Underlying and proximate drivers of biodiversity changes in Mesoamerican biosphere reserves.

Protected areas are of paramount relevance to conserving wildlife and ecosystem contributions to people. Yet, their conservation success is increasingly threatened by human activities including habitat loss, climate change, pollution, and species overexploitation. Thus, understanding the underlying and proximate drivers of anthropogenic threats is urgently needed to improve protected areas' effectiveness, especially in the biodiversity-rich tropics. We addressed this issue by analyzing expert-provided data on long-term biodiversity change (last three decades) over 14 biosphere reserves from the Mesoamerican Biodiversity Hotspot. Using multivariate analyses and structural equation modeling, we tested the influence of major socioeconomic drivers (demographic, economic, and political factors), spatial indicators of human activities (agriculture expansion and road extension), and forest landscape modifications (forest loss and isolation) as drivers of biodiversity change. We uncovered a significant proliferation of disturbance-tolerant guilds and the loss or decline of disturbance-sensitive guilds within reserves causing a "winner and loser" species replacement over time. Guild change was directly related to forest spatial changes promoted by the expansion of agriculture and roads within reserves. High human population density and low nonfarming occupation were identified as the main underlying drivers of biodiversity change. Our findings suggest that to mitigate anthropogenic threats to biodiversity within biosphere reserves, fostering human population well-being via sustainable, nonfarming livelihood opportunities around reserves is imperative.

MiR-128-3p as blood based liquid biopsy biomarker in childhood acute lymphoblastic leukemia.

BACKGROUND: Minimal residual disease (MRD) is one of the most valuable independent prognostic factors in acute lymphoblastic leukemia (ALL). Bone marrow (BM) aspiration, however, is an invasive process. Previous studies have shown that microRNAs (miR) and extracellular vesicle (EV)-related miRs show different expression profiles at the presence of malignant cells compared to healthy controls. In our previous project, we have reported that two miRs previously described to be overexpressed in blasts were significantly decreased over the first week of the therapy of patients with ALL in the platelet free plasma fraction (PFP) of peripheral blood samples (PB). The aim of the current study was to assess the relation between day 15 flow cytometry (FC) MRD and expression of miR-128-3p and miR-222-3p miRs in exosome-enriched fraction (EEF) of PFP to evaluate whether their expression in EEF correlates with day 15 FC MRD more precisely. METHODS: PB was collected from 13 patients diagnosed with pediatric pre-B ALL at 4 time points. Expression of miR-128-3p and miR-222-3p was measured by qPCR in PFP and EEF. RESULTS: Positive correlation was found between changes of miR-128-3p expression in EEF or PFP by day 8 of chemotherapy and day 15 FC MRD (rEEF = 0.99, pEEF = 1.13E-9 and rPFP = 0.99, pPFP = 4.75E-9, respectively). Furthermore, the decrease of miR-128-3p in EEF by day 15 of treatment also showed a positive correlation with day 15 FC MRD (rEEF = 0.96; pEEF = 4.89E-5). CONCLUSION: Our results show that circulating miRs are potential biomarkers of ALL MRD, asmiR-128-3p level both in PFP and EEF predicts day 15 FC MRD. In addition, the assessment of the EEF gave a more promising result.

Genomic Landscape of Normal and Breast Cancer Tissues in a Hungarian Pilot Cohort.

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations.

[New, innovative prognosis calculator for patients with metastatic spinal tumors]. / Új, innovatív prognóziskalkulátor áttétes gerinctumoros betegek számára.

