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Article ; Online: Nucleic acid-based markers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Nikolic, Aleksandra / Krivokapic, Zoran

2022 Volume 41, Page(s) 101743

Abstract: The progress that has been made in the treatment of rectal cancer has mostly resulted from multimodality strategy approach that combines surgery, chemotherapy and radiotherapy. In locally advanced rectal cancer (LARC), surgery remains the primary ... ...

Abstract	The progress that has been made in the treatment of rectal cancer has mostly resulted from multimodality strategy approach that combines surgery, chemotherapy and radiotherapy. In locally advanced rectal cancer (LARC), surgery remains the primary treatment, while neoadjuvant chemoradiotherapy (nCRT) is used to downsize or downstage the tumor before surgical resection. Highly variable response to nCRT observed in LARC patients raises the need for biomarkers to enable prediction and evaluation of treatment response in a more efficient and timely manner than currently available tools. The search for predictive biomarkers continues beyond blood proteins, which have failed in subsequent validation studies. This review presents nucleic acids-based markers and their predictive potential in LARC patients. Most of the candidate biomarkers come from relatively small single-institution studies. The only candidate biomarker that emerged as relevant in more than a single study was elevated levels of Fusobacterium nucleatum nucleic acids in tumor tissue. Considering that this marker is easily accessible through non-invasive analysis of faecal samples, its predictive potential is worth further validation. The other candidate nucleic acid-based biomarkers require more consistent studies on larger cohorts before they can be considered for use in clinical setting.
MeSH term(s)	Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Chemoradiotherapy ; Humans ; Neoadjuvant Therapy/methods ; Neoplasms, Second Primary ; Nucleic Acids/therapeutic use ; Rectal Neoplasms/pathology ; Retrospective Studies ; Treatment Outcome
Chemical Substances	Biomarkers, Tumor ; Nucleic Acids
Language	English
Publishing date	2022-03-24
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1107810-8
ISSN	1879-3320 ; 0960-7404
ISSN (online)	1879-3320
ISSN	0960-7404
DOI	10.1016/j.suronc.2022.101743
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Article: Jejunal gastrointestinal stromal tumour: a rare cause of severe small bowel bleeding.

Jankovic, Katarina / Krivokapic, Zoran / Jovanovic, Ivan

Przeglad gastroenterologiczny

2023 Volume 18, Issue 4, Page(s) 451–453

Language	English
Publishing date	2023-07-20
Publishing country	Poland
Document type	Journal Article
ZDB-ID	2596134-2
ISSN	1897-4317 ; 1895-5770
ISSN (online)	1897-4317
ISSN	1895-5770
DOI	10.5114/pg.2023.129946
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Article ; Online: SMAD4-201 transcript as a putative biomarker in colorectal cancer.

Babic, Tamara / Dragicevic, Sandra / Miladinov, Marko / Krivokapic, Zoran / Nikolic, Aleksandra

BMC cancer

2022 Volume 22, Issue 1, Page(s) 72

Abstract: Background: Transcripts with alternative 5'-untranslated regions (UTRs) result from the activity of alternative promoters and they can determine gene expression by influencing its stability and translational efficiency, thus executing complex regulation ...

