC, 2011b; Leahy, Chan, Sung, & Kim, 2011). LMS is a primary data collection method for gathering occupational and labor market information. Thus, this competency was examined because of its importance in the areas of rehabilitation counseling where this data is usually applied—transferable skills analysis, vocational decision making, job development and placement, and forensics. In this ex post facto secondary analysis, the single largest group of CRCs found LMS to beverytoextremely importantbut also reported onlymoderate preparednessto perform the function. Significant differences were found by geographical location, particularly between the Mid and South Atlantic, and in experience. Discussion, conclusions, implications, and areas for further research are addressed.
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Liu, Guang-Jian, Heng Zhang, Ya-Wei Zhu, Wen-Hao Cao, Xian-Jun Ji, Cai-Ping Lu, and Yang Liu. "Investigations of Coal-Rock Parting-Coal Structure (CRCS) Slip and Instability by Excavation." Shock and Vibration 2021 (August 18, 2021): 1–15. http://dx.doi.org/10.1155/2021/1715644.
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Slip and instability of coal-rock parting-coal structure (CRCS) subjected to excavation disturbance can easily induce coal-rock dynamic phenomena in deep coal mines. In this paper, the failure characteristics and influencing factors of CRCS slip and instability were investigated by theoretical analysis, numerical simulations, and field observations. The following main results are addressed: (1) the slip and instability of CRCS induced by excavation are due to stress release, and the damage of the rock parting is partitioned into three parts: shear failure zone, slipping zone, and splitting failure zone from inside to outside with slip; (2) the slip and instability process of CRCS is accompanied by initiation, expansion, and intersection of shear and tensile cracks. The development of the cracks is dominated by shear behaviour, while the tensile crack is the main factor affecting fracture and instability of CRCS; and (3) slip and instability of CRCS are characterized by stick-slip first and then stable slip, accompanied with high P-wave velocity and rockburst danger coefficient based on microseismic tomography.
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Kang, Guhyun, Jung-Soo Pyo, Nae Yu Kim, and Dong-Wook Kang. "Clinicopathological Significances and Prognostic Role of Intratumoral Budding in Colorectal Cancers." Journal of Clinical Medicine 11, no. 19 (September 21, 2022): 5540. http://dx.doi.org/10.3390/jcm11195540.
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Background: This study aims to evaluate the clinicopathological significance and prognostic implications of intratumoral budding (ITB) in colorectal cancers (CRCs) through a meta-analysis. Methods: We performed the meta-analysis using 13 eligible studies and investigated the rates of CRCs with high ITB. The correlation between ITB and clinicopathological characteristics, including disease-free survival, was evaluated. Results: The estimated rate of CRCs with high ITB was 0.233 (95% confidence interval (CI) 0.177–0.299) in overall CRCs. High ITB was significantly correlated with tumor grade, lymphatic invasion, perineural invasion, pT stage, and lymph node metastasis. In addition, ITBs were more frequently found in medullary and signet-ring cell carcinomas than in conventional adenocarcinomas and mucinous carcinomas. However, the high ITB rate was not correlated with tumor border, tumor-infiltrating lymphocytes, or microsatellite instability. CRCs with a good response after neoadjuvant therapy revealed a lower rate of high ITB than those with a poor response (hazard ratio (HR) 0.114, 95% CI 0.070–0.179 vs. 0.321, 95% CI 0.204–0.467). In addition, CRCs with high ITB had a worse disease-free survival than those with low ITB (HR 1.426, 95% CI 1.092–1.863). Conclusions: The ITB was significantly correlated with aggressive tumor behaviors and a worse prognosis in CRCs. The detection of ITB, as a histological parameter, can be useful for predicting clinicopathologic features and the prognosis of CRC.
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Szeszulski, Jacob, Derek W. Craig, Timothy J. Walker, Maya Foster, Patricia Dolan Mullen, and Maria E. Fernandez. "Applying evidence-based intervention (EBI) mapping to identify the components and logic of colorectal cancer screening interventions." Translational Behavioral Medicine 12, no. 2 (November 3, 2021): 304–23. http://dx.doi.org/10.1093/tbm/ibab140.
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Abstract Implementation of evidence-based interventions (EBIs) can help to increase colorectal cancer screening (CRCS). Potential users of CRCS EBIs are often unclear about the specific features, logic, and core elements of existing EBIs, making it challenging to use or adapt them. We used EBI Mapping, a systematic process developed from Intervention Mapping that identifies an EBI’s components and logic, to characterize existing CRCS EBIs from the National Cancer Institute’s Evidence-Based Cancer Control Programs website. The resulting information can facilitate intervention adoption, adaptation, and/or implementation. Two trained coders independently coded intervention materials to describe intervention components and logic (n = 20). We display CRCS EBI components (potential mechanism of change) using evidence tables and heat maps. All EBIs addressed completion of at least one CRCS behavior (stool-based test, n = 9; stool-based test or another CRCS test, n = 8; colonoscopy, n = 3; colonoscopy or sigmoidoscopy, n = 1). The psychosocial determinants most frequently addressed by these interventions were knowledge (n = 19), attitudes (n = 17), risk perception/perceived susceptibility (n = 16), skills (n = 15), and overcoming barriers (n = 15). Multi-level EBIs (n = 9) attempted to change an average of 2.1 ± 1.1 conditions in the patients’ environment (e.g., accessibility of CRCS); only four EBIs used environmental change agents (e.g., providers, nurses). From the heat maps of EBIs, we describe common theoretical change methods’ (e.g., facilitation) used for addressing determinants (e.g., overcoming barriers). EBI Mapping can help users identify important components of a CRCS EBI’s logic; these proposed mechanisms of action can inform adoption, adaptation, and implementation in new settings, and facilitate scale up of EBIs.
