ABSTRACT
This study aimed to identify microRNAs (miRNAs) whose expression levels are altered by high-risk human papillomavirus (HR-HPV) infection in women with epithelial ovarian neoplasms. MiRNA expression was quantified by real-time polymerase chain reaction, while HR-HPV DNA was quantified using digital-droplet PCR. Analysis of 11 miRNAs demonstrated significantly lower hsa-miR-25-5p expression in HPV-infected compared to uninfected ovarian tissues (p = 0.0405), while differences in miRNA expression in corresponding serum were statistically insignificant. The expression of hsa-miR-218-5p in ovarian tumors was significantly higher in high-grade serous ovarian carcinoma (HGSOC) cases than in other neoplasms (p = 0.0166). In addition, hsa-miR-218-5p was significantly upregulated, whereas hsa-miR-191-5p was significantly downregulated in tissues with stage III/IV FIGO (p = 0.0009 and p = 0.0305, respectively). Using unsupervised clustering, we identified three unique patient groups with significantly varied frequencies of HPV16/18-positive samples and varied miRNA expression profiles. In multivariate analysis, high expression of hsa-miR-16-5p was an independent prognostic factor for poor overall survival (p = 0.0068). This preliminary analysis showed the changes in miRNA expression in ovarian neoplasms during HPV infection and those collected from HGSOCs or patients with advanced disease. This prospective study can provide new insights into the pathogenesis of ovarian neoplasms and host-virus interactions.
Subject(s)
MicroRNAs , Ovarian Neoplasms , Papillomavirus Infections , Humans , Female , Papillomavirus Infections/complications , Papillomavirus Infections/genetics , Human papillomavirus 16 , Prospective Studies , Human papillomavirus 18 , MicroRNAs/genetics , Ovarian Neoplasms/geneticsABSTRACT
Vasculitis and HIT have different etiologies, although both involve autoimmune mechanisms. Treatment of vasculitis often requires the use of an anticoagulant such as heparin, which can lead to the development of HIT and subsequent life-threatening complications. The analysis covered patients hospitalized in the Department of Internal Medicine, Nephrology and Dialysis in the period from September 2020 to March 2023. After analyzing the data, we selected four patients in whom vasculitis treatment was complicated by HIT. These included two patients with ANCA vasculitis and two patients with anti-GBM disease. We also described similar cases reported in the literature.
ABSTRACT
In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT6 receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure-activity relationship (SAR) of these compounds. Our main objective is to improve their activity and selectivity against off-target receptors. Overall, our findings contribute to the advancement of novel compounds targeting the 5-HT6 receptor. Compound 29 exhibits significant promise in terms of pharmacological, physicochemical, and ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Consequently, it merits thorough exploration as a potential drug candidate due to its favorable activity profile and successful outcomes in a range of in vivo experiments.
Subject(s)
Pyridines , Serotonin Antagonists , Pyridines/chemistry , Serotonin Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Thiophenes , Humans , Basic Helix-Loop-Helix Transcription Factors/metabolism , Thiophenes/pharmacology , Transcription Factors , Hypoxia , Hypoxia-Inducible Factor 1, alpha SubunitABSTRACT
BACKGROUND: When the COVID-19 pandemic commenced in 2020, scientists assisted medical specialists with diagnostic algorithm development. One scientific research area related to COVID-19 diagnosis was medical imaging and its potential to support molecular tests. Unfortunately, several systems reported high accuracy in development but did not fare well in clinical application. The reason was poor generalization, a long-standing issue in AI development. Researchers found many causes of this issue and decided to refer to them as confounders, meaning a set of artefacts and methodological errors associated with the method. We aim to contribute to this steed by highlighting an undiscussed confounder related to image resolution. METHODS: 20 216 chest X-ray images (CXR) from worldwide centres were analyzed. The CXRs were bijectively projected into the 2D domain by performing Uniform Manifold Approximation and Projection (UMAP) embedding on the radiomic features (rUMAP) or CNN-based neural features (nUMAP) from the pre-last layer of the pre-trained classification neural network. Additional 44 339 thorax CXRs were used for validation. The comprehensive analysis of the multimodality of the density distribution in rUMAP/nUMAP domains and its relation to the original image properties was used to identify the main confounders. RESULTS: nUMAP revealed a hidden bias of neural networks towards the image resolution, which the regular up-sampling procedure cannot compensate for. The issue appears regardless of the network architecture and is not observed in a high-resolution dataset. The impact of the resolution heterogeneity can be partially diminished by applying advanced deep-learning-based super-resolution networks. CONCLUSIONS: rUMAP and nUMAP are great tools for image homogeneity analysis and bias discovery, as demonstrated by applying them to COVID-19 image data. Nonetheless, nUMAP could be applied to any type of data for which a deep neural network could be constructed. Advanced image super-resolution solutions are needed to reduce the impact of the resolution diversity on the classification network decision.