Abstract	Background: Transcripts with alternative 5'-untranslated regions (UTRs) result from the activity of alternative promoters and they can determine gene expression by influencing its stability and translational efficiency, thus executing complex regulation of developmental, physiological and pathological processes. Transcriptional regulation of human SMAD4, a key tumor suppressor deregulated in most gastrointestinal cancers, entails four alternative promoters. These promoters and alternative transcripts they generate remain unexplored as contributors to the SMAD4 deregulation in cancer. The aim of this study was to investigate the relative abundance of the transcript SMAD4-201 in colorectal cell lines and tissues in order to establish if its fluctuations may be associated with colorectal cancer (CRC). Methods: Relative abundance of SMAD4-201 in total SMAD4 mRNA was analyzed using quantitative PCR in a set of permanent human colon cell lines and tumor and corresponding healthy tissue samples from patients with CRC. Results: The relative abundance of SMAD4-201 in analyzed cell lines varied between 16 and 47%. A similar relative abundance of SMAD4-201 transcript was found in the majority of analyzed human tumor tissue samples, and it was averagely 20% lower in non-malignant in comparison to malignant tissue samples (p = 0.001). Transcript SMAD4-202 was not detectable in any of the analyzed samples, so the observed fluctuations in the composition of SMAD4 transcripts can be attributed to transcripts other than SMAD4-201 and SMAD4-202. Conclusion: The expression profile of SMAD4-201 in human tumor and non-tumor tissue samples may indicate the translational potential of this molecule in CRC, but further research is needed to clarify its usability as a potential biomarker for early diagnosis.
MeSH term(s)	Animals ; Biomarkers, Tumor/genetics ; Case-Control Studies ; Cell Line, Tumor ; Colon/metabolism ; Colorectal Neoplasms/genetics ; Humans ; Mice ; Polymerase Chain Reaction ; Smad4 Protein/genetics
Chemical Substances	Biomarkers, Tumor ; SMAD4 protein, human ; Smad4 Protein ; Smad4 protein, mouse
Language	English
Publishing date	2022-01-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-022-09186-z
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Article ; Online: Genetic analysis and allele-specific expression of SMAD7 3'UTR variants in human colorectal cancer reveal a novel somatic variant exhibiting allelic imbalance.

Rosic, Jovana / Miladinov, Marko / Dragicevic, Sandra / Eric, Katarina / Bogdanovic, Aleksandar / Krivokapic, Zoran / Nikolic, Aleksandra

Gene

2023 Volume 859, Page(s) 147217

Abstract: Background: Considering the impact of SMAD7 deregulation in colorectal cancer (CRC) progression and the significance of single nucleotide variant (SNV)-mediated disruptions of microRNA (miRNA)-dependent regulation for cancer susceptibility, our study ... ...

Abstract	Background: Considering the impact of SMAD7 deregulation in colorectal cancer (CRC) progression and the significance of single nucleotide variant (SNV)-mediated disruptions of microRNA (miRNA)-dependent regulation for cancer susceptibility, our study aimed to analyze genetic variation in the SMAD7 3' untranslated region ( 3'UTR) in CRC, measure differences in allelic mRNA expression, and evaluate its interference with miRNA-mediated post-transcriptional regulation. Patients and methods: This study included 80 patients with different CRC stages and six human colon cancer cell lines of various histological origins. SMAD7 3'UTR was analyzed by direct sequencing, followed by the relative quantification of differential allelic expression of detected variants by allele-specific qRT-PCR. In silico tools were employed for predictions of regulatory consequences of detected variants. Results: A total of four different SNVs in one cell line and nine patients were found, among which were a novel somatic point variant and three already known germline variants (rs16950113, rs1050799536, and rs1043778717). All evaluated SNVs exhibited variable extents of allelic imbalance in expression. In silico analysis predicted significant effects of SNVs on miRNA binding efficiency, with each SNV disrupting existing and creating new target sites for one or more miRNAs. Conclusion: Imbalance observed in the expression of SNV alleles altering miRNA binding suggests that all investigated SNVs are potential contributing factors impacting SMAD7 expression regulation in CRC that further studies should investigate.
MeSH term(s)	Humans ; 3' Untranslated Regions ; Alleles ; Allelic Imbalance ; Colorectal Neoplasms/genetics ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Polymorphism, Single Nucleotide ; Smad7 Protein/genetics ; Smad7 Protein/metabolism
Chemical Substances	3' Untranslated Regions ; MicroRNAs ; Smad7 Protein ; SMAD7 protein, human
Language	English
Publishing date	2023-01-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2023.147217
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Article: Perceived stress among university students in south-east Serbia during the COVID-19 outbreak.