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van Engeland, Manon, Arjen Cleven, Sarah Derks, Muriel XG Draht, Kim M. Smits, Veerle Melotte, Matty P. Weijenberg, James Gordon Herman, Adriaan P. de Bruïne, and Wim Van Criekinge. "CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e14503-e14503. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e14503.
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e14503 Background: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here we examine the prognostic impact of promoter methylation in CRC patients treated with surgery alone in the context of microsatellite instability (MSI), BRAF- and KRAS mutations. Methods: 173 CRCs were analyzed for promoter methylation of 19 tumor suppressor- and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 (CL1, 57% (98/173) of CRCs), cluster 2 (CL2, 25% (43/173) of CRCs) and cluster 3 (CL3, 18% (32/173) of CRCs). CL3 had the highest methylation index (0.25, 0.49 and 0.69 respectively, p=<0.01) and was strongly associated with CIMP (p<0.01). After stratification for tumor stage, MSI and BRAF status, no statistically significant differences in survival between CL1, CL2 and CL3 nor between CIMP and non-CIMP CRCs were detected. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, MSS, BRAF wild-type CRCs: HR=3.89 (95% CI =1.58-9.60, p=0.003) and HR=2.21 (95% CI =1.09-4.48, p=0.03) in a second population-based study (n=151). Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF wild-type CRCs.
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Guda, Kishore, Martina L. Veigl, Vinay Varadan, Arman Nosrati, Lakshmeswari Ravi, James Lutterbaugh, Lydia Beard, et al. "Novel recurrently mutated genes in African American colon cancers." Proceedings of the National Academy of Sciences 112, no. 4 (January 12, 2015): 1149–54. http://dx.doi.org/10.1073/pnas.1417064112.
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We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.
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Middha, Sumit, Rona Yaeger, Jinru Shia, Zsofia K. Stadler, Sarah King, Shanna Guercio, Victoriya Paroder, et al. "Majority of B2M-Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High." JCO Precision Oncology, no. 3 (December 2019): 1–14. http://dx.doi.org/10.1200/po.18.00321.
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PURPOSE Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). B2M mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize B2M-mutant, IO-naive CRC. PATIENTS AND METHODS All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for B2M mutations. All B2M-mutant CRCs were assessed for expression of B2M, major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3+ and CD8+ tumor-infiltrating lymphocyte counts against a control group of MSI-H B2M wild-type CRCs. RESULTS Fifty-nine (3.4%) of 1,751 patients with CRC harbored B2M mutations, with 84% (77 of 92) of the mutations predicted to be truncating. B2M mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring B2M mutations ( P < .001). Thirty-two of 44 B2M-mutant CRCs with available material (73%) had complete loss of B2M expression, whereas all 26 CRCs with wild-type B2M retained expression ( P < .001). B2M mutation status was not associated with major histocompatibility complex class I expression, KRAS or BRAF mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with B2M-mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria. CONCLUSION B2M mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of B2M expression. Most patients with B2M-mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.
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Lasky, J. L., N. M. Ponzio, and G. J. Thorbecke. "Characterization and growth factor requirements of SJL lymphomas. I. Development of a B cell growth factor-dependent in vitro cell line, cRCS-X." Journal of Immunology 140, no. 2 (January 15, 1988): 679–87. http://dx.doi.org/10.4049/jimmunol.140.2.679.
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Abstract Reticulum cell sarcomas (RCS) of SJL mice are completely dependent on host cells for their growth and therefore fail to grow in vitro. RCS cells induce marked proliferation in SJL Ly-1+2- T cells accompanied by lymphokine production. In an attempt to fully understand the host-tumor cell interaction, an RCS cell line, cRCS-X, was established in vitro from a transplantable tumor by the addition, every 3 wk, of gamma-irradiated syngeneic lymph node (LN) cells to the culture. cRCS-X maintains all of the characteristics of the parent tumor, RCS-X, including cell surface phenotype (Ks and I-As positive, Ds negative and B cell marker 14.8 positive), ability to stimulate host T cells, and ability to grow in nonirradiated but not in gamma-irradiated SJL mice. The growth factor requirements of cRCS-X were examined. It was found that human BCGF can replace gamma-irradiated LN cells in the maintenance of long term in vitro growth of cRCS-X. cRCS-X cells respond to human B cell growth factor (BCGF) or to recombinant murine interleukin (IL)-5 in a short term proliferation assay [( 3H]thymidine incorporation) in a dose-dependent manner in the presence and absence of fetal calf serum. BCGF also promotes colony formation in soft agar by cRCS-X cells. Although both IL-1 and interferon-gamma can synergize with BCGF in the induction of cRCS-X proliferation, these lymphokines, as well as IL-2, IL-3, granulocyte-macrophage colony-stimulating factor, and IL-4 have no effect on cRCS-X growth when added alone. In addition, it was shown that SJL LN cells produce both IL-4 and BCGF II activities as assayed on murine B cells, after stimulation with gamma-irradiated cRCS-X cells. In light of these results it is postulated that IL-5, [corrected] produced by syngeneic T cells [corrected] after stimulation with RCS, is essential for RCS growth, both in vitro and in vivo.
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Liu, Kewei, Shaobo Jin, Yichao Rui, Jin Huang, and Zhanxing Zhou. "Effect of Lithology on Mechanical and Damage Behaviors of Concrete in Concrete-Rock Combined Specimen." Mathematics 10, no. 5 (February 25, 2022): 727. http://dx.doi.org/10.3390/math10050727.