Subject(s)
COVID-19 , Deep Learning , Humans , COVID-19/diagnostic imaging , COVID-19 Testing , Pandemics , ArtifactsABSTRACT
The outbreak of the SARS-CoV-2 pandemic has put healthcare systems worldwide to their limits, resulting in increased waiting time for diagnosis and required medical assistance. With chest radiographs (CXR) being one of the most common COVID-19 diagnosis methods, many artificial intelligence tools for image-based COVID-19 detection have been developed, often trained on a small number of images from COVID-19-positive patients. Thus, the need for high-quality and well-annotated CXR image databases increased. This paper introduces POLCOVID dataset, containing chest X-ray (CXR) images of patients with COVID-19 or other-type pneumonia, and healthy individuals gathered from 15 Polish hospitals. The original radiographs are accompanied by the preprocessed images limited to the lung area and the corresponding lung masks obtained with the segmentation model. Moreover, the manually created lung masks are provided for a part of POLCOVID dataset and the other four publicly available CXR image collections. POLCOVID dataset can help in pneumonia or COVID-19 diagnosis, while the set of matched images and lung masks may serve for the development of lung segmentation solutions.
Subject(s)
COVID-19 , Deep Learning , Radiography, Thoracic , X-Rays , Humans , Algorithms , Artificial Intelligence , COVID-19/diagnostic imaging , COVID-19 Testing , Pneumonia , Poland , Radiography, Thoracic/methods , SARS-CoV-2ABSTRACT
The implementation of forest management generates logging residue which can be used in several ways. One of the option is to use of logging residue in the composting process. Therefore, this study determined the possibility of producing compost based on logging residue and the produced fertilizer used to fertilize forest nurseries. Pine chips and sewage sludge were used for carrying out the study. The compost, as well as the leachate produced during composting, were characterized by high NPK content. The leachate collected at the end of the experiment was characterized by nitrogen content of approximately 6500 mgâ§dm-3, phosphorus of approximately 450 mgâ§dm-3, and potassium of approximately 500-700 mgâ§dm-3. In contrast, the compost produced contained approximately 0.57 gâ§kg-1 nitrogen, approximately 0.39 gâ§kg-1 phosphorus, and approximately 0.24 gâ§kg-1 potassium. The disadvantage in terms of the usefulness of the resulting fertilizer in forest nurseries is its pH, which exceeded 9.0.
Subject(s)
Composting , Soil , Fertilizers , Potassium , Phosphorus , Sewage/chemistry , Nitrogen/analysisABSTRACT
The aim of the study was to review and discuss the management and recycling of anaerobic digestate solid fraction by composting process in the context of circular bioeconomy and sustainable development. The conversion of the solid fraction into compost can be recognized as novel process-enhancing supplements for land reclamation. Moreover, the solid fraction of the digestate is a valuable substrate for compost production, both as a monosubstrate and as a valuable additive for other raw materials to enrich in organic matter. These results should serve as reference point to target adjusting screws for anaerobic digestate solid fraction by composting process improvement, its implementation in modern bioeconomy perspective as well as provide a guideline for effective waste management.
Subject(s)
Composting , Waste Management , Soil , Anaerobiosis , Recycling , Solid WasteABSTRACT
Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.
