High Proliferative Activity Research Articles

Nodular fasciitis: USP6-associated neoplasia through multiple pathways

Even though nodular fasciitis (NF) is benign and self-limited nature, the presentations of clinical, ultrasonographic, and pathological features have been described as mimicking sarcoma. Erickson-Johnson et al. suggested that ubiquitin-specific protease 6 (USP6) transcriptional upregulation may be the driving force behind the high proliferative activity and growth of NF. When the lesion showed the proliferative findings of the margin on both ultrasonography (US) and pathology, accompanied by clinically rapid growth, self-limited and/or regress course, NF could be strongly suggested as previously described. In this article, the author reviews the current knowledge of NF as USP6-associated neoplasia and also describes the therapeutic strategy in NF. In addition to the presentations of clinical, ulrtrasonographic, and pathological appearances of NF, the evaluation of percentage of USP6 break-apart FISH signals reflecting lifetime and mitotic counts in NF may be a potential procedure for accurate diagnosis in particularly young NF. It is putative that the inhibition of USP6-related genes might be the potential therapeutic strategies for the extremely rare malignant nodular fasciitis.

Molecular and biological aspects of forecasting the oncological efficiency of cytoreductive surgery in metastatic colon cancer

Through an immunohistochemical study, the molecular biological properties of adenocarcinoma in patients with stage IV colorectal cancer with synchronous unresectable liver metastases, who underwent cytoreductive interventions for volume removal of the primary tumor, were examined. This study clarified the criteria for selecting patients with stage IV colon cancer with unresectable synchronous metastases in the liver for cytoreductive surgery from the standpoint of the molecular biological properties of the tumor. The prognostic significance of immunohistochemical markers such as the index of proliferative activity of stem cancer cells (ALDH + Ki-67 +) and the receptor for chemokines CXCR4 was established. The level of their expression correlates with the life expectancy of patients who underwent cytoreductive surgery. Thus, the high proliferative activity of cancer stem cells (ALDH + Ki67 + 50%) and the high expression of chemokine receptor (CXCR4 70%) correlate with the rapid disease progression after surgical treatment. A significant inverse relationship was traced between the expression level of the receptor for chemokine CXCR4 as well as the proliferative activity of cancer stem cells and life expectancy of patients with stage IV colon cancer after cytoreductive surgery. The expediency of immunohistochemical studies in patients with metastatic colon cancer has been substantiated. Its implementation provides important information about the potential for tumor aggressiveness, which makes it possible to clarify the indications for performing cytoreductive surgery and improve the results of surgical treatment of this category of patients.

Plexiform Cellular Schwannoma in Infancy and Childhood: A Clinicopathological Study of Seven Cases of an Underrecognized Nerve Sheath Tumor with a Tendency Toward Local Recurrence

Plexiform cellular schwannoma (PCS) is very rare, and it is not completely understood. We present our experience with 7 additional cases of PCS in infancy and childhood to further characterize its distinctive clinicopathological features. There were 5 females and 2 males with a mean age of 28 months (ranging, 2 months to 8 years). The involved sites included the left forearm (n = 2), sacrococcygeal region (n = 2), retroperitoneum (n = 1), thoracic spinal canal and thoracic cavity (n = 1), and neck (n = 1). Tumor sizes ranged from 3 to 13 cm in maximum diameter (mean, 7.1 cm). Histologically, all tumors consisted of abundant spindle cells arranged in a multinodular or plexiform growth pattern, possessing elongated, hyperchromatic nuclei and pale eosinophilic cytoplasm with indistinct cell margins. Mitotic figures were easily identified, with a mean count of 4 per 10 consecutive high power fields (HPF). Immunohistochemically, all tumors were strongly and diffusely positive for S100 protein, SOX10 and H3K27me3. The Ki-67 index ranged from 5% to 30% (mean, 15%). Follow-up (available in 6 cases) revealed that 5 patients experienced local recurrence and were treated by re-excision. There was no evidence of recurrence and metastasis in 3 patients, and the other 2 were alive with the disease. In conclusion, PCS is an uncommon nerve sheath tumor predominantly occurring in infants and children, featuring a plexiform or multinodular growth pattern and exhibiting a tendency toward local recurrence. PCS is easily mistaken as malignant peripheral nerve sheath tumor (MPNST) due to its locally aggressive behaviors and worrisome features, including hypercellularity, hyperchromatism and high proliferative activity. Increased awareness of its potential occurrence and greater familiarity with its characteristic features are helpful for both clinicians and pathologists to avoid misdiagnosis and unnecessary overtreatment.

Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by invitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.

Human three-dimensional dental pulp organoid model for toxicity screening of dental materials on dental pulp cells and tissue.

To establish a 3D model for screening the biocompatibility of dental materials/drugs on dental pulp cells and tissue. Human dental pulp cells (hDPC) and endothelial cells (EC) were mixed with or without human dental pulp derived extracellular matrix (hDP-ECM) according to several protocols and cultured in 3D plates to fabricate 3D organoids. Cell viability and proliferation in organoids were evaluated using Live/Dead cell viability assay and ATPase assay. Organoids were fixed, cut and stained with a H&E staining kit. The expressions of DSPP, DMP-1, CD31, vWF and COL1A in 3D organoids were evaluated using immunofluorescence. To assess the feasibility of 3D organoids on drug/material toxicity screening, the organoids were treated with lipopolysaccharides (LPS) or iRoot BP. Then, cell viability and apoptosis were assessed. The expressions of IL-6, TNF-α, and IL-1β were compared in LPS-treated and non-treated organoids. Alizarin Red S staining was used to evaluate calcium deposit formation in organoids. Data were analysed using one-way anova followed by Tukey's post hoc comparison. The 3D spheres/organoids were formed at day 1 or day 2. Cells in 3D organoids maintained a high viability rate and low proliferation activity. The level of CD31 increased significantly (p<.05) when EC were added to coculture with hDPC. The expressions of odontogenesis-associated proteins (DSPP, COL1A) upregulated (p<.05) with the addition of hDP-ECM. Level of IL-6 expression and rates of dead and apoptotic cells in 3D organoids were increased significantly (p<.05) in response to LPS. Calcium deposit formation was observed in iRoot BP-treated organoids. Coculture of hDPC and EC in the presence of hDP-ECM formed functional dental pulp organoids. The experimental model provides an alternative tool for toxicity screening of dental pulp capping agents and dental pulp regeneration research.

Tre-P-24 - Aggressive gamma/delta T-cell lymphoma: successful therapy with encapsulated doxorubicin

An 82-year-old female patient initially presented with a prominent, reddish-livid, sharply circumscribed tumor measuring 10×5.5 cm on the left forearm, as well as multiple small-nodular efflorescences on both arms, the trunk, and the dorsum of the feet. The histologic picture was consistent with peripheral T-cell lymphoma. Immunohistochemical workup showed CD3 expression, high proliferative activity at 70%, and staining with gamma and delta showed the impressive picture of a consistently homogeneous reaction product with delta. No clonal T-cell receptor rearrangement was found in the molecular workup. Initial staging showed no systemic involvement (pT3N0M0). We initially treated with twelve doses of gemcitabine 600 mg fix-dose and local radiotherapy of the tumor node on the left forearm. As the cutaneous manifestations progressed, we switched to off-label therapy with pembrolizumab 200 mg every three weeks in combination with radiotherapy of the tumor nodes on the right forearm, legs and feet on both sides. As the cutaneous tumors progressed again after seven doses of pembrolizumab, therapy was switched to liposomal encapsulated doxorubicin, initially 20 mg/m2 on days 1 and 15, then every four weeks. With this therapy, tumor response has been good after six administrations to date, allowing the dose to be KOF to 10 mg/m2. Incidentally, the patient suffered from arterial hypertension and sigmoid diverticulosis. Primary cutaneous gamma/delta T-cell lymphomas are a heterogeneous group of rare and highly aggressive lymphomas. Median survival is 31 months, as they are largely resistant to radiotherapy and chemotherapy. Allogeneic stem cell transplantation offers the only curative therapy. There is no standard therapy due to the low incidence and lack of prospective studies, so that an individual therapy decision must be made for each patient. Encapsulated doxorubicin may be a good therapeutic alternative to control this highly aggressive lymphoma. As an addititional immunohistochemical workup also showed a homogenous BcL2 expression in our case, the BcL2-inhbitor Venetoclax could offer a future therapeutic option.

