Introduction. Acute lymphoblastic leukemia (ALL) is characterized by recurrent copy-number alterations (CNAs) and ploidy changes that influence risk assessment and therapy. Using a targeted digitalMLPA assay (NXtec D007 ALL), we evaluated the detection of focal CNAs, whole-chromosome abnormalities, and ploidy changes, including cases with non-informative karyotypes or genetic events leading to fusion transcripts.
Methods: We applied the digitalMLPA assay NXtec D007 ALL (MRC Holland; copy number probes covering 73 genes plus 250 karyotyping probes) to 215 adult B/T-ALL cases. dMLPA results were compared with those of conventional cytogenetics and molecular tests (karyotype, MLPA, SNP array, and IKZF1-PCR) when available. In 171 cases, parallel RNA-seq and fusion detection were performed using a four-tool in-house pipeline to assess whether intrachromosomal dels generate fusion transcripts.
Results: After exclusion of 43 failed/unevaluable samples (11 of which exhibited hyper/hypodiploidy), 192 cases remained (170 B-ALL, 15 T-ALL, 3 MPAL, 2 AUL). dMLPA identified CNAs in 86% of cases (Figure 1A). Whole-chromosome dels occurred in 5.8% (predominantly chromosomes 7 and 9); hyperdiploidy was observed in 17.3% (notably chromosomes 8, 10, 14, 21, X) (Figure 1B,C). IKZF1 dels were detected in 37% (71/192), including 40 cases with an IKZF1plus profile. MTAP, a prognostic marker linked to PRMT5i response, was co-deleted with CDKN2A/B in 62 cases. Dels of ETV6, BTG1, and RB1 were found in 12%, 12%, and 10.4% of cases, respectively. BTLA and CD200 were deleted in 15 and 16 cases (co-deletion was common; only 4 cases lacked co-deletion). NR3C1 deletions, implicated in glucocorticoid resistance, were present in 7.5% of diagnostic samples and 23.9% of relapses, showing a significant association with relapse (p = 0.0067). Amplifications and dels affecting the iAMP21 locus and the PAR1 region were also observed (Fig. 1D). Comparison with RNA-seq indicated that frequent PAR1 region fusions (e.g.CRLF2-CSF2RA, P2RY8-CD99) are not primarily driven by CN changes (Figure 1B). A recurrent PAX5–ZCCHC7 deletion was detected in 29 patients, persisted in all six available diagnosis–relapse pairs, and was shown to generate a fusion transcript in 3 cases.
Conclusions: Targeted dMLPA provides high-resolution, clinically actionable CNA and ploidy profiling in adult ALL, including cases with non-informative karyotypes. It reliably detects established high-risk lesions (e.g.IKZF1/IKZF1plus), co-dels with therapeutic relevance (MTAP/CDKN2A/B), and recurrent deletion events that can produce fusion transcripts (e.g.PAX5–ZCCHC7). However, a limitation in accurately detecting aneuploidies requires further validation and methodological refinements. Ongoing analyses, integrating orthogonal data, aim to improve interpretation, increase assay reliability, and expand clinical utility for better risk stratification and personalised treatment.
Supported by PNRR-MR1-2023-12377495 MULTIDIMENSION-ALL.
