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Vaccines Apr 2024Ovarian cancer is one of the most common cancers among women and the most lethal malignancy of all gynecological cancers. Surgery is promising in the early stages;...
Ovarian cancer is one of the most common cancers among women and the most lethal malignancy of all gynecological cancers. Surgery is promising in the early stages; however, most patients are first diagnosed in the advanced stages, where treatment options are limited. Here, we present a 49-year-old patient who was first diagnosed with stage III ovarian cancer. After the tumor progressed several times under guideline therapies with no more treatment options available at that time, the patient received a fully individualized neoantigen-derived peptide vaccine in the setting of an individual healing attempt. The tumor was analyzed for somatic mutations via whole exome sequencing and potential neoepitopes were vaccinated over a period of 50 months. During vaccination, the patient additionally received anti-PD-1 therapy to prevent further disease progression. Vaccine-induced T-cell responses were detected using intracellular cytokine staining. After eleven days of in vitro expansion, four T-cell activation markers (namely IFN-ɣ, TNF-α, IL-2, and CD154) were measured. The proliferation capacity of neoantigen-specific T-cells was determined using a CFSE proliferation assay. Immune monitoring revealed a very strong CD4+ T-cell response against one of the vaccinated peptides. The vaccine-induced T-cells simultaneously expressed CD154, TNF, IL-2, and IFN-ɣ and showed a strong proliferation capacity upon neoantigen stimulation. Next-generation sequencing, as well as immunohistochemical analysis, revealed a loss of Beta-2 microglobulin (B2M), which is essential for MHC class I presentation. The results presented here implicate that the application of neoantigen-derived peptide vaccines might be considered for those cancer stages, where promising therapeutic options are lacking. Furthermore, we provide more data that endorse the intensive investigation of B2M loss as a tumor escape mechanism in clinical trials using anti-cancer vaccines together with immune-checkpoint inhibitors.
PubMed: 38675779
DOI: 10.3390/vaccines12040397 -
Biomolecules Apr 2024Cerebrovascular disease accounts for major neurologic disabilities in patients with type 2 diabetes mellitus (DM). A potential association of mitochondrial DNA () and...
Cerebrovascular disease accounts for major neurologic disabilities in patients with type 2 diabetes mellitus (DM). A potential association of mitochondrial DNA () and inflammation with cerebral vessel remodeling in patients with type 2 DM was evaluated. A cohort of 150 patients and 30 healthy controls were assessed concerning urinary albumin/creatinine ratio (UACR), synaptopodin, podocalyxin, kidney injury molecule-1 (KIM-1), N-acetyl-β-(D)-glucosaminidase (NAG), interleukins IL-17A, IL-18, IL-10, tumor necrosis factor-alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1). and nuclear DNA () were quantified in peripheral blood and urine by qRT-PCR. Cytochrome b () gene, subunit 2 of NADH dehydrogenase (), and beta 2 microglobulin nuclear gene () were assessed by TaqMan assays. was defined as the ratio of the number of copies, through analysis of the and ratio; cerebral Doppler ultrasound: intima-media thickness (IMT)-the common carotid arteries (CCAs), the pulsatility index (PI) and resistivity index (RI)- the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), the breath-holding index (BHI). The results showed direct correlations of CCAs-IMT, PI-ICAs, PI-MCAs, RI-ICAs, RI-MCAs with urinary , IL-17A, IL-18, TNFα, ICAM-1, UACR, synaptopodin, podocalyxin, KIM-1, NAG, and indirect correlations with serum , IL-10. BHI correlated directly with serum IL-10, and serum , and negatively with serum IL-17A, serum ICAM-1, and NAG. In neurologically asymptomatic patients with type 2 DM cerebrovascular remodeling and impaired cerebrovascular reactivity may be associated with variations and inflammation from the early stages of diabetic kidney disease.
Topics: Humans; DNA, Mitochondrial; Male; Female; Diabetes Mellitus, Type 2; Middle Aged; Inflammation; Diabetic Nephropathies; Aged; Vascular Remodeling; Case-Control Studies
PubMed: 38672515
DOI: 10.3390/biom14040499 -
Kidney360 Apr 2024
Topics: Humans; Renal Dialysis; Sepsis; Catheter-Related Infections; Kidney Failure, Chronic
PubMed: 38662534
DOI: 10.34067/KID.0000000000000407 -
Renal Failure Dec 2024To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance...