Background and purpose: The aim of our research was to create a scoring system that predicts prognosis and recommends therapeutic options for patients with metastatic spine tumor. Increasing oncological treatment opportunities and prolonged survival have led to a growing need to address clinical symptoms caused by meta-stases of the primary tumor. Spinal metastases can cause a significant reduction in quality of life due to the caused neurological deficits. A scoring system that predicts prognosis with sufficient accuracy could help us to achieve personalised treatment options. Methods: Methods - We performed a retrospective clinical research of data from patients over 18 years of age who underwent surgery due to symptomatic spinal metastasis at the National Institute of Mental Disorders, Neurology and Neurosurgery between 2008 and 2018. Data from 454 patients were analysed. Survival analysis (Kaplan-Meier, log-rank, Cox model) was performed, network science-based correlation analysis was used to select the proper prognostic factors of our scoring system, such that its C value (predictive ability index) was maximized. Results: Multivariate Cox analysis resulted in the identification of 5 independent prognostic factors (primary tumour type, age, ambulatory status, internal organ metastases, serum protein level). Our system predicted with an average accuracy of 70.6% over the 10-year study period. Conclusion: Our large case series of surgical dataset of patients with symptomatic spinal metastasis was used to create a risk calculator system that can help in the choice of therapy. Our risk calculator is also available online at https://emk.semmelweis.hu/gerincmet.

Strongly oversized fission yeast cells lack any size control and tend to grow linearly rather than bilinearly.

During the mitotic cycle, the rod-shaped fission yeast cells grow only at their tips. The newly born cells grow first unipolarly at their old end, but later in the cycle, the 'new end take-off' event occurs, resulting in bipolar growth. Photographs were taken of several steady-state and induction synchronous cultures of different cell cycle mutants of fission yeast, generally larger than wild type. Length measurements of many individual cells were performed from birth to division. For all the measured growth patterns, three different functions (linear, bilinear and exponential) were fitted, and the most adequate one was chosen by using specific statistical criteria, considering the altering parameter numbers. Although the growth patterns were heterogeneous in all the cultures studied, we could find some tendencies. In cultures with sufficiently wide size distribution, cells large enough at birth tend to grow linearly, whereas the other cells generally tend to grow bilinearly. We have found that among bilinearly growing cells, the larger they are at birth, the rate change point during their bilinear pattern occurs earlier in the cycle. This shifting near to the beginning of the cycle might finally cause a linear pattern, if the cells are even larger. In all of the steady-state cultures studied, a size control mechanism operates to maintain homeostasis. By contrast, strongly oversized cells of induction synchronous cultures lack any sizer, and their cycle rather behaves like an adder. We could determine the critical cell size for both the G1 and G2 size controls, where these mechanisms become cryptic. TAKE AWAY: Most individual fission yeast cells in steady-state cultures grow bilinearly. In strongly oversized fission yeast cells, linear growth dominates over bilinear. Above birth length thresholds, both the G1 and G2 size controls become cryptic.

Sterile, abscess-like cerebral lesion during trastuzumab therapy after HER2 status switch in a triple negative breast cancer patient: a case report and literature review.

BACKGROUND: Breast cancer is a global health problem - it is the most common malignancy among women. Triple negative breast cancers (TNBC) account for 10-20% of female breast cancer. Most TNBC cases confer poor prognosis. Brain metastasis appears in more than 15% in the triple negative breast cancer population, which causes serious decrease in survival. Changes of immunophenotype are not uncommon in breast cancer, offering new therapeutic options in cases where targetable proteins or pathways are being identified. CASE PRESENTATION: After five lines of chemotherapy and 82 months following the first diagnosis, our patient with brain metastatic triple negative breast cancer had human epidermal growth factor receptor 2 (HER2) genetic heterogeneity in the metastatic tissue sample interpreted as HER2 status conversion. After the removal of the metastasis, we started first line therapy for metastatic HER2 positive cancer with trastuzumab and paclitaxel. After the first cycle of trastuzumab, on day 8, she had a seizure, and neurosurgical examination showed an abscess-like lesion. The punctate proved to be sterile by microbiological and pathological examination, so we continued cytostatic therapy without the anti-HER2 antibody. 3 months later, we could not identify the previous abscess-like lesion in the control computer tomography (CT) scan, and our patient had no neurological deficits. CONCLUSION: We emphasize the importance of regular tissue confirmation of predictive markers in progressive tumorous disease even if our presented case is not unequivocally a "conversion case". Tumor subtype is determined according to algorithms and definitions published in guidelines, nevertheless, use of different guidelines may lead to controversial interpretation in cases where HER2 genetic heterogeneity is present. Furthermore, we suggest that seronegative, aseptic intracranial fluid effusion after the removal of a brain metastasis may possibly be a side effect of trastuzumab.