Introduction: Thrombocytopenia is a frequent hematologic complication in patients with solid tumors, arising from bone marrow infiltration, immune-mediated destruction, or treatment-related toxicity. Chemotherapeutic agents—especially platinum compounds, taxanes, and antiangiogenic drugs—are commonly implicated. Targeted therapies and immune checkpoint inhibitors have also been associated with immune thrombocytopenia. This condition may limit treatment intensity, increase bleeding risk, and negatively impact prognosis. Thrombopoietin receptor agonists (TPO-RAs) represent a valuable option to restore platelet counts and support the continuation of oncologic therapy in selected patients. Patients and Methods: We retrospectively analyzed 13 patients with solid tumors and thrombocytopenia, either at diagnosis or during anticancer therapy. Data were collected from 2017 to 2024. Median age was 76 years; the cohort included 6 females and 7 males. Bone marrow biopsy was performed in 12 cases, including cytogenetic and molecular analyses. Three patients harbored TP53 mutations, and one showed myelophthisis. Tumor types included breast, ovarian, prostate, bladder, lung, pancreatic and neuroendocrine carcinoma, renal cancer, and Hodgkin lymphoma. Clinical data included tumor histology, hematologic parameters, treatments, and responses to supportive therapy. Results: Four patients initially received corticosteroids or intravenous immunoglobulins, with limited or partial responses. Subsequently, 11 patients were treated with eltrombopag, 6 with romiplostim, and 1 with avatrombopag. Four patients required a switch to a second TPO-RA, and one a third as well. All achieved complete platelet responses, enabling continuation of oncologic therapy. TPO-RA dosing was individualized based on each patient’s treatment phase and platelet trend, with weekly complete blood counts submitted remotely by patients or referring oncologists. At the time of analysis, 10 patients were alive. Three patients died, including the one with myelophthisis, who continued breast cancer treatment for three years before death. (Tab. 1) Conclusion: Our experience supports the use of TPO-RAs in thrombocytopenic patients with solid tumors. These agents may enable full oncologic treatment delivery and improve clinical outcomes. In selected patients, restoring platelet counts is not just supportive care—it is a therapeutic bridge to maintaining oncologic intent and potentially prolonging survival.
Jennifer Hutchinson, Catherine R. Knight-Agarwal, Christopher J. Nolan
et al.
<b>Background:</b> Two changes to gestational diabetes mellitus (GDM) testing were implemented in the Australian Capital Territory in 2015 and 2017. <b>Aims:</b> We aimed to determine the associations between testing regimes and the prevalence of GDM and large-for-gestational-age (LGA) and small-for-gestational-age (SGA) infants and to compare the prevalence of LGA and SGA infants between women with and without GDM in each testing period. <b>Methods:</b> A total of 23,790 singleton live births with estimated GDM testing and birth dates between June 2012 and December 2019 were stratified into groups: pre-testing changes (June 2012–December 2014, group 1, <i>n</i> = 8069), revised diagnostic criteria (January 2015–May 2017, group 2, <i>n</i> = 8035) and changed pathology centrifugation protocol (June 2017-December 2019, group 3, <i>n</i> = 7686). Women were allocated to groups based on their estimated GDM testing date and stratified by their GDM status. A chi-square test, pairwise z-tests and logistic regression tested the associations. <b>Results:</b> The GDM prevalence significantly increased from 9.5% (group 1) to 19.4% (group 2) to 26.3% (group 3) (all: <i>p</i> < 0.001). The LGA infant prevalence significantly decreased in non-GDM women following revised diagnostic criteria implementation (11.6% vs. 9.7%, <i>p</i> = 0.001). Compared to group 1, women with GDM in groups 2 and 3 had significantly reduced odds of having LGA infants (aOR = 0.73, 95% CI of 0.56–0.95 and <i>p</i> = 0.021 and aOR = 0.75, 95% CI of 0.59–0.97 and <i>p</i> = 0.029, respectively). Compared to group 1, non-GDM women in groups 2 and 3 had significantly reduced odds of having LGA infants (aOR = 0.83, 95% CI of 0.74–0.92 and <i>p</i> < 0.001 and aOR = 0.88, 95% CI of 0.79–0.99 and <i>p</i> = 0.026, respectively). There were no significant associations for group 3 compared to group 2 nor for SGA infants. <b>Conclusions:</b> While significantly increasing the GDM prevalence, implementing the testing changes was associated with a reduced whole-population LGA infant prevalence without a change in the SGA infant prevalence.
Anna A. Andreeva, Konstantin A. Klochkov, Alexey I. Lobanov
Endovenous laser therapy (ELT) as a minimally invasive procedure for ablation of large superficial veins, nevertheless, can cause complications of thrombotic nature. In this regard, the study of the main patterns of thrombus formation during ELT and modelling of endovenous heat-induced thrombosis (EHIT) is relevant. Based on the assumption of diffusion limiting of biochemical processes occurring during the coagulation of blood, by recalculating the reaction rates according to the Stokes-Einstein equation, a simple point model of blood coagulation during ELT was built in this paper. As a result of the use of this model, it was demonstrated that blood heating entails an increase in the rate of thrombin production, a decrease in the time for achieving the peak of its concentration by 5-6 times with its almost constant amplitude. Heating leads to the rapid formation of fibrin clusters and the appearance of a fibrin-polymer network with a smaller cell size. The quantitative dependence on the selected rheological model was also shown. All the data necessary for using the model are given in this article for reproducibility.