OBJECTIVE
To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD).
METHODS
Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and β-microglobulin (β-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration.
RESULTS
The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, β-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased ( < 0.001 for all). The clearance rates of λFLC, β-MG, IL-6, LEP, and TNF-α were significantly higher in HFR compared to HDF ( values: 0.036, 0.042, 0.041, 0.019, and 0.036, respectively). Compared with pre-HFR and post-HFR treatment, levels of serum albumin, valine, and isoleucine showed no significant difference ( > 0.05), while post-HDF, levels of serum albumin significantly decreased ( = 0.000).
CONCLUSION
HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.
Topics: Humans; Hemodiafiltration; Pilot Projects; Uremic Toxins; Chitinase-3-Like Protein 1; Interleukin-6; Tumor Necrosis Factor-alpha; Renal Dialysis; Amino Acids, Branched-Chain; Serum Albumin; Cresols; Methylamines
PubMed: 38632963
DOI: 10.1080/0886022X.2024.2338929 -
International Journal of Nephrology and... 2024AKI is a frequent complication in sepsis patients and is estimated to occur in almost half of patients with severe sepsis. However, there is currently no effective...
INTRODUCTION
AKI is a frequent complication in sepsis patients and is estimated to occur in almost half of patients with severe sepsis. However, there is currently no effective therapy for AKI in sepsis. Therefore, the therapeutic approach is focused on prevention. Based on this, there is an opportunity to examine a panel of biomarker models for predicting AKI.
MATERIAL AND METHODS
This prospective cohort study analysed the differences in Cystatin C, Beta-2 Microglobulin, and NGAL levels in sepsis patients with AKI and sepsis patients without AKI. The biomarker modelling of AKI prediction was done using machine learning, namely Orange Data Mining. In this study, 130 samples were analysed by machine learning. The parameters used to obtain the biomarker panel were 23 laboratory examination parameters.
RESULTS
This study used SVM and the Naïve Bayes model of machine learning. The SVM model's sensitivity, specificity, NPV, and PPV were 50%, 94.4%, 71.4%, and 87.5%, respectively. For the Naïve Bayes model, the sensitivity, specificity, NPV, and PPV were 83.3%, 77.8%, 87.5%, and 71.4%, respectively.
DISCUSSION
This study's SVM machine learning model has higher AUC and specificity but lower sensitivity. The Naïve Bayes model had better sensitivity; it can be used to predict AKI in sepsis patients.
CONCLUSION
The Naïve Bayes machine learning model in this study is useful for predicting AKI in sepsis patients.
PubMed: 38562530
DOI: 10.2147/IJNRD.S450901 -
Cancer Medicine Apr 2024The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International...
The quantitative parameters based on marrow metabolism derived from synthetic MRI: A pilot study of prognostic value in participants with newly diagnosed multiple myeloma.
BACKGROUND
The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International Staging System (R-ISS) in participants with multiple myeloma (MM) is unknown.
METHODS
We prospectively enrolled participants with newly diagnosed MM before treatment. The SyMRI of lumbar marrow was used to calculate T1, T2, and PD values and the clinical features were collected. All participants were divided into good response (≥VGPR) and poor response (
RESULTS
Fifty-nine participants (good response, n = 33; poor response, n = 26) were evaluated. The bone marrow plasma cell percentage, β-microglobulin, T1 and T2 value were difference between two groups (all p < 0.05). The T1 (odds ratio 1.003, p = 0.005) and T2 values (odds ratio 0.910, p = 0.002) were independent predictors and the AUC and cut-off values were 0.787, 967.2 ms and 0.784, 75.9 ms, respectively. There were no significant differences in SyMRI parameters between genders. Participants with both T1 value ≥967.2 ms and T2 value ≤75.9 ms in the R-ISS II stage were potentially to get poor response.
CONCLUSIONS
Synthetic MRI is a promising tool for predicting early treatment response to MM and promoting R-ISS II stage risk stratification.
