Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II-IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC.
- MeSH
- dědičné nádorové syndromy * MeSH
- DNA-helikasy genetika metabolismus MeSH
- dospělí MeSH
- epiteliální ovariální karcinom MeSH
- jaderné proteiny genetika MeSH
- karcinom * patologie MeSH
- kolorektální nádory * MeSH
- lidé středního věku MeSH
- lidé MeSH
- malobuněčný karcinom * MeSH
- mladý dospělý MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory endometria * patologie MeSH
- nádory mozku * MeSH
- nádory vaječníků * genetika patologie MeSH
- senioři MeSH
- transkripční faktory genetika metabolismus MeSH
- variabilita počtu kopií segmentů DNA MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-β/SMAD, and β-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.
- MeSH
- Helicobacter pylori * genetika MeSH
- infekce virem Epsteina-Barrové * mikrobiologie patologie MeSH
- infekce vyvolané Helicobacter pylori * mikrobiologie MeSH
- koinfekce * mikrobiologie MeSH
- lidé MeSH
- nádory žaludku * genetika mikrobiologie patologie MeSH
- polarita buněk MeSH
- virové proteiny MeSH
- virus Epsteinův-Barrové genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The human intestine is a habitat for microorganisms and, recently, the composition of the intestinal microbiota has been correlated with the etiology of diseases such as inflammations, sores, and tumors. Although many studies have been conducted to understand the composition of that microbiota, expanding these studies to more samples and different backgrounds will improve our knowledge. In this work, we showed the colon microbiota composition and diversity of healthy subjects, patients with inflammatory bowel disease (IBD), and colon cancer by metagenomic sequencing. Our results indicated that the relative abundance of prokaryotic and eukaryotic microbes differs between the healthy vs. tumor biopsies, tumor vs. IBD biopsies, and fresh vs. paraffin-embedded tumor biopsies. Fusobacterium, Escherichia-Shigella, and Streptococcus genera were relatively abundant in fresh tumor biopsies, while Pseudomonas was significantly elevated in IBD biopsies. Additionally, another opportunist pathogen Malasseziales was revealed as the most abundant fungal clade in IBD biopsies, especially in ulcerative colitis. We also found that, while the Basidiomycota:Ascomycota ratio was slightly lower in tumor biopsies compared to biopsies from healthy subjects, there was a significant increase in IBD biopsies. Our work will contribute to the known diversity of prokaryotic and eukaryotic microbes in the colon biopsies in patients with IBD and colon cancer.
Robotická chirurgie je celosvětově rychle se rozvíjející operační technika, která přináší řadu výhod ve srovnání s dosud většinově užívanými operačními postupy (kratší doba hospitalizace, rychlejší rekonvalescence, menší bolestivost operačních ran, méně infekcí v ráně, nižší riziko kýly v jizvě a méně konverzí). Článek prezentuje kazuistiku pacienta s diagnostikovaným kolorektálním karcinomem v oblasti hepatální flexury a se solitární jaterní metastázou druhého segmentu (SII). Operační výkon byl proveden robotickým systémem DaVinci Xi v rozsahu pravostranné hemikolektomie s intrakorporální anastomózou side-to-side a robotické resekce druhého segmentu jater, bez nutnosti změny umístění (dokování) robotických nástrojů. Použití miniinvazivní robotické techniky a ERAS protokolu výrazně urychlilo pooperační rekonvalescenci a obnovu pasáže, snížilo potřebu analgetik a pacient byl propuštěn pátý poopeční den.
Robotic surgery is a rapidly emerging surgical technique worldwide, which has a number of advantages in comparison to the majority of surgical procedures used so far (shorter hospital stay, faster recovery, less pain at the surgical site, fewer surgical site infections, lower risk of incisional hernia and fewer conversions). We present a patient with colorectal cancer in the hepatic flexure and solitary hepatic metastasis (segment 2). Right-sided hemicolectomy with intracorporeal side-to-side anastomosis was performed with the DaVinci Xi robotic system, as well as robotic resection of the second hepatic segment, without the necessity of changing the location (docking) of the robotic instruments. Use of the minimally invasive robotic technique and ERAS protocol significantly accelerated postoperative recovery, including recovery of peristalsis, reduced the need for analgesics, and the patient was discharged on the 5th postoperative day.