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A concrete structure built on rock foundation works together with the connected rock mass, which has a significant effect on the mechanical behaviors of the concrete structure. To study the effect of lithology on the mechanical and damage behaviors of concrete in a concrete-rock combined specimen (CRCS), first, a test method for measuring the concrete part (concrete in CRCS) is adopted, then, uniaxial compression tests on seven types of specimens are performed and acoustic emission (AE) events are simultaneously monitored. Test results show that the low-strength concrete part plays a major role in the fracture behavior of CRCS. When the CRCS is failed, a sudden stress drop happens in CRCS, and the rock part (rock in CRCS) experiences a rapid axial strain recovery and intensifies the failure of the concrete part. The load-bearing and deformation capacities of the concrete part increase with the strength of the rock part, but the rock part shows the opposite behaviors under the influence of the concrete part. Furthermore, the damage of CRCS is mainly formed in the concrete part, and the damage extent of the concrete part is positively correlated with the strength of the rock part. Finally, a damage constitutive model of the concrete part is established and validated. This model can be used to accurately describe the effect of lithology on the mechanical response of the concrete part under uniaxial compression loading.
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Moon, Hyung-In, and Okpyo Zee. "Sesquiterpene lactones from Carpesium rosulatum with potential cytotoxicity against five human cancer cell lines." Human & Experimental Toxicology 30, no. 8 (October 11, 2010): 1083–87. http://dx.doi.org/10.1177/0960327110386818.
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In search for plant-derived cytotoxicity compound against human cancer cells (A549, SK-OV-3, SK-MEL-2, XF498, HCT15), it was found that the chloroform extracts obtained from the whole plant of Carpesium rosulatum MlQ. (Compositae) exhibited significant cytotoxic activity. Four sesquiterpene lactone, CRC1 (2α, 5-epoxy-5,10-dihydroxy-6-angeloyl-oxy-9β-isobutyloxy-germacran-8α,12-olide), CRC2 (2α,5-epoxy-5,10-dihydroxy-6α,9β-diangeloyloxy-germacran-8α,12-olide), CRC3 (2α,5-epoxy-5,10-dihydroxy-6α-angeloyloxy-9β-(3-methyl-butanoyloxy)-gemacran-8α,12-olide), CRC4 (2β,5-epoxy-5,10-dihydroxy-6α,9β-diangeloyloxy-germacran-8α,12-olide) were isolated from the whole parts of C. rosulatum. 2α,5-epoxy-5,10-dihydroxy-6α,9β-diangeloyloxy-germacran-8α,12-olide (CRC2) showed the most potent cytotoxicity with IC50 value of 6.01 μM against SK-MEL-2.
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Sadanandam, Anguraj, Pawan Poudel, Elisa Fontana, and Chanthirika Ragulan. "Characterizing heterogeneity in KRAS mutant colorectal cancers (CRC) using cellular, mutation, and immune profiles." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 657. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.657.
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657 Background: Approximately 30%-50% of CRC patients have KRAS mutation, and they are associated with lack of treatment response to anti-EGFR therapy. KRAS mutant CRCs are heterogeneous that not all mutant tumors are dependent on its downstream signaling. At this era of the search for therapeutic targets related to mutant KRAS, it is essential to understand the underlying heterogeneity in KRAS mutant metastatic CRCs with a goal of identifying personalized therapeutic vulnerabilities. To understand KRAS mutation further, in this study we classified KRAS mutant CRCs based on individual cell types in the normal colon crypt and associated them with PIK3CA mutations and interferon-gamma responsive signature. Methods: Publicly available RNAseq gene expression data from KRAS mutant samples were used. Classification of CRC samples into CRCassigner subtypes, KRAS mutation dependents/independent groups, and interferon gamma-responsive status was performed using published signatures. Results: CRC samples (n>200) with KRAS mutant and wild-type statuses were classified into all the five CRCAssigner subtypes (goblet-like, enterocyte, transit-amplifying, stem-like and inflammatory) that represent individual cell types in the normal colon crypt. Interestingly, goblet-like subtype was found to be enriched for KRAS mutation. Among those KRAS mutant CRCs from all the subtypes (n=61), goblet-like samples showed significant enrichment (false discovery rate <0.05; hypergeometric test) for KRAS dependent signature, whereas stem-like subtype showed KRAS independent signature. KRAS independent stem-like CRCs showed increased PIK3CA mutation and expression of interferon-gamma responsive genes compared to dependent CRCs. Conclusions: Overall, KRAS mutant CRCs are heterogeneous with differentiated subtype highly dependent on the mutation and its signalling pathway, whereas less differentiated/stem-like subtype CRCs are independent of the mutation. Also, the enrichment of PIK3CA mutation and interferon-gamma responsive genes mainly in KRAS independent CRC subtype present a potential opportunity to target them using combination immunotherapeutics.
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Khan, Fawad, Tahir Hussain, and Sumaira Saleem Akhtar. "Conformal Ricci collineations in LRS Bianchi type V spacetimes with perfect fluid matter." Modern Physics Letters A 32, no. 24 (July 17, 2017): 1750124. http://dx.doi.org/10.1142/s0217732317501243.
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Considering the perfect fluid as a source of energy–momentum tensor, we have classified locally rotationally symmetric (LRS) Bianchi type V spacetimes according to their conformal Ricci collineations (CRCs). It is shown that the LRS Bianchi type V spacetimes with perfect fluid matter admit 9- or 15-dimensional Lie algebra of CRCs when the Ricci tensor is non-degenerate, while the group of CRCs is infinite for degenerate Ricci tensor.
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Lee, Seung Eun, Ha Young Park, Dae-Yong Hwang, and Hye Seung Han. "High Concordance of Genomic Profiles between Primary and Metastatic Colorectal Cancer." International Journal of Molecular Sciences 22, no. 11 (May 24, 2021): 5561. http://dx.doi.org/10.3390/ijms22115561.