Topics: Humans; Male; Female; Prognosis; Multiple Myeloma; Bone Marrow; Pilot Projects; Neoplasm Staging; Magnetic Resonance Imaging; Retrospective Studies
PubMed: 38553942
DOI: 10.1002/cam4.7109 -
PLoS Neglected Tropical Diseases Mar 2024Acute kidney injury (AKI) is a critical systemic complication caused by Bothrops envenoming, a neglected health problem in the Brazilian Amazon. Understanding the...
Acute kidney injury (AKI) is a critical systemic complication caused by Bothrops envenoming, a neglected health problem in the Brazilian Amazon. Understanding the underlying mechanisms leading to AKI is crucial for effectively mitigating the burden of this complication. This study aimed to characterize the urinary protein profile of Bothrops atrox snakebite victims who developed AKI. We analyzed three groups of samples collected on admission: healthy subjects (controls, n = 10), snakebite victims who developed AKI (AKI, n = 10), and those who did not evolve to AKI (No-AKI, n = 10). Using liquid-chromatography tandem mass spectrometry, we identified and quantified (label-free) 1190 proteins. A panel of 65 proteins was identified exclusively in the urine of snakebite victims, with 32 exclusives to the AKI condition. Proteins more abundant or exclusive in AKI's urine were associated with acute phase response, endopeptidase inhibition, complement cascade, and inflammation. Notable proteins include serotransferrin, SERPINA-1, alpha-1B-glycoprotein, and NHL repeat-containing protein 3. Furthermore, evaluating previously reported biomarkers candidates for AKI and renal injury, we found retinol-binding protein, beta-2-microglobulin, cystatin-C, and hepcidin to be significant in cases of AKI induced by Bothrops envenoming. This work sheds light on physiological disturbances caused by Bothrops envenoming, highlighting potential biological processes contributing to AKI. Such insights may aid in better understanding and managing this life-threatening complication.
Topics: Animals; Humans; Snake Bites; Bothrops atrox; Proteomics; Acute Kidney Injury; Bothrops; Biological Phenomena
PubMed: 38536893
DOI: 10.1371/journal.pntd.0012072 -
Current Issues in Molecular Biology Feb 2024Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)...
Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flow cytometry. Basal levels of B2M in patients with CLL were measured using an enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, < 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, < 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.
PubMed: 38534728
DOI: 10.3390/cimb46030112 -
Scientific Reports Mar 2024COVID-19 has been a global public health and economic challenge. Screening for the SARS-CoV-2 virus has been a key part of disease mitigation while the world continues...
COVID-19 has been a global public health and economic challenge. Screening for the SARS-CoV-2 virus has been a key part of disease mitigation while the world continues to move forward, and lessons learned will benefit disease detection beyond COVID-19. Saliva specimen collection offers a less invasive, time- and cost-effective alternative to standard nasopharyngeal swabs. We optimized two different methods of saliva sample processing for RT-qPCR testing. Two methods were optimized to provide two cost-efficient ways to do testing for a minimum of four samples by pooling in a 2.0 mL tube and decrease the need for more highly trained personnel. Acid-pH-based RNA extraction method can be done without the need for expensive kits. Direct Lysis is a quick one-step reaction that can be applied quickly. Our optimized Acid-pH and Direct Lysis protocols are reliable and reproducible, detecting the beta-2 microglobulin (B2M) mRNA in saliva as an internal control from 97 to 96.7% of samples, respectively. The cycle threshold (Ct) values for B2M were significantly higher in the Direct Lysis protocol than in the Acid-pH protocol. The limit of detection for N1 gene was higher in Direct Lysis at ≤ 5 copies/μL than Acid-pH. Saliva samples collected over the course of several days from two COVID-positive individuals demonstrated Ct values for N1 that were consistently higher from Direct Lysis compared to Acid-pH. Collectively, this work supports that each of these techniques can be used to screen for SARS-CoV-2 in saliva for a cost-effective screening platform.
Topics: Humans; COVID-19; RNA, Viral; SARS-CoV-2; Saliva; Hydrogen-Ion Concentration; Specimen Handling; Nasopharynx
PubMed: 38527999
DOI: 10.1038/s41598-024-54183-w