Microcirculation of blood and oxygen transport play important roles in biological function of optic nerve and are directly affected by damages or pathologies. This work develops a multi-domain model for optic nerve, that includes important biological structures and various physical mechanisms in blood flow and oxygen delivery. The two sets of vasculature network are treated as five domains in the same geometric region, with various exchanges among them (such as Darcy's law for fluid flow) and with the tissue domain (such as water leak, diffusion). The numerical results of the coupled model for a uniform case of vasculature distribution show mechanisms and scales consistent with literature and intuition. The effects of various important model parameters (relevant to pathological conditions) are investigated to provide insights into the possible implications. The vasculature distribution (resting volume fractions here) has significant impacts on the blood circulation and could lead to insufficient blood supply in certain local region and in turn affect the oxygen delivery. The water leak across the capillary wall will have nontrivial effects after the leak coefficients pass a threshold. The periodic arterial pressure conditions lead to expected periodic patterns and stable spatial profiles, and the uniform case is almost the averaged version of periodic case. The effects of viscosity, the stiffness of blood vessel wall, oxygen demand, etc. have also been analyzed. The framework can be extended to include ionic transport or to study the retina when more biological structural information is available.
Shaghayegh Z. Ashtiani, Mohammad Sarabian, Kaveh Laksari
et al.
Blood flow reconstruction in the vasculature is important for many clinical applications. However, in clinical settings, the available data are often quite limited. For instance, Transcranial Doppler ultrasound (TCD) is a noninvasive clinical tool that is commonly used in the clinical settings to measure blood velocity waveform at several locations on brain's vasculature. This amount of data is grossly insufficient for training machine learning surrogate models, such as deep neural networks or Gaussian process regression. In this work, we propose a Gaussian process regression approach based on physics-informed kernels, enabling near-real-time reconstruction of blood flow in data-poor regimes. We introduce a novel methodology to reconstruct the kernel within the vascular network, which is a non-Euclidean space. The proposed kernel encodes both spatiotemporal and vessel-to-vessel correlations, thus enabling blood flow reconstruction in vessels that lack direct measurements. We demonstrate that any prediction made with the proposed kernel satisfies the conservation of mass principle. The kernel is constructed by running stochastic one-dimensional blood flow simulations, where the stochasticity captures the epistemic uncertainties, such as lack of knowledge about boundary conditions and uncertainties in vasculature geometries. We demonstrate the performance of the model on three test cases, namely, a simple Y-shaped bifurcation, abdominal aorta, and the Circle of Willis in the brain.
ABSTRACTBackground Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. We aimed to build a ferroptosis-related gene (FRG) prognostic signature to predict the outcome of DLBCLs.Methods Our study retrospectively investigated the mRNA expression level and clinical data of 604 DLBCL patients from three GEO public datasets. We performed Cox regression analysis to extract the FRGs with prognostic values. ConsensusClusterPlus was used to categorize the DLBCL samples according to gene expression. The least absolute shrinkage and selection operator (LASSO) method and univariate Cox regression were implemented to construct the FRG prognostic signature. The association between the FRG model and clinical characteristics was also investigated.Results We identified 19 FRGs with potential prognostic values and classified the patients into clusters 1 and 2. Cluster 1 showed a shorter overall survival (OS) time than cluster 2. The two clusters had different patterns of infiltrating immune cells. LASSO was used to generate a six-gene risk signature (GCLC, LPCAT3, NFE2L2, ABCC1, SLC1A5, and GOT1), based on which a risk score formula and prognostic model were constructed for predicting the OS of DLBCL patients. Kaplan–Meier survival analysis proved that poorer OS was exhibited in the higher-risk patients stratified by the prognostic model in both the training and test cohorts. In addition, both the decision curve and the calibration plots showed that the nomogram had good agreement between the predicted results and actual observations.Conclusions We developed and validated a novel FRG-based prognostic model which could help to predict the outcomes of DLBCL patient.