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The comparison of the genetic profiles between primary and metastatic colorectal cancer (CRC) is needed to enable the discovery of useful therapeutic targets against metastatic CRCs. We performed the targeted next generation sequencing assay of 170 cancer-associated genes for 142 metastatic CRCs, including 95 pairs of primary and metastatic CRCs, to reveal their genomic characteristics and to assess the genetic heterogeneity. The most frequently mutated gene in primary and metastatic CRCs was APC (71% vs. 65%), TP53 (54% vs. 57%), KRAS (45% vs. 44%), PIK3CA (16% vs. 19%), SMAD4 (15% vs. 14%) and FBXW7 (11% vs. 11%). The concordance in the top six frequently mutated genes was 85%, on average. The overall mutation frequencies were consistent with two sets of public data (TCGA and MSKCC). To the author’s knowledge, this is the first study to compare the genetic profiles of our cohort with that of the metastatic CRCs from MSKCC. Comparative sequencing analysis between primary and metastatic CRCs revealed a high degree of genetic concordance in the current clinically actionable genes. Therefore, the genetic investigation of archived primary tumor samples with the challenges of obtaining an adequate sample from metastatic sites appears to be sufficient for the application of cancer precision medicine in the metastatic setting.
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Bolzacchini, Elena, Laura Libera, Sarah E. Church, Nora Sahnane, Raffaella Bombelli, Nunzio Digiacomo, Monica Giordano, et al. "Tumor Antigenicity and a Pre-Existing Adaptive Immune Response in Advanced BRAF Mutant Colorectal Cancers." Cancers 14, no. 16 (August 16, 2022): 3951. http://dx.doi.org/10.3390/cancers14163951.
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The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to immunotherapy. GEPs of 89 immunotherapy-naïve BRAF-CRCs were generated using the Pan-Cancer IO 360 gene expression panel and the NanoString nCounter platform and were correlated with microsatellite instability (MSI) status and with CD8+ tumor-infiltrating lymphocyte (TIL) content. Hot/inflamed profiles were found in 52% of all cases, and high scores of Tumor Inflammation Signature were observed in 42% of the metastatic BRAF-CRCs. A subset of MSI tumors showed a cold profile. Antigen Processing Machinery (APM) signature was not differentially expressed in MSI tumors compared with MSS cases. By contrast, the APM signature was significantly upregulated in CD8+ BRAF-CRCs versus CD8− tumors. Our study demonstrates that a significant fraction of BRAF-CRCs may be a candidate for immunotherapy and that the simultaneous analysis of MSI status and CD8+ TIL content increases accuracy in identifying patients who can potentially benefit from immune checkpoint inhibitors. GEPs may be very useful in expanding the spectrum of patients with BRAF-CRCs who can benefit from immune checkpoint blockade.
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Kang, Gyeong Hoon. "Four Molecular Subtypes of Colorectal Cancer and Their Precursor Lesions." Archives of Pathology & Laboratory Medicine 135, no. 6 (June 1, 2011): 698–703. http://dx.doi.org/10.5858/2010-0523-ra.1.
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Abstract Context.—In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI−, CIMP−/MSI+, and CIMP−/MSI−. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. Objective.—To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. Data Sources.—This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). Conclusion.—The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.
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Nagasaka, Takeshi, Hiromi Sasamoto, Kenji Notohara, Harry M. Cullings, Masanori Takeda, Keigo Kimura, Takeshi Kambara, et al. "Colorectal Cancer With Mutation in BRAF, KRAS, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation." Journal of Clinical Oncology 22, no. 22 (November 15, 2004): 4584–94. http://dx.doi.org/10.1200/jco.2004.02.154.
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Purpose BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. Conclusion In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.
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Frain, Michael, Malachy Bishop, Timothy Tansey, Jennifer Sanchez, and Frank Wijngaarde. "Current Knowledge and Training Needs of Certified Rehabilitation Counselors to Work Effectively With Veterans With Disabilities." Rehabilitation Research, Policy, and Education 27, no. 1 (2013): 2–17. http://dx.doi.org/10.1891/2168-6653.27.1.2.
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Veterans with disabilities have gained national attention in recent years because of the wars in Iraq and Afghanistan. This study examined certified rehabilitation counselors’ (CRCs ) knowledge and preparation for working with veterans with disabilities on their rehabilitation. Results indicate that CRCs report low levels of preparation in some of the areas deemed important by veterans and professionals. However, CRCs report high knowledge in many important areas to work effectively with veterans with disabilities.
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Bazargan, Mohsen, James L. Smith, Paul Robinson, John Uyanne, Ruqayyah Abdulrahoof, Chika Chuku, and Shervin Assari. "Chronic Respiratory Disease and Health-Related Quality of Life of African American Older Adults in an Economically Disadvantaged Area of Los Angeles." International Journal of Environmental Research and Public Health 16, no. 10 (May 17, 2019): 1756. http://dx.doi.org/10.3390/ijerph16101756.
