Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.
- Klíčová slova
- colorectal cancer, survival, synchronous and metachronous liver metastases, tumor‐infiltrating lymphocytes,
- MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- dospělí MeSH
- kolorektální nádory * patologie imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetné primární nádory patologie imunologie MeSH
- nádory jater * sekundární imunologie patologie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- sekundární malignity patologie MeSH
- senioři MeSH
- T-lymfocyty imunologie patologie MeSH
- tumor infiltrující lymfocyty imunologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Cannabigerol is a bioactive compound derived from Cannabis sativa. It displays many promising pharmaceutical and nutraceutical properties. Its use and research are complicated by its thermally unstable solid form with low solubility and needle habit, preventing easy formulation into tablets or capsules. To overcome these problems, we conducted a crystallization screening with the aim to discover new crystal forms with enhanced properties. Though polymorph and solvate screenings did not yield new forms, the cocrystal screening was successful. Two cocrystals were discovered, one with piperazine and another with tetramethylpirazine, both in a 1:1 ratio. The latter can exist in three polymorphic forms. Both offer improvements in the melting point and crystal habit, and the cocrystal with tetramethylpirazine also shows a significant enhancement in dissolution rate. The new solid forms were analysed by a combination of methods, including X-ray powder diffraction, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate. Single-crystal X-ray diffraction data were used to solve the crystal structures, which were then compared with that of pure CBG. The crystal morphologies and surfaces were comprehensively analysed using the CSD-Particle suite, with various properties correlated against dissolution rates. While surface attachment energy and roughness (rugosity) did not show significant effects, the concentration of unsatisfied hydrogen-bond donors displayed a positive correlation. There were two parameters with a very strong correlation to dissolution rate: the propensity for interactions with water molecules, determined by the maximum range in the full interaction maps on the surface calculated for the water probe, and also the difference in the positive and negative electrostatic charges. These parameters proved highly predictive of aqueous dissolution, offering immense utility in pharmaceutical development.
- Klíčová slova
- CSD-Particle, Cambridge Structural Database, cannabigerol, cocrystals, crystal design, crystal engineering, crystal structures, dissolution, particles, properties of solids, surfaces, topology,
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Maternal perinatal mental health is essential for optimal brain development and mental health of the offspring. We evaluated whether maternal depression during the perinatal period and early life of the offspring might be selectively associated with altered brain function during emotion regulation and whether those may further correlate with physiological responses and the typical use of emotion regulation strategies. METHODS: Participants included 163 young adults (49% female, 28-30 years) from the ELSPAC prenatal birth cohort who took part in its neuroimaging follow-up and had complete mental health data from the perinatal period and early life. Maternal depressive symptoms were measured mid-pregnancy, 2 weeks, 6 months, and 18 months after birth. Regulation of negative affect was studied using functional magnetic resonance imaging, concurrent skin conductance response (SCR) and heart rate variability (HRV), and assessment of typical emotion regulation strategy. RESULTS: Maternal depression 2 weeks after birth interacted with sex and showed a relationship with greater brain response during emotion regulation in a right frontal cluster in women. Moreover, this brain response mediated the relationship between greater maternal depression 2 weeks after birth and greater suppression of emotions in young adult women (ab = 0.11, SE = 0.05, 95% CI [0.016; 0.226]). The altered brain response during emotion regulation and the typical emotion regulation strategy were also as sociated with SCR and HRV. CONCLUSIONS: These findings suggest that maternal depression 2 weeks after birth predisposes female offspring to maladaptive emotion regulation skills and particularly to emotion suppression in young adulthood.
- Klíčová slova
- emotion regulation, fMRI, heart rate variability, maternal perinatal depression, prenatal birth cohort, skin conductance,
- MeSH
- deprese patofyziologie diagnostické zobrazování MeSH
- dospělí MeSH
- emoční regulace * fyziologie MeSH
- galvanická kožní odpověď fyziologie MeSH
- kohortové studie MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- matky psychologie MeSH
- mozek diagnostické zobrazování patofyziologie MeSH
- srdeční frekvence fyziologie MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
High-grade B-cell lymphomas (HGBCLs) are aggressive blood cancers with a severe disease course, especially when the central nervous system (CNS) is involved. Standard histological examination depends on tissue availability and is currently supplemented with molecular tests, as the status of MYC, BCL2, or BCL6 gene rearrangements is required for proper lymphoma classification. This case report demonstrates the relevance of cerebrospinal fluid (CSF) cell-free DNA testing by integrative next-generation sequencing (NGS) panel. The benefit of this approach resided in tumor genotyping alongside the proof of CNS progression despite MRI negativity, revealing a clonal relationship with the primary tumor lesion. In addition, our strategy allowed us to classify the tumor as DLBCL/HGBL-MYC/BCL2 entity. In clinical practice, such a minimally invasive approach provides a more sensitive tool than standard imaging and cell analyzing techniques, enabling more accurate disease monitoring and relapse prediction in particular cases.