Research on the predicting power of the revised Tokuhashi system: how much time can surgery give to patients with short life expectancy?

OBJECT: The primary treatment option for symptomatic metastatic spinal tumors is surgery. Prognostic systems are designed to assist in the establishment of the indication and the choice of surgical methodology. The best-known prognostic system is the revised Tokuhashi system, which has a predictive ability of about 60%. In our study, we are attempting to find the reason for its poor predictive ability, despite its proper separation ability. METHODS: We have designed a one-center-based retrospective clinical trial, by which we would like to test the feasibility and the inaccuracy of the revised Tokuhashi system. In our database, there are 329 patients who underwent surgery. Statistical analysis was performed. RESULTS: A significant increase in survival time was observed in the 'conservative' category. Earlier studies reported OS 0.15 at the 180-day control time, in contrast with our 0.38 OS value. The literature suggested supportive care for this category, but in our population, every patient underwent surgery. Our population passes the 0.15 OS value on day 475. We propose an adjustment of the Tokuhashi category scores. We observed significant success in resolving pain. Motor functions were improved or stabilized compared to changes in vegetative dysfunction. CONCLUSION: According to our results, the Tokuhashi scoring system makes very conservative predictions and prefers non-surgical palliative or supportive care. Surgical treatment increases the life expectancy of patients in poor condition. We propose modifying the therapeutic options of the revised Tokuhashi system, taking into consideration modern spine surgery techniques.

How do fission yeast cells grow and connect growth to the mitotic cycle?

To maintain size homeostasis in a unicellular culture, cells should coordinate growth to the division cycle. This is achieved via size control mechanisms (also known as size checkpoints), i.e. some events during the mitotic cycle supervene only if the cell has reached a critical size. Rod-shaped cells like those of fission yeast are ideal model organisms to study these checkpoints via time-lapse microphotography. By applying this method, once we can analyse the growth process between two consecutive divisions at a single (or even at an 'average') cellular level, moreover, we can also position the size checkpoint(s) at the population level. Finally, any of these controls can be abolished in appropriate cell cycle mutants, either in steady-state or in induction synchronised cultures. In the latter case, we produce abnormally oversized cells, and microscopic experiments with them clearly show the existence of a critical size above which the size checkpoint ceases (becomes cryptic). In this review, we delineate the development of our knowledge both on the growth mode of fission yeast and on the operating size control(s) during its mitotic cycle. We finish these historical stories with our recent findings, arguing that three different size checkpoints exist in the fission yeast cell cycle, namely in late G1, in mid G2 and in late G2, which has been concluded by analysing these controls in several cell cycle mutants.

Cell length growth patterns in fission yeast reveal a novel size control mechanism operating in late G2 phase.