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Background. Most of the attention of policy makers, program planners, clinicians, and researchers in the area of physical health disparities among African American older adults has been traditionally focused on cardiometabolic disease and cancer. Among a long list of chronic medical conditions, chronic respiratory conditions (CRCs), such as asthma, chronic bronchitis, and emphysema, have received less attention. Purpose. This study investigated whether CRCs contribute to physical and mental health-related quality of life (HRQoL) of African American older adults who live in economically disadvantaged urban areas, and whether these effects are due to demographic factors, socioeconomic status (SES), health behaviors, and comorbid medical and mental conditions. Methods. This community-based study recruited 617 African American older adults (age ≥ 65 years) from Service Planning Areas (SPA) 6, an economically disadvantaged area in South Los Angeles. Structured face-to-face interviews were used to collect data on demographic factors (age and gender), SES (educational attainment and financial difficulty), living arrangements, marital status, health behaviors (cigarette smoking and alcohol drinking), health (CRC, number of comorbid medical conditions, depressive symptoms, and pain intensity), and physical and mental HRQoL (Physical and Mental Component Summary Scores; PCS and MCS; SF-12). Linear regressions were used to analyze the data. Results. The presence of CRCs was associated with lower PCS and MCS in bivariate analysis. The association between CRCs and PCS remained significant above and beyond all confounders. However, the association between CRCs and MCS disappeared after controlling for confounders. Conclusion. For African American older adults living in economically disadvantaged urban areas, CRCs contribute to poor physical HRQoL. Evaluation and treatment of CRCs in African American older adults may be a strategy for reduction of disparities in HRQoL in this population. As smoking is the major modifiable risk factor for CRCs, there is a need to increase accessibility of smoking cessation programs in economically disadvantaged urban areas. More research is needed on the types, management, and prognosis of CRCs such as asthma, chronic bronchitis, and emphysema in African American older adults who reside in low-income and resource limited urban areas.
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Hyngstrom, John Robert, Miguel A. Rodriguez-Bigas, George J. Chang, Melissa W. Taggart, John Michael Skibber, Barry W. Feig, and Y. Nancy You. "Microsatellite high colorectal cancer: Does the underlying mechanism for instability matter?" Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 575. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.575.
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575 Background: Microsatellite instability (MSI) testing in colorectal cancer (CRC) provides prognosis, predicts chemotherapy response, and guides diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MSI can be sporadic or hereditary, arising from somatic or germline mutations in DNA mismatch repair (MMR) genes respectively. The clinical implications of these distinct mechanisms are uncertain. Methods: Patients who underwent MSI testing for CRC between 2000 and 2011 were identified. MSI-high (MSH) CRCs were defined by: pathogenic mutation in MMR genes; >30% of markers with allelic shift in PCR-based MSI testing; or loss of expression in at least 1 MMR protein on immunohistochemistry. The subset with MLH1 gene promoter methylation, BRAF mutation, or EPCAM mutation was considered sporadic. Clinicopathologic features and disease-free survival (DFS) were examined in reference to microsatellite stable (MSS) CRCs. Results: MSH CRC’s, 92 germline and 49 sporadic, were compared with 105 MSS CRCs. Compared to MSS CRCs, both germline and sporadic MSH CRCs more commonly arose in the proximal colon (63% and 92%, vs. 30%; p<.001), exhibited mucinous/signet ring histology (40% and 47%, vs. 16%; p<.001) and lymphocytic infiltrate/Crohn’s like reaction (15% and 49%, vs. 8%; p<.001). Further comparison between germline vs. sporadic MSH CRCs revealed significant differences in median age (44 yrs. vs. 66; p<.001), proximal colon tumor location (63% vs. 91%; p<.001), AJCC stage (33% vs. 51% Stage III or IV; p<.025) and presence of lymphocytic/Crohn’s like reaction (49% vs. 15%, p<.001). Moreover, sporadic MSH CRCs more often had poor prognostic features including poor differentiation (51% vs. 28% in germline, p<.025) and lymphovascular invasion (57% vs. 34% in germline, p<.007). No difference was observed in stage-stratified DFS between germline vs sporadic MSH CRCs. Conclusions: Patients with sporadic MSH CRCs exhibit distinct clinicopathologic features compared to those with germline MSH tumors. Despite poor prognostic features, no apparent survival difference was observed. Further characterization of these distinct groups is warranted to explain the discordance between risk factors and outcomes.
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Zhang, Xiaotian, Runqi Hong, Lanxin Bei, Zhiqing Hu, Ximin Yang, Tao Song, Liang Chen, He Meng, Gengming Niu, and Chongwei Ke. "SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition." Open Medicine 17, no. 1 (January 1, 2022): 1390–404. http://dx.doi.org/10.1515/med-2022-0532.
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Abstract Selenium-binding protein 1 (SELENBP1) is frequently dysregulated in various malignancies including colorectal cancer (CRC); however, its roles in progression of CRCs and the underlying mechanism remain to be elucidated. In this study, we compared the expression of SELENBP1 between CRCs and colorectal normal tissues (NTs), as well as between primary and metastatic CRCs; we determined the association between SELENBP1 expression and CRC patient prognoses; we conducted both in vitro and in vivo experiments to explore the functional roles of SELENBP1 in CRC progression; and we characterized the potential underlying mechanisms associated with SELENBP1 activities. We found that the expression of SELENBP1 was significantly and consistently decreased in CRCs than that in adjacent NTs, while significantly and frequently decreased in metastatic than primary CRCs. High expression of SELENBP1 was an independent predictor of favorable prognoses in CRC patients. Overexpression of SELENBP1 suppressed, while silencing of SELENBP1 promoted cell proliferation, migration and invasion, and in vivo tumorigenesis of CRC. Mechanically, SELENBP1 may suppress CRC progression by inhibiting the epithelial–mesenchymal transition.
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Choi, Hong Bae, Jung-Soo Pyo, Soomin Son, Kyungdoc Kim, and Guhyun Kang. "Diagnostic and Prognostic Roles of CDX2 Immunohistochemical Expression in Colorectal Cancers." Diagnostics 12, no. 3 (March 20, 2022): 757. http://dx.doi.org/10.3390/diagnostics12030757.