- Klíčová slova
- Cell-free DNA, Central nervous system involvement, High-grade B-cell lymphoma, Integrative diagnostics, Next-generation sequencing,
- MeSH
- B-buněčný lymfom genetika patologie diagnóza diagnostické zobrazování MeSH
- cirkulující nádorová DNA genetika MeSH
- difúzní velkobuněčný B-lymfom genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru patologie genetika MeSH
- magnetická rezonanční tomografie * MeSH
- nádorové biomarkery genetika MeSH
- nádory centrálního nervového systému genetika patologie diagnostické zobrazování MeSH
- vysoce účinné nukleotidové sekvenování * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- cirkulující nádorová DNA MeSH
- nádorové biomarkery MeSH
BACKGROUND: Glioblastoma is the commonest malignant brain tumor and has a very poor prognosis. Reduced expression of the MGMT gene (10q26.3), influenced primarily by the methylation of two differentially methylated regions (DMR1 and DMR2), is associated with a good response to temozolomide treatment. However, suitable methods for detecting the methylation of the MGMT gene promoter and setting appropriate cutoff values are debated. RESULTS: A cohort of 108 patients with histologically and genetically defined glioblastoma was retrospectively examined with methylation-specific Sanger sequencing (sSeq) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methods. The DMR2 region was methylated in 29% of samples, whereas DMR1 was methylated in 12% of samples. Methylation detected with the MS-MLPA method using probes MGMT_215, MGMT_190, and MGMT_124 from the ME012-A1 kit (located in DMR1 and DMR2) correlated with the methylation of the corresponding CpG dinucleotides detected with sSeq (p = 0.005 for probe MGMT_215; p < 0.001 for probe MGMT_190; p = 0.016 for probe MGMT_124). The threshold for methylation detection with the MS-MLPA method was calculated with a ROC curve analysis and principal components analysis of the data obtained with the MS-MLPA and sSeq methods, yielding a weighted value of 0.362. Thus, methylation of the MGMT gene promoter was confirmed in 36% of samples. These patients had statistically significantly better overall survival (p = 0.003). CONCLUSIONS: Our results show that the threshold for methylation detection with the MS-MLPA method determined here is useful from a diagnostic perspective because it allows the stratification of patients who will benefit from specific treatment protocols, including temozolomide. Detailed analysis of the MGMT gene promoter enables the more-precise and personalized treatment of patients with glioblastoma.
- Klíčová slova
- MGMT, Glioblastoma, MS-MLPA, Methylation, Sanger sequencing, Stupp protocol,
- MeSH
- CpG ostrůvky genetika MeSH
- DNA modifikační methylasy * genetika MeSH
- dospělí MeSH
- enzymy opravy DNA * genetika MeSH
- glioblastom * genetika farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA * genetika MeSH
- nádorové supresorové proteiny * genetika MeSH
- nádory mozku * genetika MeSH
- promotorové oblasti (genetika) * genetika MeSH
- retrospektivní studie MeSH
- sekvenční analýza DNA metody MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- temozolomid terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- validační studie MeSH
- Názvy látek
- DNA modifikační methylasy * MeSH
- enzymy opravy DNA * MeSH
- MGMT protein, human MeSH Prohlížeč
- nádorové supresorové proteiny * MeSH
- temozolomid MeSH
The histological grade is crucial for therapeutic management, and its reliable preoperative detection can significantly influence treatment approach. Lacking established risk factors, this study identifies preoperative predictors of high-grade skull base meningiomas and discusses the implications of non-invasive detection. A multicentric study was conducted on 552 patients with skull base meningiomas who underwent primary surgical resection between 2014 and 2019. Data were gathered from clinical, surgical and pathology records and radiological diagnostics. The predictive factors of higher WHO grade were analysed in univariate analysis and multivariate stepwise selection logistic regression analysis. Histological analysis revealed 511 grade 1 (92.6%) and 41 grade 2 (7.4%) meningiomas. A prognostic model predicting the probability of WHO grade 2 skull base meningioma (AUC 0.79; SE 0.04; 95% Wald Confidence Limits (0.71; 0.86)) based on meningioma diameter, presence of an arachnoid plane and cranial nerve palsy was built. Accurate preoperative detection of WHO grade in skull base meningiomas is essential for effective treatment planning. Our logistic regression model, based on diameter, cranial nerve palsy, and arachnoid plane, is tailored for detecting WHO grade 2 skull base meningiomas, even in outpatient settings.