Subject(s)
Antipsychotic Agents , Quinazolinones , Receptors, Metabotropic Glutamate , Schizophrenia , Animals , Humans , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Dizocilpine Maleate , Quinazolinones/pharmacology , Quinazolinones/therapeutic use , Receptors, Metabotropic Glutamate/drug effects , Receptors, Metabotropic Glutamate/metabolism , Schizophrenia/drug therapy , Schizophrenia/metabolism , Drug DesignABSTRACT
New protocol for screening efficient and environmentally friendly solvents was proposed and experimentally verified. The guidance for solvent selection comes from computed solubility via COSMO-RS approach. Furthermore, solute-solvent affinities computed using advanced quantum chemistry level were used as a rationale for observed solvents ranking. The screening protocol pointed out that 4-formylomorpholine (4FM) is an attractive solubilizer compared to commonly used aprotic solvents such as DMSO and DMF. This was tested experimentally by measuring the solubility of the title compounds in aqueous binary mixtures in the temperature range between 298.15 K and 313.15 K. Additional measurements were also performed for aqueous binary mixtures of DMSO and DMF. It has been found that the solubility of studied aromatic amides is very high and quite similar in all three aprotic solvents. For most aqueous binary mixtures, a significant decrease in solubility with a decrease in the organic fraction is observed, indicating that all systems can be regarded as efficient solvent-anti-solvent pairs. In the case of salicylamide dissolved in aqueous-4FM binary mixtures, a strong synergistic effect has been found leading to the highest solubility for 0.6 mole fraction of 4-FM.
Subject(s)
Dimethyl Sulfoxide , Salicylamides , Benzamides , Dimethyl Sulfoxide/chemistry , Solvents/chemistry , Water/chemistryABSTRACT
INTRODUCTION: Urine concentration of human kidney injury molecule-1 (KIM-1) is suggested to be increased in patients with renal cell carcinoma (RCC). However, it has never been tested in patients with urothelial tumors, while preoperative differentiation between RCC and upper tract urothelial carcinoma (UTUC) plays an essential role in therapeutic decisions.The aim of the study was to evaluate the role of urinary KIM-1 expression in preoperative differentiation between RCC and urothelial carcinoma (UC). MATERIAL AND METHODS: Sixty-four participants were enrolled in the study, including 30 patients with RCC and 27 with UC (16 with UTUC and 11 with bladder tumor). Preoperative urinary KIM-1 levels were measured using a commercially available ELISA kit and normalized to urinary creatinine levels. RESULTS: The median concentration of urinary KIM-1 normalized to urinary creatinine was lower in patients with RCC compared to UC (1.35 vs 1.86 ng/mg creatinine, p = 0.04). The comparison between RCC and UTUC shows even more significant difference (1.33 vs 2.23 ng/mg creatinine, p = 0.02). Urinary KIM-1 concentration did not correlate with tumor stage nor grade in any of the groups. ROC analysis to identify UC revealed AUC of 0.657 with sensitivity 33.3% and specificity 96.7% at the cut-off value of 3.226 ng/mg creatinine. Among patients with eGFR ≥60 mL/min/1.73 m², ROC analysis to detect UC achieved AUC of 0.727 with sensitivity 69.5% and specificity 70.2%. CONCLUSIONS: Urine KIM-1 can potentially differentiate UC from RCC. However, a wide range of observed results and limited sensitivity and specificity requires caution in making clinical decisions before confirmatory studies.
ABSTRACT
Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient lactate transport to avoid intracellular lactate accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a lactate transporter that plays a central role in tumor pH modulation. The discovery and optimization of a novel class of MCT4 inhibitors (hit 9a), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound 18n with the cytosolic domain of MCT4 was shown after solubilization of the GFP-tagged transporter by fluorescence cross-correlation spectroscopy and microscopic studies. In vitro treatment with 18n resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of 18n allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus, 18n represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.