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The study is aimed to evaluate the diagnostic and prognostic role of the immunohistochemical expression of the Caudal-type homeobox transcription factor 2 (CDX2) in colorectal cancers (CRCs) through a meta-analysis. By searching relevant databases, 38 articles were eligible to be included in this study. We extracted the information for CDX2 expression rates and the correlation between CDX2 expression and clinicopathological characteristics. The estimated rates of CDX2 expression were 0.882 [95% confidence interval (CI) 0.774–0.861] and 0.893 (95% CI 0.820–0.938) in primary and metastatic CRCs, respectively. Furthermore, based on their histologic subtype, CDX2 expression rates of adenocarcinoma and medullary carcinoma were 0.886 (95% CI 0.837–0.923) and 0.436 (95% CI 0.269–0.618), respectively. There was a significant difference in CDX2 expression rates between adenocarcinoma and medullary carcinoma in the meta-regression test (p < 0.001). In addition, CDX2 expression was significantly lower in CRCs with the BRAFV600E mutation than in CRCs without mutation. Patients with CDX2 expression had better overall and cancer-specific survival rates than those without CDX2 expression. Thus, CDX2 is a useful diagnostic and prognostic marker CRCs.
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Chu, Yu-De, Siew-Na Lim, Chau-Ting Yeh, and Wey-Ran Lin. "COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers." Biomedicines 10, no. 1 (December 28, 2021): 60. http://dx.doi.org/10.3390/biomedicines10010060.
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Oxidative phosphorylation (OXPHOS) consists of four enzyme complexes and ATP synthase, and is crucial for maintaining physiological tissue and cell growth by supporting the main bioenergy pool. Cytochrome c oxidase (COX) has been implicated as a primary regulatory site of OXPHOS. Recently, COX subunit 5B (COX5B) emerged as a potential biomarker associated with unfavorable prognosis by modulating cell behaviors in specific cancer types. However, its molecular mechanism remains unclear, particularly in colorectal cancers (CRCs). To understand the role of COX5B in CRCs, the expression and postoperative outcome associations using independent in-house patient cohorts were evaluated. A higher COX5B tumor/nontumor expression ratio was associated with unfavorable clinical outcomes (p = 0.001 and 0.011 for overall and disease-free survival, respectively. In cell-based experiments, the silencing of COX5B repressed cell growth and enhanced the susceptibility of CRCs cells to anticancer drugs. Finally, downstream effectors identified by RNA sequencing followed by RT-qPCR and functional compensation experiments revealed that the tight junction protein Claudin-2 (CLDN2) acts downstream of COX5B-mediated bioenergetic alterations in controlling cell growth and the sensitivity to anticancer drugs in CRCs cells. In conclusion, it was found that COX5B promoted cell growth and attenuated anticancer drugs susceptibility in CRCs cells by orchestrating CLDN2 expression, which may contribute to unfavorable postoperative outcomes of patients with CRCs.
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Bongartz, Lennart G., Siddarth Soni, Maarten-Jan Cramer, Paul Steendijk, Carlo A. J. M. Gaillard, Marianne C. Verhaar, Pieter A. Doevendans, Toon A. van Veen, Jaap A. Joles, and Branko Braam. "Neuronal Nitric Oxide Synthase-Dependent Amelioration of Diastolic Dysfunction in Rats with Chronic Renocardiac Syndrome." Cardiorenal Medicine 5, no. 1 (2015): 69–78. http://dx.doi.org/10.1159/000370052.
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We have recently described the chronic renocardiac syndrome (CRCS) in rats with renal failure, cardiac dysfunction and low nitric oxide (NO) availability by combining subtotal nephrectomy and transient low-dose NO synthase (NOS) inhibition. Cardiac gene expression of the neuronal isoform of NOS (nNOS) was induced. Hence, we studied the role of nNOS, in vivo cardiac function and β-adrenergic response in our CRCS model by micromanometer/conductance catheter. Left ventricular (LV) hemodynamics were studied during administration of dobutamine (dobu), the highly specific irreversible inhibitor of nNOS L-VNIO [L-N5-(1-Imino-3-butenyl)-ornithine], or both at steady state and during preload reduction. Rats with CRCS showed LV systolic dysfunction at baseline, together with prolonged diastolic relaxation and rightward shift of the end-systolic pressure-volume relationships. After L-VNIO infusion, diastolic relaxation of CRCS rats further prolonged. The time constant of active relaxation (tau) increased by 25 ± 6% from baseline (p < 0.05), and the maximal rate of pressure decrease was 36 ± 7% slower (p < 0.001). These variables did not change in controls. In our CRCS model, nNOS did not seem to affect systolic dysfunction. In summary, in this model of CRCS, blockade of nNOS further worsens diastolic dysfunction and L-VNIO does not influence inherent contractility and the response to dobu stress.
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Kim, Dong Uk, Min Ji Lim, and Yoonkyoung Cho. "Comprehensive characterization of single circulating rare cells through automated picking and high-throughput mRNA profiling in patients with pancreatic cancer." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 271. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.271.
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271 Background: Circulating rare cells (CRCs) such as circulating tumor cells (CTCs), tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression. However, there are limited reports characterizing single CRCs comprehensively because of technical limitations including isolation and analysis of rare cells. We aimed to test the feasibility of the automated picking and mRNA profiling platforms of CRCs for evaluating the phenotypic heterogeneity of CRCs and the relationship between clinical outcomes and CRCs in patients with pancreatic cancer. Methods: CRCs were collected from 3ml of whole blood in 4 patients with pancreatic cancer using filter-based lab-on-a-disc platform. The filter membrane was transferred to ALS CellCelector (ALS, Germany) which is picking single nucleated CD45 negative cells to 96-well plate. The single cells were analyzed with the BioMark HD (Fluidigm, USA) which is digital PCR-based mRNA profiling for 48 markers such as epithelial, mesenchymal, stem-like, macrophage, fibroblast, oncogenic and immunogenic markers. Results: CRCs were detected in 3 of 4 patients (75%). Sixty-six-year-old female who had large pancreatic cancer with liver and lung metastasis presented 13 single rare cells including 7 epithelial CTCs with hematopoietic features (CD45 and CD14 positive), 3 mesenchymal CTCs, 2 stem-like CTCs, and 1 CAF. One epithelial CTC with hematopoietic features and one stem-like CTC were detected in 51-year-old male and 61-year-old female with metastatic pancreatic cancer, respectively. There was no CTC in 80-year-old male with localized pancreatic cancer. Conclusions: The automated picking and mRNA profiling platforms showed the feasibility of showing tumor heterogeneity and predicting clinical outcomes in patients with pancreatic cancer.