BACKGROUND INFORMATION: Because cylindrically shaped fission yeast cells grow exclusively at their tips, cell volume is proportional to length and can be easily monitored by time-lapse microscopy. Here, we analysed the growth pattern of individual cells from several fission yeast strains to determine the growth function that describes them most adequately and to perform size control studies. RESULTS: The growth pattern of most cells during their growth period is best described by a bilinear function (i.e., two linear segments of different growth rates separated by a rate-change point). Linear growth patterns were also observed in several cases, but exponential ones only rarely. Since the bilinear patterns are separated into two segments by a breakpoint, we examined the existence of size control by regression analyses of the appropriate growth parameters in both segments. This confirmed the existence of known size controls in late G1, mid-G2 and late G2 during the fission yeast cycle. The present analyses also revealed that, contrary to the commonly accepted current view, late G2 size control is a general characteristic third event in the cycle. The level of the critical late G2 size that needs to be reached in an individual fission yeast cell is influenced by the growth rate of the cell in a manner similar to budding yeast, suggesting an evolutionary conserved mechanism. CONCLUSIONS: The present study of individual cell growth patterns in wild-type and several cell cycle mutant fission yeast strains confirmed that, for most cells, growth is best described by a bilinear function. Three different size control mechanisms were found to operate in the different strains, and, as a novel observation, cell size was always found to be monitored before mitotic onset, irrespective of the existence of any earlier size checkpoints. SIGNIFICANCE: Studying the pattern of growth and the mechanism of size control helps to clarify the connections between cell growth and division, since their coordination must work properly to maintain size homeostasis. In this study, we argue that most individual fission yeast cells grow following a bilinear pattern, and we confirm the existence of three different size control mechanisms.

Phylogenetic and comparative functional analysis of the cell-separation α-glucanase Agn1p in Schizosaccharomyces.

The post-cytokinetic separation of cells in cell-walled organisms involves enzymic processes that degrade a specific layer of the division septum and the region of the mother cell wall that edges the septum. In the fission yeast Schizosaccharomyces pombe, the 1,3-α-glucanase Agn1p, originally identified as a mutanase-like glycoside hydrolase family 71 (GH71) enzyme, dissolves the mother cell wall around the septum edge. Our search in the genomes of completely sequenced fungi identified GH71 hydrolases in Basidiomycota, Taphrinomycotina and Pezizomycotina, but not in Saccharomycotina. The most likely Agn1p orthologues in Pezizomycotina species are not mutanases having mutanase-binding domains, but experimentally non-characterized hypothetical proteins that have no carbohydrate-binding domains. The analysis of the GH71 domains corroborated the phylogenetic relationships of the Schizosaccharomyces species determined by previous studies, but suggested a closer relationship to the Basidiomycota proteins than to the Ascomycota proteins. In the Schizosaccharomyces genus, the Agn1p proteins are structurally conserved: their GH71 domains are flanked by N-terminal secretion signals and C-terminal sequences containing the conserved block YNFNA(Y)/HTG. The inactivation of the agn1(Sj) gene in Schizosaccharomyces japonicus, the only true dimorphic member of the genus, caused a severe cell-separation defect in its yeast phase, but had no effect on the hyphal growth and yeast-to-mycelium transition. It did not affect the mycelium-to-yeast transition either, only delaying the separation of the yeast cells arising from the fragmenting hyphae. The heterologous expression of agn1(Sj) partially rescued the separation defect of the agn1Δ cells of Schizosaccharomyces pombe. The results presented indicate that the fission yeast Agn1p 1,3-α-glucanases of Schizosaccharomyces japonicus and Schizosaccharomyces pombe share conserved functions in the yeast phase.

Characterization of antibiotic and disinfectant susceptibility in biofilm-forming Acinetobacter baumannii: A focus on environmental isolates.