Kostić, Jelena / Žikić, Olivera / Đorđević, Vladimir / Krivokapić, Žilijeta

Annals of general psychiatry

2021 Volume 20, Issue 1, Page(s) 25

Abstract: Background: The COVID-19 pandemic has brought into focus the mental health of the student population. The study aimed to analyze the psychological response to the COVID-19 outbreak in terms of perceived stress and its related factors among university ... ...

Abstract	Background: The COVID-19 pandemic has brought into focus the mental health of the student population. The study aimed to analyze the psychological response to the COVID-19 outbreak in terms of perceived stress and its related factors among university students in south-east Serbia. The study was conducted during the increased incidence of COVID-19 in Serbia. Method: A total of 434 students from the public university in south-east Serbia enrolled in the study and completed the measures of socio-demographic data, the perceived stress scale (PSS-10), the Coping Strategy Indicator (CSI) and the General Health Questionnaire (GHQ-28). The data were analyzed through quantitative and qualitative methods. Results: Study findings suggest that the mean perceived stress score was placed to 20.43 (± 7.67). Our model showed that female gender, higher scores on anxiety/insomnia and depression subscale as well as the coping strategy avoidance predicted higher perceived stress, while higher scores on social dysfunction were related to the reduced perceived stress scores. CONCLUSION: Notwithstanding the study limitation, findings provided authentic data of stress reactions of the students in south-east Serbia during the COVID-19 outbreak. The findings confirm the need to examine students' experiences in emergencies and crises, as well as to make a plan for online stress management programs that would help alleviate stress during a global pandemic.
Language	English
Publishing date	2021-04-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2090401-0
ISSN	1744-859X ; 1475-2832
ISSN	1744-859X ; 1475-2832
DOI	10.1186/s12991-021-00346-2
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Article: Prognostic potential of circulating miR-93-5p in patients with colorectal cancer liver metastases.

Despotović, Jovana / Bogdanović, Aleksandar / Dragičević, Sandra / Galun, Danijel / Krivokapić, Zoran / Nikolić, Aleksandra

Neoplasma

2022 Volume 69, Issue 2, Page(s) 430–442

Abstract: This study aimed to examine the expression pattern of tumoral and circulating miR-93-5p in patients with colorectal cancer (CRC) liver metastasis (CRLM) and to explore its predictive and prognostic potential. CRLM tissue, surrounding non-tumor liver ... ...

Abstract	This study aimed to examine the expression pattern of tumoral and circulating miR-93-5p in patients with colorectal cancer (CRC) liver metastasis (CRLM) and to explore its predictive and prognostic potential. CRLM tissue, surrounding non-tumor liver tissue, and serum were obtained from 35 patients with CRLM. The expression pattern of tissue and circulating miR-93-5p in patients with CRLM was determined using quantitative polymerase chain reaction, using miR-16-5p for normalization. Sample-based cut-off values for CRLM and serum miR-93-5p expression were calculated using Receiver Operating Characteristic curve analysis to stratify the patients into high and low miR-93-5p expression groups which were that compared with patients' clinicopathological data, therapy response, one-year disease-free survival, and disease recurrence. Relative miR-93-5p expression was higher in CRLM in comparison to the non-metastatic liver tissue (p<0.001). CRLM miR-93-5p expression showed moderate negative correlation with carcinoembryonic antigen levels (r=-0.406; p=0.016). There were no differences in high-/low-miR-93-5p expression and therapy responders vs. non-responders, which was confirmed in vitro using metastatic and normal colonic cells SW620 and HCEC-1CT, respectively. No difference was observed in one-year recurrence-free survival in patients with high vs. low miR-93-5p expression in CRLM or serum. However, high miR-93-5p serum levels were significantly associated with early disease recurrence (p=0.035). In conclusion, miR-93-5p serum levels could be potentially used as a prognostic factor for early disease recurrence in CRLM patients.
MeSH term(s)	Biomarkers, Tumor ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Humans ; Liver Neoplasms/secondary ; MicroRNAs/metabolism ; Neoplasm Recurrence, Local ; Prognosis
Chemical Substances	Biomarkers, Tumor ; MIRN93 microRNA, human ; MicroRNAs
Language	English
Publishing date	2022-01-18
Publishing country	Slovakia
Document type	Journal Article
ZDB-ID	415445-9
ISSN	0028-2685
ISSN	0028-2685
DOI	10.4149/neo_2021_210603N749
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Article: Matrix Metalloproteinase-2 and -9, Lactate, and Malate Dehydrogenase and Lipid Peroxides in Sera of Patients with Colorectal Carcinoma.