Nádory krčního úseku jícnu jsou vzácným onemocněním, které se standardně léčí samostatnou (definitivní) chemoradioterapií bez chirurgického výkonu. Chemoradioterapie je provázena několika kontroverzemi, z nichž hlavní je nejistota v účinné dávce a přínosu dávkové eskalace. Běžná aplikovaná normofrakcionovaná dávka je přes 60 Gy. Příznivá dávková distribuce predikuje benefit protonové radioterapie (PRT). V PTC Praha lze výsledky PRT hodnotit u 29 nemocných, kteří byli ozařováni do c. d. 70 GyE technikou „pencil beam scanning“ IMPT s konkomitantní chemoterapií carboplatina + paclitaxel. U 18, resp. 7 nemocných byla dosažena kompletní, resp. parciální regrese, response rate je 86,3 %. Medián sledování je 14 měsíců (2,6–66,0). Medián přežívání je 13,7 měs., 2leté přežívání 45 %. Medián doby do relapsu/progrese je 28,7 měs., 2leté přežívání bez relapsu je 52 %. V době analýzy přežívá 13 nemocných, 12 z nich v kompletní regresi onemocnění. Akutní toxicita nepřesahuje stupeň 2 kromě kožní (st. 3 u 22,6 %). Chronická toxicita nepřesahuje st. 2 kromě 2 případů tracheoezofageální píštěle v místě primárního postižení u onemocnění stadia T4. PRT v mírně eskalované dávce s konkomitantní chemoterapií dosáhla vysokou protinádorovou účinnost, naproti tomu parametry přežívání jsou zřejmě vlivem velkého podílu primárně lokoregionálně pokročilých onemocnění méně příznivé. Přesto určitý podíl nemocných dlouhodobě přežívá s kompletní regresí onemocnění. Obligátní výskyt lymfopenie a řada recentních poznatků v protinádorové imunologii vyžaduje rozvahu nad dosavadním konceptem určování objemu a frakcionace.
Cancer of cervical esophagus belongs to rare diseases. Its standard treatment includes definitive chemoradiotherapy without subsequent surgery. There are several controversies concerning chemoradiotherapy, the most substantial of them being uncertain effective dose and uncertain benefit of dose escalation. The doses exceeding 60 Gy in 30 fractions are frequently administered. A benefit of proton radiotherapy (PRT) is predicted by favorable dose distribution. The results of PRT administered in PTC Prague have been assessed in 29 patients who have been irradiated up to 70 Gy (equivalent) in 35 fractions using pencil beam scanning technique with concomitant weekly chemotherapy carboplatinum plus paclitaxel. A complete and partial regression has been achieved in 18 and 7 patients respectively, response rate 86,3%. The median follow up time is 14 months (2,6-66,0). Median survival time is 13,7 months, 2-year survival 45%, median time to relapse/progression 28,7 months and 2-year relapse free survival 52%. 13 patients survive at the time of analysis, 12 in complete regression. The acute toxicity does not exceed the grade 2, except radiation dermatitis (22,6% grade 3). The late toxicity does not exceed grade 2, except tracheoesophageal fistulation in 2 patients with primary T4 lesion. The PRT in moderately escalated dose with concomitant chemotherapy achieved a high antitumor efficacy opposed to less favorable survival results, presumably originating of substantial number of locoregionally advanced diseases. Still a durable complete regression long time survival is being observed in a certain share of patients. A lymphopenia is obligatory and in a scope of recent observations in antitumor immunology it desires a deeper contemplation on target volume and fractionation concept.
- Klíčová slova
- protonová chemoradioterapie,
- MeSH
- chemoradioterapie metody MeSH
- lidé MeSH
- lymfopenie MeSH
- nádory jícnu * farmakoterapie radioterapie MeSH
- protonová terapie * metody MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
Though new targeted therapies for colorectal cancer, which progresses from local intestinal tumors to metastatic disease, are being developed, tumor specificity remains an important problem, and side effects a major concern. Here, we show that the protein-fatty acid complex BAMLET (bovine alpha-lactalbumin made lethal to tumor cells) can act as a peroral treatment for colorectal cancer. ApcMin/+ mice, which carry mutations relevant to hereditary and sporadic human colorectal cancer, that received BAMLET in the drinking water showed long-term protection against tumor development and decreased expression of tumor growth-, migration-, metastasis- and angiogenesis-related genes. BAMLET treatment via drinking water inhibited the Wnt/β-catenin and PD-1 signaling pathways and prolonged survival without evidence of toxicity. Systemic disease in the lungs, livers, spleens, and kidneys, which accompanied tumor progression, was inhibited by BAMLET treatment. The metabolic response to BAMLET included carbohydrate and lipid metabolism, which were inhibited in tumor prone ApcMin/+ mice and weakly regulated in C57BL/6 mice, suggesting potential health benefits of peroral BAMLET administration in addition to the potent antitumor effects. Together, these findings suggest that BAMLET administration in the drinking water maintains antitumor pressure by removing emergent cancer cells and reprogramming gene expression in intestinal and extra-intestinal tissues.