The clinical role of Acinetobacter baumannii has been highlighted in numerous infectious syndromes with a high mortality rate, due to the high prevalence of multidrug-resistant (MDR) isolates. The treatment and eradication of this pathogen is hindered by biofilm-formation, providing protection from noxious environmental factors and antimicrobials. The aim of this study was to assess the antibiotic susceptibility, antiseptic susceptibility and biofilm-forming capacity using phenotypic methods in environmental A. baumannii isolates. One hundred and fourteen (n = 114) isolates were collected, originating from various environmental sources and geographical regions. Antimicrobial susceptibility testing was carried out using the disk diffusion method, while antiseptic susceptibility was performed using the agar dilution method. Determination of biofilm-forming capacity was carried out using a microtiter-plate based method. Resistance in environmental A. baumannii isolates were highest for ciprofloxacin (64.03%, n = 73), levofloxacin (62.18%, n = 71) and trimethoprim-sulfamethoxazole (61.40%, n = 70), while lowest for colistin (1.75%, n = 2). Efflux pump overexpression was seen in 48.25% of isolates (n = 55), 49.12% (n = 56) were classified as MDR. 6.14% (n = 7), 9.65% (n = 11), 24.65% (n = 28) and 59.65% (n = 68) of isolates were non-biofilm producers, weak, medium, and strong biofilm producers, respectively. No significant differences were observed between non-MDR vs. MDR isolates regarding their distribution of biofilm-producers (P = 0.655). The MIC ranges for the tested antiseptics were as follows: benzalkonium chloride 16-128 µg mL-1, chlorhexidine digluconate 4-128 µg mL-1, formaldehyde 64-256 µg mL-1 and triclosan 2-16 µg mL-1, respectively. The conscientious use of antiseptics, together with periodic surveillance, is essential to curb the spread of these bacteria, and to maintain current infection prevention capabilities.

The potential of Hungarian bauxite residue isolates for biotechnological applications.

Bauxite residue (red mud) is considered an extremely alkaline and salty environment for the biota. We present the first attempt to isolate, identify and characterise microbes from Hungarian bauxite residues. Four identified bacterial strains belonged to the Bacilli class, one each to the Actinomycetia, Gammaproteobacteria, and Betaproteobacteria classes, and two to the Alphaproteobacteria class. All three identified fungi strains belonged to the Ascomycota division. Most strains tolerated pH 8-10 and salt content at 5-7% NaCl concentration. Alkalihalobacillus pseudofirmus BRHUB7 and Robertmurraya beringensis BRHUB9 can be considered halophilic and alkalitolerant. Priestia aryabhattai BRHUB2, Penicillium chrysogenum BRHUF1 and Aspergillus sp. BRHUF2 are halo- and alkalitolerant strains. Most strains produced siderophores and extracellular polymeric substances, could mobilise phosphorous, and were cellulose degraders. These strains and their enzymes are possible candidates for biotechnological applications in processes requiring extreme conditions, e.g. bioleaching of critical raw materials and rehabilitation of alkaline waste deposits.

Systematic detection of co-infection and intra-host recombination in more than 2 million global SARS-CoV-2 samples.

Systematic monitoring of SARS-CoV-2 co-infections between different lineages and assessing the risk of intra-host recombinant emergence are crucial for forecasting viral evolution. Here we present a comprehensive analysis of more than 2 million SARS-CoV-2 raw read datasets submitted to the European COVID-19 Data Portal to identify co-infections and intra-host recombination. Co-infection was observed in 0.35% of the investigated cases. Two independent procedures were implemented to detect intra-host recombination. We show that sensitivity is predominantly determined by the density of lineage-defining mutations along the genome, thus we used an expanded list of mutually exclusive defining mutations of specific variant combinations to increase statistical power. We call attention to multiple challenges rendering recombinant detection difficult and provide guidelines for the reduction of false positives arising from chimeric sequences produced during PCR amplification. Additionally, we identify three recombination hotspots of Delta - Omicron BA.1 intra-host recombinants.

Cell length growth in fission yeast: an analysis of its bilinear character and the nature of its rate change transition.

During their mitotic cycle, cylindrical fission yeast cells grow exclusively at their tips. Length growth starts at birth and halts at mitotic onset when the cells begin to prepare for division. While the growth pattern was initially considered to be exponential, during the last three decades an increasing amount of evidence indicated that it is rather a bilinear function [two linear segments separated by a rate change point (RCP)]. The main focus of this work was to clarify this and to elucidate the further question of whether the rate change occurs abruptly at the RCP or more smoothly during a transition period around it. We have analyzed the individual growth patterns obtained by time-lapse microscopy of 60 wild-type cells separately as well as that of the 'average' cell generated from their superposition. Linear, exponential, and bilinear functions were fitted to the data, and their suitability was compared using objective model selection criteria. This analysis found the overwhelming majority of the cells (70%) to have a bilinear growth pattern with close to half of them showing a smooth and not an abrupt transition. The growth pattern of the average cell was also found to be bilinear with a smooth transition.