Gopcevic, K / Rovcanin, B / Kekic, D / Krivokapic, Z / Dragutinovic, V

Folia biologica

2017 Volume 63, Issue 5-6, Page(s) 190–196

Abstract: Matrix metalloproteinases (MMPs) are involved in tumour invasion and metastasis of colorectal carcinoma. Oxidative stress represents one of the possible mechanisms that activate inactive MMPs. Oxidative stress increases lipid peroxidation, which causes ... ...

Abstract	Matrix metalloproteinases (MMPs) are involved in tumour invasion and metastasis of colorectal carcinoma. Oxidative stress represents one of the possible mechanisms that activate inactive MMPs. Oxidative stress increases lipid peroxidation, which causes impaired membrane permeability and leakage of lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) into circulation. Our aim was to assess the activity of MMP-2 and MMP-9 and its relation to the parameters of oxidative stress and membrane damage markers in patients with different TNM (tumour, lymph nodes, metastasis) stages of colorectal carcinoma. MMP-2 and -9 activities were evaluated by gelatin zymography. Oxidative stress was examined by quantifying serum malondialdehyde (MDA) concentration. LDH and MDH activities were determined spectrophotometrically. The activities of MMP-2 and -9 were significantly higher in the sera of colorectal carcinoma patients when compared to healthy subjects. There was a stage-dependent increase in relative MMP-2 activity compared to the overall serum gelatinolytic activity. The activity of MMP-9 was the highest in TNM III. The MDA concentration and the LDH and MDH activities were significantly higher in colorectal carcinoma patients than in controls, while LDH and MDH activities were stage dependent. There was significant correlation between serum MMP-2 and LDH activity in TNM II, III and IV patients. A stage-dependent increase of LDH and MDH activity was observed. We highlight here that MMP-9 could be a 100% sensitive marker of TNM stage III of colorectal carcinogenesis. In this study it was shown for the first time that gelatinolytic activity in colorectal carcinoma is associated with redox imbalance.
MeSH term(s)	Colorectal Neoplasms/metabolism ; Female ; Humans ; Lipid Peroxides/metabolism ; Malate Dehydrogenase/metabolism ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Peroxides/metabolism
Chemical Substances	Lipid Peroxides ; Peroxides ; Malate Dehydrogenase (EC 1.1.1.37) ; malate dehydrogenase (decarboxylating) (EC 1.1.1.39) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2017-12-29
Publishing country	Czech Republic
Document type	Journal Article
ZDB-ID	419223-0
ISSN	0015-5500
ISSN	0015-5500
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Article ; Online: Detection of Somatic Mutations with ddPCR from Liquid Biopsy of Colorectal Cancer Patients.

Zmrzljak, Uršula Prosenc / Košir, Rok / Krivokapić, Zoran / Radojković, Dragica / Nikolić, Aleksandra

Genes

2021 Volume 12, Issue 2

Abstract: Liquid biopsy and cell-free DNA (cfDNA) show great promise in cancer diagnostics. In this study, we designed a custom droplet digital PCR (ddPCR) assay for the quantification and quality control of cfDNA isolated from serum. The assay was validated on a ... ...