Subject(s)
Antineoplastic Agents/therapeutic use , Monocarboxylic Acid Transporters/antagonists & inhibitors , Muscle Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Picolinic Acids/therapeutic use , Sulfonamides/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , HEK293 Cells , Humans , Lactic Acid/metabolism , Mice, Inbred C57BL , Mice, Nude , Mice, SCID , Molecular Structure , Picolinic Acids/chemical synthesis , Picolinic Acids/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The short latency required by IoT devices that need to access specific services have led to the development of Fog architectures that can serve as a useful intermediary between IoT systems and the Cloud. However, the massive numbers of IoT devices that are being deployed raise concerns about the power consumption of such systems as the number of IoT devices and Fog servers increase. Thus, in this paper, we describe a software-defined network (SDN)-based control scheme for client-server interaction that constantly measures ongoing client-server response times and estimates network power consumption, in order to select connection paths that minimize a composite goal function, including both QoS and power consumption. The approach using reinforcement learning with neural networks has been implemented in a test-bed and is detailed in this paper. Experiments are presented that show the effectiveness of our proposed system in the presence of a time-varying workload of client-to-service requests, resulting in a reduction of power consumption of approximately 15% for an average response time increase of under 2%.
ABSTRACT
Immunosuppression is one of the main mechanisms facilitating tumor expansion. It may be driven by immune checkpoint protein expression, anti-inflammatory cytokine secretion or enhanced metabolic enzyme production, leading to the subsequent build-up of metabolites such as adenosine. Under physiological conditions, adenosine prevents the development of tissue damage resulting from a prolonged immune response; the same mechanism might be employed by tumor tissue to promote immunosuppression. Immune cells expressing A2A and A2B adenosine receptors present in an adenosine-rich environment have suppressed effector functions, such as cytotoxicity, proinflammatory cytokine release, antigen presentation and others, making them inert to cancer cells. This study was designed to investigate the dual antagonist potential of SEL330-639 to abolish adenosine-driven immunosuppression. SEL330-639 has slow dissociation kinetics. It inhibits cAMP production in human CD4+ cells, CD8+ cells and moDCs, which leads to diminished CREB phosphorylation and restoration of antitumor cytokine production (IL-2, TNFα, IL-12) in multiple primary human immune cells. The aforementioned results were additionally validated by gene expression analysis and functional assays in which NK cell line cytotoxicity was recovered by SEL330-639. Adenosine-driven immunosuppression is believed to preclude the effectiveness of immune checkpoint inhibitor therapies. Hence, there is an urgent need to develop new immuno-oncological strategies. Here, we comprehensively characterize SEL330-639, a novel dual A2A/A2B receptor antagonist effective in both lymphoid and myeloid cell populations with nanomolar potency. Due to its tight binding to the A2A and A2B receptors, this binding is sustained even at high adenosine concentrations mimicking the upper limit of the range of adenosine levels observed in the tumor microenvironment.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Adenosine/immunology , Immunosuppression Therapy/methods , Animals , Cell Line , Cyclic AMP/antagonists & inhibitors , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cytokines/metabolism , Dendritic Cells/metabolism , Humans , Killer Cells, Natural/drug effects , Kinetics , Phosphorylation/drug effects , Rats , Receptor, Adenosine A2A/drug effects , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/immunology , Receptor, Adenosine A2B/drug effects , Receptor, Adenosine A2B/genetics , Receptor, Adenosine A2B/immunology , T-Lymphocytes/metabolismABSTRACT
Breast cancer is the most common female malignant neoplasm in Poland and around the world. Precise determination of tumor molecular profile allows application of appropriate anticancer therapy, increasing the chances of recovery. A 28-year-old woman detected a thickening in her left breast. Mammography showed a change measuring 60 mm (radiologically BIRADS 5). The biopsy revealed invasive ductal carcinoma, luminal subtype B, HER2 positive (cT3N1M0). Neoadjuvant chemotherapy was administered and then breast conserving surgery was performed. In postoperative histopathology cancer, biological subtype was evaluated: HER2 positive, nonluminal (ypT2ypN0cM0). Then, postoperative radiotherapy was performed. After 14 months, breast ultrasonography (US) and mammography (MGF) revealed the presence of suspicious changes (BIRADS 4). Tru-cut biopsy confirmed cancer recurrence (luminal subtype B, HER2 negative, ER negative, PgR: 10%, Ki-67: 70%). Despite implemented and modified chemotherapy regimens, local progression occurred. Genetic testing excluded BRCA gene mutation. The patient qualified for radical mastectomy modo Halsted (ypT4bN0cM0). Postoperative microscopic examination revealed triple negative breast invasive carcinoma of no special type. After 22 months, metastatic lesions in lungs and left retrosternal nodes appeared. Due to the limited possibilities of systemic treatment, the patient qualified for stereotactic radiotherapy of tumors in the lungs' and left retrosternal nodes. Advancement, histological type and molecular profile should be controlled at each stage of the disease, as they may change several times and require modification of therapy.