Manish Bhatia, Balram Meena, Vipin Kumar Rathi
et al.
The shape of erythrocytes or red blood cells is altered in several pathological conditions. Therefore, identifying and quantifying different erythrocyte shapes can help diagnose various diseases and assist in designing a treatment strategy. Machine Learning (ML) can be efficiently used to identify and quantify distorted erythrocyte morphologies. In this paper, we proposed a customized deep convolutional neural network (CNN) model to classify and quantify the distorted and normal morphology of erythrocytes from the images taken from the blood samples of patients suffering from Sickle cell disease ( SCD). We chose SCD as a model disease condition due to the presence of diverse erythrocyte morphologies in the blood samples of SCD patients. For the analysis, we used 428 raw microscopic images of SCD blood samples and generated the dataset consisting of 10, 377 single-cell images. We focused on three well-defined erythrocyte shapes, including discocytes, oval, and sickle. We used 18 layered deep CNN architecture to identify and quantify these shapes with 81% accuracy, outperforming other models. We also used SHAP and LIME for further interpretability. The proposed model can be helpful for the quick and accurate analysis of SCD blood samples by the clinicians and help them make the right decision for better management of SCD.
Microscopy plays a crucial role in hematology and diagnosis of infectious diseases worldwide. For malaria alone, more than 200 million slides are read by manual microscopists every year. High quality thin blood smears are essential for subsequent microscopy examinations including malaria microscopy, but are hard to make in field settings. Existing devices for assisting in making thin smears are available but are limited by cost or complexity for wider use. Here we present Inkwell, a portable mechanical device capable of making high quality thin blood smears in field settings. Inkwell is simple, low-cost, does not use electricity, and requires minimal training prior to use. By utilizing passive dissipative dynamics of a spiral spring coupled to an air dashpot with a tunable valve - we demonstrate a highly tunable mechanism for constant velocity smears at prescribed angle. Inkwell is capable of producing high quality blood smears of tunable cell density with more than 12 million individually distinguishable red blood cells on a single slide. The current design, which exploits precision manufacturing of a 17 cents plastic syringe and a spring, can be printed on a standard 3D printer with overall unit cost of less than a few dollars in large quantities. We further present usability tests to confirm performance over 10,000 unit cycle operations with no degradation in quality of the smear and demonstrate ease of use with minimal training. Inkwell enhances the broader toolbox of open innovations in diagnostics for providing high quality medical care in low and medium resource settings. Combined with rise of 3D printing, Inkwell presents an alternative to traditional centralized manufacturing and opens up distributed manufacturing of medical diagnostics in global context.
Mumu Aktar, Hassan Rivaz, Marta Kersten-Oertel
et al.
Angiography is widely used to detect, diagnose, and treat cerebrovascular diseases. While numerous techniques have been proposed to segment the vascular network from different imaging modalities, deep learning (DL) has emerged as a promising approach. However, existing DL methods often depend on proprietary datasets and extensive manual annotation. Moreover, the availability of pre-trained networks specifically for medical domains and 3D volumes is limited. To overcome these challenges, we propose a few-shot learning approach called VesselShot for cerebrovascular segmentation. VesselShot leverages knowledge from a few annotated support images and mitigates the scarcity of labeled data and the need for extensive annotation in cerebral blood vessel segmentation. We evaluated the performance of VesselShot using the publicly available TubeTK dataset for the segmentation task, achieving a mean Dice coefficient (DC) of 0.62(0.03).
Alla K. Ovsyannikova, Vlada I. Alferova, Oksana D. Rymar
Of all types of diabetes mellitus (DM), type 1 diabetes mellitus (DM1) and type 2 diabetes (DM2) are most often diagnosed in young people. However, up to 10 % of all cases of DM diagnosed at a young age are monogenic forms of DM – MODY (Maturity-Onset Diabetes of the Young), the most common forms of which are MODY2 (GCK-MODY) and MODY3 (HNF1AMODY). These genetic forms of DM are poorly understood, so the investigation of their clinical and biochemical parameters, including lipid profile, and comparison with more studied forms of DM is of high importance. The aim of this study was to analyze the characteristics of the lipid profile in patients aged 18–45 years with DM1, DM2, GCK-MODY and HNF1A-MODY.