Electrical Conductivity of Bone Marrow Cell Cultures and Their Connection with Proliferative Activity: Age Aspect

Functional activity is a basic concept of biology; however, instrumental methods of its determination are absent. The interrelation between bone marrow cell proliferative activity, as one of the functional activity parameters, the content of calcium, copper, and reactive oxygen species (ROS) in the cells, and the electrical conductivity of the cell culture was studied in young and old Wistar rats aged 3 and 20 months. We determined the electrical conductivity of the bone marrow cell cultures and parameters of bone marrow cells (proliferative activity and calcium, copper and ROS content). The bone marrow cells of old intact animals had higher proliferative activity in the primary culture as compared to that of young animals. The content of the 8 main morphological cell types in the young and old animals were similar, while the lymphocyte content was larger in the old animals. Content of ions in the bone marrow cell cultures of old animals as compared with that in young animals varied as follows: Content of calcium was 75 % higher, copper was 5 times lower, and ROS was 2.5 times lower. It was found that the conductivities of the pure culture medium and of that after the cultivation of the bone marrow cells in the nutrient medium were significantly different. It has been suggested that the electrical conductivity of biological media could be used as an integral characteristic of the ionic composition and structural organization of biological media. HIGHLIGHTS Electrical conductivity of bone marrow cells suspension of young animals was decrease to compared with this indicator of old animals Proliferative activity is correlated with electrical conductivity Electrical conductivity of biological media is influenced both the composition, and macromolecules and their state of aggregation

1756TiP Dabrafenib and trametinib combination as a neoadjuvant strategy in BRAF-positive anaplastic thyroid cancer (ANAPLAST-NEO)

Anaplastic thyroid cancer (ATC) has a poor prognosis, with median overall survival (OS) duration in the range of 5–12 months. ATC have high proliferative activity and are prone to numerous somatic mutations, BRAF V600 mutations are a common driver of the ATC and are present in up to 50% of ATCs. Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Presented here is a trial-in-progress that will evaluate whether dabrafenib and trametinib may help to control BRAF V600-mutated ATC when given before surgery and improve the response rate.

α-glucosyl-rutin activates immediate early genes in human induced pluripotent stem cells

Rutin is a natural flavonoid glycoside found in several vegetables and fruits such as buckwheat and onion. Rutin has a range of pharmacological effects that include anti-oxidant, anti-inflammation, anti-bacterial, and anti-cancer activities. α-glucosyl-rutin (AGR) is a derivative of rutin with increased water solubility that is used in cosmetics and foods. However, the effects of AGR on cellular responses have not been clarified, especially in stem cells. Induced pluripotent stem cells (iPSCs) show high proliferative activity and pluripotency; however, regulation of molecular machinery such as cell cycle, metabolism, and DNA repair differs between iPSCs and somatic cells. Here, we compared the effects of AGR on iPSCs and differentiated cells (fibroblasts and skin keratinocytes). AGR-treated iPSCs exhibited increased cell viability. RNA sequencing and reverse transcriptase PCR analysis revealed that AGR induced expression of immediate early genes (IEGs) and differentiation-related genes in iPSCs. Our results suggest that AGR may activate differentiation signals mediated by IEG responses in iPSCs, resulting in altered metabolic activity and increased cell viability.

Opposite Roles of Tumor Cell Proliferation and Immune Cell Infiltration in Postoperative Liver Metastasis of PDAC.

BackgroundRecurrence of liver metastasis after pancreatectomy is often a predictor of poor prognosis. Comprehensive genomic analysis may contribute to a better understanding of the molecular mechanisms of postoperative liver metastasis and provide new therapeutic targets.MethodsA total of 67 patients from The Cancer Genome Atlas (TCGA) were included in this study. We analyzed differentially expressed genes (DEGs) by R package “DESeq2.” Weighted gene co-expression network analysis (WGCNA) was applied to investigate the key modules and hub genes. Immunohistochemistry was used to analyze tumor cell proliferation index and CD4+ T cells infiltration.ResultsFunctional analysis of DEGs between the liver metastatic and recurrence-free groups was mainly concentrated in the immune response. The liver metastasis group had lower immune and stroma scores and a higher TP53 mutation rate. WGCNA showed that the genes in key modules related to disease-free survival (DFS) and overall survival (OS) were mainly enriched in the cell proliferation process and tumor immune response. Immunohistochemical analysis showed that the pancreatic cancer cells of patients with early postoperative liver metastasis had higher proliferative activity, while the infiltration of CD4+ T cells in tumor specimens was less.ConclusionOur study suggested that increased immune cell infiltration (especially CD4+ T cells) and tumor cell proliferation may play an opposite role in liver metastasis recurrence after pancreatic cancer.

Production and identification of peptides with activity promoting osteoblast proliferation from meat dregs of Pinctada martensii.