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Buffart, Tineke, Robin Beekhof, Rosanne van den Oord, Richard R. de Haas, Thang V. Pham, Henk Dekker, Nicole C. T. van Grieken, et al. "Comparison of phosphoproteomic profiles in left- and right-sided colorectal cancers." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 582. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.582.
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582 Background: Left- and right-sided colorectal cancers (CRCs) are different in terms of prognosis, treatment response and underlying molecular mechanisms. The aim of this study was to unravel the phosphoproteomic profiles of left- and right-sided primary CRCs and to identify potential drug targets for both primary tumor sites. Methods: In total phosphoproteomic profiles of 69 fresh-frozen biopsies, including 34 left-sided and 35 right-sided primary CRCs, were obtained by LC-MS/MS after cell lysis, digestion and phosphopeptide enrichment using anti-phosphotyrosine antibodies. MS/MS spectra were searched against a UniProt human reference proteome FASTA file using MaxQuant software. Fold changes between normalized intensities were calculated. Group comparison was performed using the R package Limma. P values below 0.01 and fold changes > two were considered significant and biologically relevant. Results: In total 2,840 phosphopeptides were detected in at least 5% of the samples. Of these, 36 phosphopeptides were significantly upregulated and 14 were significantly downregulated in right-sided compared to left-sided CRCs using our stringent selection criteria. Since BRAF mutations and deficient DNA mismatch repair (dMMR) were more frequently observed in right-sided CRC (p < 0.01), group comparison was repeated with MMR proficient CRCs only, resulting in 21 phosphopeptides up- and one downregulated in left- versus right-sided CRC. The identified phosphoproteins from the phosphopeptides included three FDA approved drug targets. Conclusions: Differences in phosphoproteomic profiles were detected between left- and right-sided CRCs, besides molecular differences such as BRAF mutation and MMR status. These results indicate that the molecular biology of left-and right-sided CRCs may explain their differences in clinical behavior and response to treatment.
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Wei, Zhen, Ke Yang, Xiang He, Xiaolou Chi, Xinyuan Zhao, and Jiqiang Zhang. "Mechanical Characteristics and Energy Dissipation Trends of Coal-Rock Combination System Samples with Different Inclination Angles under Uniaxial Compression." Geofluids 2021 (August 12, 2021): 1–12. http://dx.doi.org/10.1155/2021/7702751.
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Coal mines are composed of multiple complex rock strata with different mechanical characteristics and energy accumulation and release performances. This implies uneven energy distribution in the coal-rock combination system (CRCS). To explore the effect of the included angle between the loading direction and the coal-rock contact surface on the mechanical properties, crack propagation mode, and energy evolution characteristics of the CRCS, the uniaxial compression tests were carried out on the CRCS samples with zero and 30° inclination angles. The obtained mechanical properties and energy dissipation trends of the tested samples were similar to those of the pure (raw) coal and rock ones but strongly depended on the inclination angles. The impact energy index of the CRCS samples was smaller than those of the pure coal and pure rock samples, and its impact tendency was less pronounced. The deformation and failure of the CRCS samples occurred in the coal part, the rock part inhibiting the development and deformation of the coal. According to the deformation and failure characteristics of the CRCS, the coal support far away from the contact surface should be strengthened in engineering practice to avoid the rock mass failure caused by the expansion and evolution of cracks in the coal part. At a 30° inclination angle, the CRCS sample was tensioned at the coal-rock contact surface, and the original cracks and pores were gradually compacted under the stress component perpendicular to the contact surface. With an increase in the inclination angle, the difference between the total energy accumulated before the peak and the released energy after the peak was reduced, and the difference between the total energy accumulated before the peak and the dissipated energy increased gradually. CRCS samples with different inclinations exhibited three damage stages: initial damage, stable damage growth, and rapid damage growth. The results obtained are considered instrumental in rockburst preventing, monitoring, and early warning under different stress environments.
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Elsas, Caroline, Holly LaDuca, Jessica Profato, and Bryan Mak. "Importance of genetic testing for patients with multiple colorectal cancer primaries." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 528. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.528.
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528 Background: Individuals with hereditary colorectal cancer (CRC) may be at increased risk for a second primary CRC. Therefore, a personal history of multiple CRCs may be considered an indication for genetic testing. Methods: Multi-gene panel test (MGPT) results and age at CRC diagnoses were reviewed for 7046 CRC patients who underwent testing from March 2012 to June 2016. Depending on the panel ordered, analysis of up to 49 genes associated with CRC and/or other cancers was performed. The diagnostic yield and age at CRC diagnoses were compared between patients with a history of one CRC (n=6739) and those with two or more CRCs (n=307). Results: Individuals with a history of multiple CRCs had an overall positive rate of 23.8% (n=73), as compared to 12.4% (n=836) in those with a history of one CRC (OR=2.2; p=1.1E-7; 95%CI [1.653,2.907]). In the multiple CRCs group, 77 mutations were identified as follows: MLH1 (n=29), MSH2 (n=18), MSH6 (n=5), PMS2 (n=5), biallelic MUTYH (n=5), CHEK2 (n=5), APC (n=2), BRCA2 (n=3), RAD50 (n=1), BRIP1 (n=1), BRCA1 (n=1), ATM (n=1), and PTEN(n=1). Four patients carried mutations in two different genes. Of the mutation-positive patients with multiple CRCs, 72.6% were diagnosed with their first CRC before age 50, as compared to 59.3% of mutation-positive patients with one CRC. Consequently, the mutation-positive rate increased to 36.3% in patients with multiple CRCs whose first CRC was diagnosed before age 50; whereas it was 12.4% for patients diagnosed with both CRCs at age 50 or above. Conclusions: Overall, individuals with multiple CRCs were approximately twice as likely to be mutation-positive than those with a history of one CRC. This data highlights the importance of genetic testing for those with multiple CRCs, particularly in cases where the first CRC is diagnosed before age 50. Additionally, genetic testing of patients with early onset CRC at the time of diagnosis has the potential to capture patients who may benefit from consideration of additional options to reduce their risk of developing a secondary CRC. Furthermore, mutations were identified in various genes associated with extra-colonic cancers, presenting additional opportunities for cancer risk reduction in patients and their relatives.
