"PROGRESS Q39"
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The liquid biopsy has the potential to improve current clinical practice in oncology by providing real-time personalized information about a patient's disease status and response to treatment. In this study, we evaluated 161 peripheral blood (PB) samples that were collected around surgical resection from 47 metastatic colorectal cancer (mCRC) patients using the High-Definition Single Cell Assay (HDSCA) workflow. In conjunction with the standard circulating tumor cell (CTC) enumeration, cellular morphology and kinetics between time-points of collection were considered in the survival analysis. CTCs, CTC-Apoptotic, and CTC clusters were found to indicate poor survival with an increase in cell count from pre-resection to post-resection. This study demonstrates that CTC subcategorization based on morphological differences leads to nuanced results between the subtypes, emphasizing the heterogeneity within the CTC classification. Furthermore, we show that factoring in the time-point of each blood collection is critical, both for its static enumeration and for the change in cell populations between draws. By integrating morphology and time-based analysis alongside standard CTC enumeration, liquid biopsy platforms can provide greater insight into the pathophysiology of mCRC by highlighting the complexity of the disease across a patient's treatment.
- Publikační typ
- časopisecké články MeSH
Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.
- Publikační typ
- časopisecké články MeSH
Breast cancer is the most frequent cancer in the female population worldwide. The role of germline genetic variability in cytochromes P450 (CYP) in breast cancer prognosis and individualized therapy awaits detailed elucidation. In the present study, we used the next-generation sequencing to assess associations of germline variants in the coding and regulatory sequences of all human CYP genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 22 prioritized variants associating with a response or survival in the above evaluation phase were then analyzed by allelic discrimination in the large confirmation set (n = 802). Associations of variants in CYP1B1, CYP4F12, CYP4X1, and TBXAS1 with the response to the neoadjuvant cytotoxic chemotherapy were replicated by the confirmation phase. However, just association of variant rs17102977 in CYP4X1 passed the correction for multiple testing and can be considered clinically and statistically validated. Replicated associations for variants in CYP4X1, CYP24A1, and CYP26B1 with disease-free survival of all patients or patients stratified to subgroups according to therapy type have not passed a false discovery rate test. Although statistically not confirmed by the present study, the role of CYP genes in breast cancer prognosis should not be ruled out. In conclusion, the present study brings replicated association of variant rs17102977 in CYP4X1 with the response of patients to the neoadjuvant cytotoxic chemotherapy and warrants further research of genetic variation CYPs in breast cancer.
- MeSH
- genetická variace * MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- nádorové proteiny * genetika metabolismus MeSH
- nádory prsu * farmakoterapie enzymologie genetika mortalita MeSH
- neoadjuvantní terapie * MeSH
- přežití bez známek nemoci MeSH
- systém (enzymů) cytochromů P-450 * genetika metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
INTRODUCTION AND HYPOTHESIS: Sacrocolpopexy is the preferred contemporary approach to managing significant apical pelvic organ prolapse. Obesity is an established risk factor for several surgical procedures and can have a negative impact on outcomes. Our goal was to evaluate the impact of BMI on the safety and efficacy of laparoscopic sacrocolpopexy in women with pelvic organ prolapse. METHODS: A single-center retrospective observational study of women undergoing laparoscopic sacrocolpopexy between January 1, 2015, and December 31, 2017. RESULTS: We found 299 procedures: 82 (27.4%), 147 (49.2%) and 70 (23.4%) in women with BMI <25 (normal weight), BMI ≥ 25 - < 30 (overweight) and BMI ≥ 30 (obese), respectively. Perioperative and early postoperative complications were generally low and not statistically significantly different between the groups. At 12 months postoperatively, 81 (98.8%), 136 (92.5%) and 62 (88.6%) normal-weight, overweight and obese women attended their follow-up, respectively. All obese women attending the follow-up scored an overall Patient Global Impression of Improvement (PGI-I) of ≤ 3. The Pelvic Floor Distress Inventory (PFDI) scores showed a significant improvement in all domains and were similar between the study groups. In total, there was one (0.4%) anatomical apical compartment failure, three (1.1%) anterior compartment failures and two (0.7%) posterior compartment failures with no significant differences between the groups. Similarly, there were no differences in functional outcomes or mesh position as assessed by ultrasound. CONCLUSIONS: There were no differences in surgical, short- and long-term outcomes of laparoscopic sacrocolpopexy for pelvic organ prolapse in obese compared with non-obese women.
BACKGROUND: Bisphenol S (BPS) is increasingly used as a replacement for bisphenol A in the manufacture of products containing polycarbonates and epoxy resins. However, further studies of BPS exposure are needed for the assessment of health risks to humans. In this study we assessed the potential harmfulness of low-dose BPS on reproduction in male mice. METHODS: To simulate human exposure under experimental conditions, 8-week-old outbred ICR male mice received 8 weeks of drinking water containing a broad range of BPS doses [0.001, 1.0, or 100 μg/kg body weight (bw)/day, BPS1-3] or vehicle control. Mice were sacrificed and testicular tissue taken for histological analysis and protein identification by nano-liquid chromatography/mass spectrometry (MS) and sperm collected for immunodetection of acetylated lysine and phosphorylated tyrosine followed by protein characterisation using matrix-assisted laser desorption ionisation time-of-flight MS (MALDI-TOF MS). RESULTS: The results indicate that compared to vehicle, 100 μg/kg/day exposure (BPS3) leads to 1) significant histopathology in testicular tissue; and, 2) higher levels of the histone protein γH2AX, a reliable marker of DNA damage. There were fewer mature spermatozoa in the germ layer in the experimental group treated with 1 μg/kg bw (BPS2). Finally, western blot and MALDI-TOF MS studies showed significant alterations in the sperm acetylome and phosphorylome in mice treated with the lowest exposure (0.001 μg/kg/day; BPS1), although the dose is several times lower than what has been published so far. CONCLUSIONS: In summary, this range of qualitative and quantitative findings in young male mice raise the possibility that very low doses of BPS may impair mammalian reproduction through epigenetic modifications of sperm proteins.
- MeSH
- acetylace účinky léků MeSH
- endokrinní disruptory farmakologie MeSH
- epigeneze genetická MeSH
- fenoly farmakologie MeSH
- fosforylace účinky léků MeSH
- myši MeSH
- poškození DNA účinky léků MeSH
- posttranslační úpravy proteinů účinky léků MeSH
- spermie účinky léků MeSH
- sulfony farmakologie MeSH
- testis účinky léků patologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zrání spermie účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