As a by-product of pearl production, Pinctada martensii meat dregs have a high level of protein but cannot be fully utilized. In this study, P. martensii meat dregs were first hydrolyzed by three pepsin enzymes, resulting in neutral proteinase enzymatic hydrolysate that had a higher effect on stimulating the proliferation of MC3T3-E1 cells, and cell proliferation increases of 37.37±0.03%. Subsequently, after purification of alcohol precipitation, ultrafiltration, and Superdex G-25 gel chromatography, five fractions were further separated and purified in which fraction ZP2 could effectively improve cell proliferation induced an increase of 43.95±0.03% in MC3T3-E1 cells growth. Consequently, with the help of alkaline phosphatase and methyl thiazolyl tetrazolium assay, five novel peptides (FDNEGKGKLPEEY, FWDGRDGEVDGFK, VLQTDNDALGKAK, IVLDSGDGVTH, and MVAPEEHP) derived from fraction ZP2 with the strongest osteogenic activity were screened, and their sequences were identified using Orbitrap Fusion Lumos Tribrid Orbital liquid chromatography-mass spectrometry. Therefore, the research results demonstrated that P. martensii meat could be used as a promising material for producing food additives for improving osteoporosis. PRACTICAL APPLICATIONS: In this study, after enzymolysis and purification, the fraction ZP2, derived from Pinctada martensii meat dregs were found to have a better activity of promoting osteoblast proliferation, showing the higher osteogenic activity with an increase of 43.95±0.03% in terms of cell proliferation. It is beneficial to realize the high value and resource utilization of P. martensii meat dregs as a by-product of pearl production. The research demonstrated that the meat dregs of P. martensii could be used as an attractive material for producing active peptides in functional foods. In addition, the molecular weight of the peptides we identified from the ZP2 fraction is suitable for the proliferation of MC3T3-E1 cells, which lays a foundation for the further synthesis of peptides that promote the high proliferation activity of osteocytes.

Prognostic value of proliferation, PD-L1 and nuclear size in patients with superior sulcus tumours treated with chemoradiotherapy and surgery

AimsThe aim of this study was to determine the relationship between proliferative activity, PD-L1 status and nuclear size changes after preoperative chemoradiotherapy (CRT) and the clinical outcome in patients with...

Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes

AbstractThe proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell–derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in >10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYC-high B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC–driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.

Age at Diagnosis and Baseline Myelomalacia Sign Predict Functional Outcome After Spinal Meningioma Surgery.

Objective: Spinal meningioma (SM) accounts for 12% of all meningiomas. Clinical and immunohistochemical factors were analyzed with regard to functional outcome, surgical adverse events, and tumor recurrence.Methods: One-hundred and twenty-three consecutive SM patients underwent surgery and were retrospectively reviewed with regard to demographic parameters, imaging features, neurological function, and immunohistochemical items. Neurological function was graded according to the Modified McCormick Scale (MMS) and dichotomized as “good (grade I + II)” and “poor (grade III–V)” function.Results: One-hundred and fourteen (92.7%) WHO grade I and 9 (7.3%) WHO grade II SM were included in this study. Univariate analysis identified a baseline T2 hyperintensity of the spinal cord, baseline symptom duration ≥4 weeks, age ≥66 years, and dural tail sign as predictors of poor MMS. Baseline T2 hyperintensity of the spinal cord [Odds ratio (OR) = 13.3, 95% CI = 3.4–52.1, p < 0.001] and age ≥66 years (OR = 10.3, 95% CI = 2.6–41.1, p = 0.001) were independent predictors of a poor MMS grade at discharge after SM surgery in the multivariate binary logistic regression analysis. The 12- and 24-month recurrence-free survival rates were 98.7 % (1/80) and 94.7% (2/38), respectively. In those patients with tumor recurrence of the SM, highly increased MIB-1 (≥5%) labeling indices were observed.Conclusion: Baseline T2 hyperintensity, especially in the elderly patients, is a strong predictor of poorer recovery after spinal meningioma surgery. SMs with high proliferative activity should be followed-up closely despite maximal safe resection.

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis.

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. SIGNIFICANCE: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.

Construction and Validation of a Reliable Six-Gene Prognostic Signature Based on the TP53 Alteration for Hepatocellular Carcinoma.

BackgroundThe high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood.Material and ApproachThis study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan–Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis.ResultsA prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression.ConclusionOur study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.