SPOCK1 Overexpression Suggests Poor Prognosis of Ovarian Cancer.

PURPOSE: Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been found in a variety of malignant tumors and is associated with a poor prognosis. We aimed to explore the role of SPOCK1 in ovarian cancer. METHODS: Ovarian cancer cell lines SKOV3 and SW626 were transfected with SPOCK1 overexpressing or empty vector using electroporation. Cells were studied by immunostaining and an automated Western blotting system. BrdU uptake and wound healing assays assessed cell proliferation and migration. SPOCK1 expression in human ovarian cancer tissues and in blood samples were studied by immunostaining and ELISA. Survival of patients with tumors exhibiting low and high SPOCK1 expression was analyzed using online tools. RESULTS: Both transfected cell lines synthesized different SPOCK1 variants; SKOV3 cells also secreted the proteoglycan. SPOCK1 overexpression stimulated DNA synthesis and cell migration involving p21CIP1. Ovarian cancer patients had increased SPOCK1 serum levels compared to healthy controls. Tumor cells of tissues also displayed abundant SPOCK1. Moreover, SPOCK1 levels were higher in untreated ovarian cancer serum and tissue samples and lower in recipients of chemotherapy. According to in silico analyses, high SPOCK1 expression was correlated with shorter survival. CONCLUSION: Our findings suggest SPOCK1 may be a viable anti-tumor therapeutic target and could be used for monitoring ovarian cancer.

Detection and genetic characterization of circoviruses in more than 80 bat species from eight countries on four continents.

Several bat-associated circoviruses and circular rep-encoding single-stranded DNA (CRESS DNA) viruses have been described, but the exact diversity and host species of these viruses are often unknown. Our goal was to describe the diversity of bat-associated circoviruses and cirliviruses, thus, 424 bat samples from more than 80 species were collected on four continents. The samples were screened for circoviruses using PCR and the resulting amino acid sequences were subjected to phylogenetic analysis. The majority of bat strains were classified in the genus Circovirus and some strains in the genus Cyclovirus and the clades CRESS1 and CRESS3. Some strains, however, could only be classified at the taxonomic level of the order and were not classified in any of the accepted or proposed clades. In the family Circoviridae, 71 new species have been predicted. This screening of bat samples revealed a great diversity of circoviruses and cirliviruses. These studies underline the importance of the discovery and description of new cirliviruses and the need to establish new species and families in the order Cirlivirales.

Patterns of Somatic Variants in Colorectal Adenoma and Carcinoma Tissue and Matched Plasma Samples from the Hungarian Oncogenome Program.

Analysis of circulating cell-free DNA (cfDNA) of colorectal adenoma (AD) and cancer (CRC) patients provides a minimally invasive approach that is able to explore genetic alterations. It is unknown whether there are specific genetic variants that could explain the high prevalence of CRC in Hungary. Whole-exome sequencing (WES) was performed on colon tissues (27 AD, 51 CRC) and matched cfDNAs (17 AD, 33 CRC); furthermore, targeted panel sequencing was performed on a subset of cfDNA samples. The most frequently mutated genes were APC, KRAS, and FBN3 in AD, while APC, TP53, TTN, and KRAS were the most frequently mutated in CRC tissue. Variants in KRAS codons 12 (AD: 8/27, CRC: 11/51 (0.216)) and 13 (CRC: 3/51 (0.06)) were the most frequent in our sample set, with G12V (5/27) dominance in ADs and G12D (5/51 (0.098)) in CRCs. In terms of the cfDNA WES results, tumor somatic variants were found in 6/33 of CRC cases. Panel sequencing revealed somatic variants in 8 out of the 12 enrolled patients, identifying 12/20 tumor somatic variants falling on its targeted regions, while WES recovered only 20% in the respective regions in cfDNA of the same patients. In liquid biopsy analyses, WES is less efficient compared to the targeted panel sequencing with a higher coverage depth that can hold a relevant clinical potential to be applied in everyday practice in the future.