ABSTRACT
PURPOSE: Human Kidney Injury Molecule-1 (hKIM-1) was proposed as urinary biomarker of renal cell carcinoma (RCC). The aim of the study was to validate urinary hKIM-1 as a biomarker of RCC. MATERIAL AND METHODS: Forty-six participants were enrolled into the study, including 30 patients with clear-cell or papillary RCC and 16 matched patients in the comparison group. Preoperative urinary hKIM-1 levels were measured using commercially available ELISA kit and normalized to urinary creatinine levels. RESULTS: The concentrations of urinary hKIM-1 normalized to urinary creatinine in patients with RCC and comparison group did not differ significantly (1.35 vs. 1.32 ng/mg creatinine, p=.25). There was also no difference in urinary hKIM-1 concentration regarding stage or grade of renal cancer. Additional analysis of patients without chronic kidney disease (defined as eGFR ≥60mL/min/1.73m²) also did not reveal significant difference in urinary hKIM-1 concentrations between the groups (1.54 vs. 1.37; p=.47). CONCLUSION: Results of our study do not confirm recent suggestions that urinary hKIM-1 may be a biomarker of RCC.
Subject(s)
Biomarkers, Tumor/urine , Carcinoma, Renal Cell/urine , Hepatitis A Virus Cellular Receptor 1/analysis , Kidney Neoplasms/urine , Aged , Female , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
BACKGROUND: X-linked EDA-ID1 (ectodermal dysplasia, anhidrotic, with immunodeficiency 1, Online Mendelian Inheritance in Man [OMIM] 300291), or NEMO (nuclear factor kappa B essential modulator) deficiency syndrome, is caused by mutations in the IKBKG/NEMO gene. We report the case of a boy with EDA-ID1 who underwent allogeneic stem cell transplantation. METHODS: In early infancy, the patient developed an atypical, severe, initial manifestation resembling Omenn syndrome with infections, and he underwent allogeneic stem cell transplantation from an unrelated 9 of 10 HLA matched donor with a mismatch in the DQB1 allele after conditioning with treosulfan, fludarabine, thiotepa, and antithymocyte globulin (Grafalon). The post-transplant period was complicated by cytomegalovirus replication and mild, grade 2 graft vs host disease. Because of NEMO deficiency syndrome-associated enteropathy and continuous weight loss, parenteral nutrition was started and the patient was fed an elemental formula and a gluten-free diet. Over a period of 3 years, the patient had 7 incidents of blood stream infections caused by Staphylococci or gut-derived Gram-negative flora, with 1 incident of septic shock caused by Escherichia coli. The blood stream infection stopped after gastrointestinal tract decontamination was done once per month for 7-day courses alternately with rifaximin, vancomycin, and gentamicin sulfate. CONCLUSIONS: Patients with NEMO deficiency syndrome require very complex, multidisciplinary care, and immunodeficiency correction can only be observed as one of the critical points in patient care. Developmental problems, enteropathy with the need for intravenous hyperalimentation, and specific interventions for other clinical manifestations of multifaceted syndrome are needed for proper care.