Abstract	Liquid biopsy and cell-free DNA (cfDNA) show great promise in cancer diagnostics. In this study, we designed a custom droplet digital PCR (ddPCR) assay for the quantification and quality control of cfDNA isolated from serum. The assay was validated on a group of locally advanced colorectal cancer (CRC) patients and two control groups-patients with hemorrhoids and healthy individuals. The assay shows a high correlation with Qubit measurement (r = 0.976) but offers a higher dynamic range. Mean concentrations of cfDNA were 12.36 ng/µL, 5.17 ng/µL, and 0.29 ng/µL for CRC, hemorrhoid patients, and healthy controls, respectively. The quality of cfDNA was assessed with the measurement of B-cell DNA contamination. On a subset of CRC patients, we compared the mutation status on KRAS (G12A, G12D, G12V, G13D) and BRAF (V600E) genes in the primary tumor and cfDNA isolated from the serum. A total of 70.6% of primary tumor samples were mutated, and the mean fractional abundance of mutations was 9.50%. The matching serum samples were mutated in 38% cases with an average fractional abundance of 0.23%. We conclude that any decisions based solely on the amount of cfDNA present in patient serum must be interpreted carefully and in the context of co-morbidities. This study explores the potential of ddPCR somatic mutations detection from liquid biopsy as a supplement to tissue biopsy in targeted personalized CRC patient management.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Cell-Free Nucleic Acids/blood ; Cell-Free Nucleic Acids/genetics ; Circulating Tumor DNA ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Female ; Humans ; Liquid Biopsy ; Male ; Middle Aged ; Mutation/genetics ; Proto-Oncogene Proteins B-raf/blood ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/blood ; Proto-Oncogene Proteins p21(ras)/genetics
Chemical Substances	Biomarkers, Tumor ; Cell-Free Nucleic Acids ; Circulating Tumor DNA ; KRAS protein, human ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2021-02-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12020289
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Article: Prognostic Significance of

Bogdanovic, Aleksandar / Despotovic, Jovana / Galun, Danijel / Bidzic, Nemanja / Nikolic, Aleksandra / Rosic, Jovana / Krivokapic, Zoran

Cancer management and research

2021 Volume 13, Page(s) 163–171

Abstract: Purpose: There are limited data on expression of epithelial-mesenchymal transition (EMT) markers in patients with colorectal liver metastases (CRLM). The study aim was to evaluate the expression and prognostic significance of E-cadherin (: Patients ... ...

Abstract	Purpose: There are limited data on expression of epithelial-mesenchymal transition (EMT) markers in patients with colorectal liver metastases (CRLM). The study aim was to evaluate the expression and prognostic significance of E-cadherin ( Patients and methods: Thirty patients with CRLM managed by curative-intent liver resection were included in this prospective pilot study. Blood samples, colorectal liver metastases and surrounding non-tumor liver tissue were collected. Expression of Results: The expression of Conclusion: Lower expression of
Language	English
Publishing date	2021-01-11
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2508013-1
ISSN	1179-1322
ISSN	1179-1322
DOI	10.2147/CMAR.S287974
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Article ; Online: SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response.

Rosic, Jovana / Dragicevic, Sandra / Miladinov, Marko / Despotovic, Jovana / Bogdanovic, Aleksandar / Krivokapic, Zoran / Nikolic, Aleksandra

Experimental and molecular pathology

2021 Volume 123, Page(s) 104714

Abstract: Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-β signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to ... ...

Abstract	Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-β signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value.
MeSH term(s)	Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/radiotherapy ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Signal Transduction/drug effects ; Signal Transduction/radiation effects ; Smad4 Protein/genetics ; Smad7 Protein/genetics ; Transforming Growth Factor beta/genetics
Chemical Substances	SMAD4 protein, human ; SMAD7 protein, human ; Smad4 Protein ; Smad7 Protein ; Transforming Growth Factor beta
Language	English
Publishing date	2021-10-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207655-x
ISSN	1096-0945 ; 0014-4800
ISSN (online)	1096-0945
ISSN	0014-4800
DOI	10.1016/j.yexmp.2021.104714
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