- MeSH
- beta-katenin MeSH
- kolorektální nádory * MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- pitná voda * MeSH
- signální transdukce MeSH
- skot MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
This work reports the first electrochemical bioplatforms developed for the determination of the total contents of either target miRNA or methylated target miRNA. The bioplatforms are based on the hybridization of the target miRNA with a synthetic biotinylated DNA probe, the capture of the formed DNA/miRNA heterohybrids on the surface of magnetic microcarriers, and their recognition with an antibody selective to these heterohybrids or to the N6-methyladenosine (m6A) epimark. The determination of the total or methylated target miRNA was accomplished by labeling such secondary antibodies with the horseradish peroxidase (HRP) enzyme. In both cases, amperometric transduction was performed on the surface of disposable electrodes after capturing the resulting HRP-tagged magnetic bioconjugates. Because of their increasing relevance in colorectal cancer (CRC) diagnosis and prognosis, miRNA let-7a and m6A methylation were selected. The proposed electrochemical bioplatforms showed attractive analytical and operational characteristics for the determination of the total and m6A-methylated target miRNA in less than 75 min. These bioplatforms, innovative in design and application, were applied to the analysis of total RNA samples extracted from cultured cancer cells with different metastatic profiles and from paired healthy and tumor tissues of patients diagnosed with CRC at different stages. The obtained results demonstrated, for the first time using electrochemical platforms, the potential of interrogating the target miRNA methylation level to discriminate the metastatic capacities of cancer cells and to identify tumor tissues and, in a pioneering way, the potential of the m6A methylation in miRNA let-7a to serve as a prognostic biomarker for CRC.
Bafilomycin A1 inhibits V-type H+ ATPases on the molecular level, which acidifies endo-lysosomes. The main objective of the study was to assess the effect of bafilomycin A1 on Ca2+ content, NAADP-induced Ca2+ release, and ATPase activity in rat hepatocytes and human colon cancer samples. Chlortetracycline (CTC) was used for a quantitative measure of stored calcium in permeabilized rat hepatocytes. ATPase activity was determined by orthophosphate content released after ATP hydrolysis in subcellular post-mitochondrial fraction obtained from rat liver as well as from patients' samples of colon mucosa and colorectal cancer samples. In rat hepatocytes, bafilomycin A1 decreased stored Ca2+ and prevented the effect of NAADP on stored Ca2+. This effect was dependent on EGTA-Ca2+ buffers in the medium. Bafilomycin A1 significantly increased the activity of Ca2+ ATPases of endoplasmic reticulum (EPR), but not plasma membrane (PM) Ca2+ ATPases in rat liver. Bafilomycin A1 also prevented the effect of NAADP on these pumps. In addition, bafilomycin A1 reduced Na+/K+ ATPase activity and increased basal Mg2+ ATPase activity in the subcellular fraction of rat liver. Concomitant administration of bafilomycin A1 and NAADP enhanced these effects. Bafilomycin A1 increased the activity of the Ca2+ ATPase of EPR in the subcellular fraction of normal human colon mucosa and also in colon cancer tissue samples. In contrast, it decreased Ca2+ ATPase PM activity in samples of normal human colon mucosa and caused no changes in colon cancer. Bafilomycin A1 decreased Na+/K+ ATPase activity and increased basal Mg2+ ATPase activity in normal colon mucosa samples and in human colon cancer samples. It can be concluded that bafilomycin A1 targets NAADP-sensitive acidic Ca2+ stores, effectively modulates ATPase activity, and assumes the link between acidic stores and EPR. Bafilomycin A1 may be useful for cancer therapy.
- MeSH
- játra metabolismus MeSH
- kolorektální nádory * MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- makrolidy farmakologie MeSH
- nádory tračníku * MeSH
- subcelulární frakce metabolismus MeSH
- vakuolární protonové ATPasy * metabolismus MeSH
- vápník metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
- MeSH
- celogenomová asociační studie MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- represorové proteiny genetika MeSH
- RNA MeSH
- transkriptom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- kolorektální nádory prevence a kontrola MeSH
- lidé MeSH
- nádory děložního čípku prevence a kontrola MeSH
- nádory plic prevence a kontrola MeSH
- nádory prostaty prevence a kontrola MeSH
- nádory prsu prevence a kontrola MeSH
- nádory * diagnóza prevence a kontrola MeSH
- screeningové diagnostické programy * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