Subject(s)
Busulfan/analogs & derivatives , Ectodermal Dysplasia/therapy , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Antilymphocyte Serum/therapeutic use , Busulfan/therapeutic use , Humans , I-kappa B Kinase/deficiency , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/therapy , Infant , Male , Thiotepa/therapeutic use , Transplantation, Homologous , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
ABSTRACT Purpose: Radical treatment in elderly patients with renal tumor remains debatable due to uncertainties regarding the risk of surgical complications, risk of end-stage renal disease (ESRD) and survival benefit. The aim of the study was to assess outcomes of radical treatment for renal cancer in elderly patients. Materials and Methods: This retrospective analysis enrolled 507 consecutive patients treated with partial or radical nephrectomy due to renal mass. Patients with upfront metastatic disease (n=46) and patients lost to follow-up (n=110) were excluded from the analysis. Surgical, functional (screen for ESRD development) and survival outcomes were analyzed in patients aged >75 years in comparison to younger individuals. Results: The analyzed group included 55 elderly patients and 296 younger controls. Within the cohort a total of 148 and 203 patients underwent radical and partial nephrectomies respectively. The rate of surgical complications, including grade ≥3 Clavien- Dindo complications, did not differ between groups (3.6% vs. 4.4%, p=0.63). Median length of hospital stay was equal in both groups (7 days). During a follow-up (median 51.9 months, no difference between groups), ESRD occurred in 3.4% of controls and was not reported in elderly group (p=0.37). Younger patients demonstrated a statistically significant advantage in both overall survival and cancer-specific survival over elderly patients (OS 94.6% vs. 87% p=0.036, CSS 97.3% vs. 89.1% p=0.0008). Conclusions: Surgical treatment in elderly patients with renal tumor is as safe as in younger individuals and does not increase the risk of ESRD. However, cancer specific survival among these patients remains shorter than in younger patients.
Subject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Carcinoma, Renal Cell/surgery , Kidney Neoplasms/surgery , Nephrectomy/methods , Postoperative Complications , Carcinoma, Renal Cell/mortality , Retrospective Studies , Risk Factors , Treatment Outcome , Statistics, Nonparametric , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Middle Aged , Nephrectomy/adverse effects , Nephrectomy/mortalityABSTRACT
PURPOSE: Radical treatment in elderly patients with renal tumor remains debatable due to uncertainties regarding the risk of surgical complications, risk of end-stage renal disease (ESRD) and survival benefit. The aim of the study was to assess outcomes of radical treatment for renal cancer in elderly patients. MATERIALS AND METHODS: This retrospective analysis enrolled 507 consecutive patients treated with partial or radical nephrectomy due to renal mass. Patients with upfront metastatic disease (n=46) and patients lost to follow-up (n=110) were excluded from the analysis. Surgical, functional (screen for ESRD development) and survival outcomes were analyzed in patients aged >75 years in comparison to younger individuals. RESULTS: The analyzed group included 55 elderly patients and 296 younger controls. Within the cohort a total of 148 and 203 patients underwent radical and partial nephrectomies respectively. The rate of surgical complications, including grade >3 Clavien- Dindo complications, did not differ between groups (3.6% vs. 4.4%, p=0.63). Median length of hospital stay was equal in both groups (7 days). During a follow-up (median 51.9 months, no difference between groups), ESRD occurred in 3.4% of controls and was not reported in elderly group (p=0.37). Younger patients demonstrated a statistically significant advantage in both overall survival and cancer-specific survival over elderly patients (OS 94.6% vs. 87% p=0.036, CSS 97.3% vs. 89.1% p=0.0008). CONCLUSIONS: Surgical treatment in elderly patients with renal tumor is as safe as in younger individuals and does not increase the risk of ESRD. However, cancer specific survival among these patients remains shorter than in younger patients.
Subject(s)
Carcinoma, Renal Cell/surgery , Kidney Neoplasms/surgery , Nephrectomy/methods , Aged , Aged, 80 and over , Carcinoma, Renal Cell/mortality , Female , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Male , Middle Aged , Nephrectomy/adverse effects , Nephrectomy/mortality , Postoperative Complications , Retrospective Studies , Risk Factors , Statistics, Nonparametric , Treatment OutcomeABSTRACT
In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.