- Klíčová slova
- Case series, Meningioma, Risk factors, Skull base, Surgery, Tumor grading,
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- meningeální nádory * patologie chirurgie diagnostické zobrazování MeSH
- meningeom * patologie chirurgie diagnostické zobrazování MeSH
- mladý dospělý MeSH
- nádory baze lební * patologie chirurgie diagnostické zobrazování MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň nádoru * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND: Myelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source of genome instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors of TEs. However, the roles of TEs and piRNAs in MDS remain unclear. METHODS: In this study, we examined TE and piRNA expression through parallel RNA and small RNA sequencing of CD34+ hematopoietic stem cells from MDS patients. RESULTS: Comparative analysis of TE and piRNA expression between MDS and control samples revealed several significantly dysregulated molecules. However, significant differences were observed between lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS) samples. In HR-MDS, we found an inverse correlation between decreased TE levels and increased piRNA expression and these TE and piRNA levels were significantly associated with patient outcomes. Importantly, the upregulation of PIWIL2, which encodes a key factor in the piRNA pathway, independently predicted poor prognosis in MDS patients, underscoring its potential as a valuable disease marker. Furthermore, pathway analysis of RNA sequencing data revealed that dysregulation of the TE‒piRNA axis is linked to the suppression of processes related to energy metabolism, the cell cycle, and the immune response, suggesting that these disruptions significantly affect cellular activity. CONCLUSIONS: Our findings demonstrate the parallel dysregulation of TEs and piRNAs in HR-MDS patients, highlighting their potential role in MDS progression and indicating that the PIWIL2 level is a promising molecular marker for prognosis.
- Klíčová slova
- Bioinformatics, Biomarkers, Myelodysplastic neoplasms, Next-generation sequencing, Transposable elements, piRNA,
- Publikační typ
- časopisecké články MeSH
Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic and associated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001 resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.
Brain metastases (BMs) are the most common intracranial tumors in adults and occur 3-10 times more frequently than primary brain tumors. Despite intensive multimodal therapies, including resection, radiotherapy, and chemotherapy, BMs are associated with poor prognosis and remain challenging to treat. BMs predominantly originate from primary lung (20-56%), breast (5-20%), and melanoma (7-16%) tumors, although they can arise from other cancer types less frequently. The metastatic cascade is a multistep process involving local invasion, intravasation into the bloodstream or lymphatic system, extravasation into normal tissue, and colonization of the distal site. After reaching the brain, circulating tumor cells (CTCs) breach the blood-brain barrier (BBB).The selective permeability of the BBB poses a significant challenge for therapeutic compounds, limiting the treatment efficacy of BMs. Understanding the mechanisms of tumor cell interactions with the BBB is crucial for the development of effective treatments. This review provides an in-depth analysis of the brain barriers, including the BBB, blood-spinal cord barrier, blood-meningeal barrier, blood-arachnoid barrier, and blood-cerebrospinal fluid barrier. It explores the molecular and cellular components of these barriers and their roles in brain metastasis, highlighting the importance of this knowledge for identifying druggable targets to prevent or limit BM formation.
- Klíčová slova
- Blood-cerebrospinal fluid barrier, Blood-spinal cord barrier, Blood–brain barrier, Brain Metastasis, Cancer,
- MeSH
- hematoencefalická bariéra * metabolismus patologie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádorové cirkulující buňky patologie MeSH
- nádory mozku * sekundární metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
We assessed the diagnostic performance of the Narrow-Band Imaging (NBI) International Colorectal Endoscopic Classification (NICE) and the Japan NBI Expert Team classification (JNET) in predicting histological outcomes of advanced colorectal lesions. Additionally, we evaluated the sensitivity and positive predictive value (PPV) of the JNET and NICE classifications individually for high-grade lesions (including HGD adenomas, intramucosal carcinomas, and T1 carcinomas). This was a retrospective analysis of prospectively collected data, involving 211 patients (130 men, mean age 60 years) who underwent colonoscopy with endoscopic resection of advanced colorectal neoplasia (lesions ≥ 10 mm). Lesions were classified using both NICE and JNET criteria, and final histopathological results were used for comparison. Of the 257 lesions analyzed, the NICE classification accurately classifies a large proportion of lesions (93.8%). In JNET classification we observed 77.4% correctly classified lesions. Specifically, the sensitivity and positive predictive value (PPV) of the NICE classification for high-grade lesions were 100% and 24.4%, respectively. For the JNET classification, the sensitivity and PPV for high-grade lesions were 56.6% and 57.7%, respectively. The JNET classification, with a positive predictive value of 57.7% for high-grade colorectal lesions (including HGD adenomas, intramucosal carcinomas, and T1 carcinomas), should be used for decision-making regarding appropriate subsequent endoscopic therapy.
- Klíčová slova
- Colon tumour, Colonoscopy, Diagnostic accuracy, JNET classification, NICE classification, Narrow-band imaging,
- MeSH
- adenom diagnostické zobrazování patologie MeSH
- dospělí MeSH
- kolonoskopie * metody MeSH
- kolorektální nádory * patologie diagnostické zobrazování diagnóza MeSH
- lidé středního věku MeSH
- lidé MeSH
- prediktivní hodnota testů MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- úzkopásmové zobrazení * metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