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Abou-Bakr, Amany A., Alshaymaa A. Abdelaziz, Ibrahim A. Malash, Osman Mansour, Ibrahim M. Abdelsalam, Omnia M. Abo-Elazm, Heba A. Ibrahim, Mai S. Mohammed, and Rasha Khairy. "The Prognostic Significance of c-Met and p53 Immunohistochemical Expression in Gastric and Colorectal Carcinomas." Open Access Macedonian Journal of Medical Sciences 9, A (March 19, 2021): 134–42. http://dx.doi.org/10.3889/oamjms.2021.5910.
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BACKGROUND: Colorectal and gastric carcinomas are the most common and deadly gastrointestinal (GIT) malignancies. AIM: This study aimed to evaluate the expression of c-Met and p53 in gastric and colorectal carcinomas (CRCs) as well as colorectal adenomas using immunohistochemistry. MATERIALS AND METHODS: c-Met and p53 immunohistochemical expression was conducted on 66 cases of gastric adenocarcinomas and total of 60 colonic cases (36 CRCs and 24 colorectal adenomas). RESULTS: In this study, c-Met was positively expressed in 54.5% of gastric carcinomas and 50% of CRCs. In addition, p53 was positively expressed in 56.1% of gastric carcinomas and 72.2% of CRCs. Moreover, higher expression of both c-Met (p = 0.001) and p53 expression (p < 0.001) was reported in CRCs compared to colorectal adenomas. In the same context, c-Met and p53 expressions were positively correlated with intestinal type gastric adenocarcinoma (p < 0.001 and p = 0.03, respectively). Moreover, c-Met was correlated with non-mucinous adenocarcinomas (p = 0.008) and lower grades (p < 0.001) of gastric carcinomas. As regard survival analysis in gastric carcinomas, median overall survival (OS) was better in p53 positive patients (p = 0.05), patients with negative lymph node metastasis (p = 0.03), and patients with better response to neoadjuvant chemotherapy (p = 0.04). In contrast, c-Met did not exhibit significant correlation with OS (p > 0.05). Both c-Met and p53 did not reveal significant correlation with tumor stage and site in both CRCs and gastric carcinomas (p > 0.05). CONCLUSION: We concluded that c-Met and p53 are expressed in the most common GIT malignancies addressing them as potential biomarkers. In addition, c- Met and p53 may have a potential role in colorectal cancer development as they showed higher positivity in CRCs compared to adenomas.
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Perna, Cristian, Antonia Navarro, Ignacio Ruz-Caracuel, Tamara Caniego-Casas, Eva Cristóbal, Susanna Leskelä, Federico Longo, et al. "Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma." Cancers 13, no. 2 (January 10, 2021): 233. http://dx.doi.org/10.3390/cancers13020233.
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High grade colorectal carcinomas (HG-CRCs), which comprise 15% of colorectal carcinomas, are underrepresented in reported molecular studies. Clinicopathological, immunohistochemical, and molecular features of 40 HG-CRCs are described. Moreover, glandular and solid areas of 25 tumors were separately analyzed. The expression of MLH1, PMS2, MSH2, MSH6, p53, E-cadherin, CDX2, CK20, CD8, PDL1, PAN-TRK, c-MET, SMARCB1, ARID1A, SMARCA2, and SMARCA4 was analyzed by immunohistochemistry. Promoter MLH1 methylation was analyzed in tumors with MLH1/PMS2 loss. Next-generation sequencing was used to screen 161 genes for hotspot mutations, copy number variations and gene fusions. In this series, 72.5% of HG-CRCs showed mismatch repair deficiency (MMRd). MMR deficient tumor and MMR proficient (MMRp) tumors showed striking molecular differences. Thus, whereas BRAF mutations were only observed in MMRd tumors, mutations in KRAS and TP53 were more frequent in MMR proficient tumors. Moreover, gene fusions (NTRK1 and MET) were detected only in MMRd tumors, whereas gene amplification (MYC, CCND1 and EGFR) predominated in MMRp/TP53-mutated tumors. Loss of expression of proteins involved in chromatin remodeling, such as ARID1A, was observed only in MMRd HG-CRCs, which also showed more frequently PD-L1 expression and a higher number of tumor infiltrating lymphocytes. The separate analysis of glandular and solid areas indicated that the clonal or subclonal nature of the molecular alterations also depended on MMR status. Mutations in genes such as TP53 and KRAS were always clonal in MMRp-CRCs but occurred as subclonal events in MMRd-CRCs. Gene amplification was implicated in the progression of MMRp tumors, but not in MMRd tumors, in which clonal diversity was due to accumulation of mutations in genes of different pathways such as NOTCH, MMR, or PIK3CA. In summary, intertumor and intratumor molecular heterogeneity in HG-CRCs is mainly due to MMR status.