ПОСЛЕДСТВИЯ ПОЗДНЕЙ ДИАГНОСТИКИ ЛИМФОМ У ДЕТЕЙ

Lymphoma is the third leading cause of malignant neoplasms (MNs) in children. Childhood lymphoma is characterized by the prevalence of highly aggressive variants with high proliferation activity and rapid tumor dissimilation. Prolonged diagnosis becomes a reason of advanced-stage therapy. Despite the good results of long-term survival rate in patients, exceeding 90% even with late (III-IV) stages of lymphomas, the persistence of pathogenic (including multi-drug resistant) microorganisms in the patient's body becomes a major therapeutic problem, contamination of which occurs during the patient's stay in various medical organizations at the stage of diagnostics. The case reports of fatal infectious complications with the development of sepsis caused by polyresistant microorganisms in 2 children with anaplastic large cell lymphoma stage IV are presented in this article. Both case reports are unfavourable, despite the use of all medications and effective treatments. The analysis of diagnostic errors and necessity of cancer alarm generation in medical staff and patients' parents will make it possible to reduce the duration of diagnosis and probability of contamination of patient’s body with multi-resistant flora.

Clinical characteristics and outcomes of patients with hepatic angiomyolipoma: A literature review.

First reported in 1976, hepatic angiomyolipoma (HAML) is a rare mesenchymal liver tumor occurring mostly in middle-aged women. Diagnosis of the liver mass is often incidental on abdominal imaging due to the frequent absence of specific symptoms. Nearly 10% of HAMLs are associated with tuberous sclerosis complex. HAML contains variable proportions of blood vessels, smooth muscle cells and adipose tissue, which renders radiological diagnosis hazardous. Cells express positivity for HMB-45 and actin, thus these tumors are integrated into the group of perivascular epithelioid cell tumors. Typically, a HAML appears on magnetic resonance imaging (or computed tomography scan) as a hypervascular solid tumor with fatty areas and with washout, and can easily be misdiagnosed as other liver tumors, particularly hepatocellular carcinoma. The therapeutic strategy is not clearly defined, but surgical resection is indicated for symptomatic patients, for tumors showing an aggressive pattern (i.e., changes in size on imaging or high proliferation activity and atypical epithelioid pattern on liver biopsy), for large (> 5 cm) biopsy-proven HAML, and if doubts remain on imaging or histology. Conservative management may be justified in other conditions, since most cases follow a benign clinical course. In summary, the correct diagnosis of HAML is challenging on imaging and relies mainly on pathological findings.

HLA-DR-Positive NK Cells Expand in Response to MycobacteriumTuberculosis Antigens and Mediate Mycobacteria-Induced T Cell Activation.

NK cells play an important role in the control of tuberculosis infection: they are not only able to kill the infected cells, but also control the activity of macrophages and development of the adaptive immune response. Still, there is little information on the role of specific NK cell subsets in this network. In this study, we focused on the mycobacteria-driven responses of the NK cells expressing HLA-DR – a type of MHC class II. We have revealed that this subset is increased in the peripheral blood of patients with primary diagnosed tuberculosis, and expands in response to in vitro stimulation with ultrasonically destroyed Mycobacterium tuberculosis cells (sonicate). The expanded HLA-DR+ NK cells had less differentiated phenotype, higher proliferative activity and increased expression of NKp30 and NKp46 receptors. HLA-DR+CD56dim NK cells showed higher IFNγ production and degranulation level than the respective HLA-DR− NK cells in response to both 24 h and 7 day stimulation with sonicate, while HLA-DR+CD56bright NK cells mostly demonstarted similar high responsiveness to the same stimulating conditions as their HLA-DR−CD56bright counterparts. After preliminary incubation with destroyed mycobacteria, cytokine-activated HLA-DR-expressing NK cells were able to mediate mycobacteria-induced and HLA-DR-dependent cytokine production in autologous CD4+ T cells. Thus, functionally active HLA-DR+ cells seem to be one of the NK cell subsets providing an important link to the adaptive immunity.

In vitro proliferative activity of 6-substituted uracil derivatives

Context: Previously, we investigated the relationship between the nature of the substituent at the 5-position of the uracil ring and the action of the corresponding uracil derivatives on immortalized lung cells. In the present study, we analyzed the impact of some 6-substituted uracil-derivatives on the regeneration potential of the lung cells (LC). Aims: To evaluate uracil derivatives capable of stimulating lung cell proliferation to create drugs that accelerate lung regeneration. Methods: The level of cell proliferation, maximum tolerated dose, and toxic effect of 6-substituted uracil derivatives (9 compounds) were studied on the immortalized lung epithelial cells and compared with the known drug 6-methyluracil. Results: The maximum tolerated dose of compounds for the LC line depends on the chemical structure of the compounds. The highest level of cell proliferation and tolerated was demonstrated when was used 3-methyl-6-cyclopropyluracil and 1-butyl-6-methyluracil. Conclusions: 3-methyl-6-cyclopropyluracil and 1-butyl-6-methyluracil exhibit a high proliferative activity in vitro so they could be recommended for additional studies of regenerative activity in vivo.