Breast cancer-related lymphedema and treatment / Emlotumorhoz társuló lymphoedema és kezelése

Breast cancer-related lymphedema may impact life quality and cause co-morbidity of several types. Though breast cancer-related lymphedema does not directly follow the initial intervention, it may develop even years after it; timely diagnosis and treatment are essential. The combined therapies such as radiation, chemo- and endocrine therapy, and other events (e.g., injury, infection, inflammation, or systemic disease) may further impair the lymphatic function. A prospective surveillance program for the early detection of subclinical edema in high-risk patient groups may improve quality of life. Currently, complex decongestive physiotherapy is the first-line treatment of breast cancer-related lymphedema. It should start soon after the diagnosis. After the early-stage treatment, the lifelong care and followup of the patients are necessary. The article presents pathophysiology, treatment, and future trends of therapies in breast cancer-related lymphedema.

The Role of Cell-Free DNA in Cancer Treatment Decision Making.

The aim of this review is to evaluate the present status of the use of cell-free DNA and its fraction of circulating tumor DNA (ctDNA) because this year July 2022, an ESMO guideline was published regarding the application of ctDNA in patient care. This review is for clinical oncologists to explain the concept, the terms used, the pros and cons of ctDNA; thus, the technical aspects of the different platforms are not reviewed in detail, but we try to help in navigating the current knowledge in liquid biopsy. Since the validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, ctDNA may be used for this soon in routine clinical practice and in other different areas as well. The cfDNA fragments can be obtained by liquid biopsy and can be used for diagnosis, prognosis, and selecting among treatment options in cancer patients. A great proportion of cfDNA comes from normal cells of the body or from food uptake. Only a small part (<1%) of it is related to tumors, originating from primary tumors, metastatic sites, or circulating tumor cells (CTCs). Soon the data obtained from ctDNA may routinely be used for finding minimal residual disease, detecting relapse, and determining the sites of metastases. It might also be used for deciding appropriate therapy, and/or emerging resistance to the therapy and the data analysis of ctDNA may be combined with imaging or other markers. However, to achieve this goal, further clinical validations are inevitable. As a result, clinicians should be aware of the limitations of the assays. Of course, several open questions are still under research and because of it cfDNA and ctDNA testing are not part of routine care yet.

Co-Detection of VEGF-A and Its Regulator, microRNA-181a, May Indicate Central Nervous System Involvement in Pediatric Leukemia.

Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing CNS disease with the currently used cell-based approach of cerebrospinal fluid (CSF) diagnostics. Our study focused on developing novel subcellular CNS leukemia indicators in the CSF and the bone marrow (BM) of patients with pALL. Serial liquid biopsy samples (n = 65) were analyzed by Elisas to measure the level of essential proteins associated with blast cell CNS trafficking, vascular endothelial growth factor A (VEGF-A) and integrin alpha 6 (ITGA6). In CSF samples from early induction chemotherapy, VEGF-A concentration were uniformly elevated in the CNS-positive group compared to those patients without unambiguous meningeal infiltration (9 vs Nine patients, Δc = 17.2 pg/ml, p = 0.016). Expression of miR-181a, a VEGFA-regulating microRNA which showed increased level in CNS leukemia in our previous experiments, was then paralleled with VEGF-A concentration. A slight correlation between the levels of miR-181a and VEGF-A indicators in CSF and BM samples was revealed (n = 46, Pearson's r = 0.36, p = 0.015). After validating in international cohorts, the joint quantification of miR-181a and VEGF-A might provide a novel tool to precisely diagnose CNS involvement and adjust CNS-directed therapy in pALL.