Material and methods. In 56 patients diagnosed by the molecular genetic method MODY, as well as in 82 patients with DM2 and 14 patients with DM1, matched by sex, age, a lipid profile was studied.
Results. There were no statistically significant differences in total cholesterol and low-density lipoprotein cholesterol between young patients with different types of DM. In HNF1a-MODY, the highest level of triglycerides was revealed; in DM1, the level of high-density lipoprotein cholesterol was significantly higher than in other types of DM. Among the changes in the lipid profile among all types of DM, hypercholesterolemia was more often determined.
Diseases of the blood and blood-forming organs, Diseases of the circulatory (Cardiovascular) system
We conducted a randomized controlled trial in older adults with hematologic malignancies to determine the impact of geriatrician consultation embedded in our oncology clinic alongside standard care. From February 2015 to May 2018, transplant-ineligible patients aged ≥75 years who presented for initial consultation for lymphoma, leukemia, or multiple myeloma at Dana-Farber Cancer Institute (Boston, MA, USA) were eligible. Pre-frail and frail patients, classified based on phenotypic and deficit-accumulation approaches, were randomized to receive either standard oncologic care with or without consultation with a geriatrician. The primary outcome was 1-year overall survival. Secondary outcomes included unplanned care utilization within 6 months of follow-up and documented end-of-life (EOL) goals-of-care discussions. Clinicians were surveyed as to their impressions of geriatric consultation. One hundred sixty patients were randomized to either geriatric consultation plus standard care (n=60) or standard care alone (n=100). The median age of the patients was 80.4 years (standard deviation = 4.2). Of those randomized to geriatric consultation, 48 (80%) completed at least one visit with a geriatrician. Consultation did not improve survival at 1 year compared to standard care (difference: 2.9%, 95% confidence interval: -9.5% to 15.2%, P=0.65), and did not significantly reduce the incidence of emergency department visits, hospital admissions, or days in hospital. Consultation did improve the odds of having EOL goals-of-care discussions (odds ratio = 3.12, 95% confidence interval: 1.03 to 9.41) and was valued by surveyed hematologic-oncology clinicians, with 62.9%-88.2% of them rating consultation as useful in the management of several geriatric domains.
Sara Napoli, Luciano Cascione, Andrea Rinaldi
et al.
Enhancers are regulatory regions of DNA, which play a key role in cell-type specific differentiation and development. Most active enhancers are transcribed into enhancer RNA (eRNA) that can regulate transcription of target genes by means of in cis as well as in trans action. eRNA stabilize contacts between distal genomic regions and mediate the interaction of DNA with master transcription factors. Here, we characterized an enhancer eRNA, GECPAR (germinal center proliferative adapter RNA), which is specifically transcribed in normal and neoplastic germinal center B cells from the super-enhancer of POU2AF1, a key regulatory gene of the germinal center reaction. Using diffuse large B-cell lymphoma cell line models, we demonstrated the tumor suppressor activity of GECPAR, which is mediated via its transcriptional regulation of proliferation and differentiation genes, particularly MYC and the Wnt pathway.
Adventitial cystic disease (ACD) of the veins is a rare vascular disease. Most cases of venous ACD are located adjacent to the joint area, such as the common femoral, external iliac, and popliteal veins. To the best of our knowledge, 67 cases of venous ACD have been reported, and ACD of the superficial femoral vein (SFV) has never been reported. Herein, we report the case of a 57-year-old male who presented with swelling and discomfort in the left leg. Computed tomography venography revealed multiple cystic lesions in the left distal SFV. The patient underwent cyst excision, which relieved the compression in the vein, although mild stenosis prevailed in the SFV. After a week, thrombosis developed in the popliteal vein. The thrombosis resolved after three months of anticoagulant therapy, and the patient showed no recurrence of ACD during three years of follow-up.
Diseases of the blood and blood-forming organs, Diseases of the circulatory (Cardiovascular) system
What breathes life into an embodied agent or avatar? While body motions such as facial expressions, speech and gestures have been well studied, relatively little attention has been applied to subtle changes due to underlying physiology. We argue that subtle pulse signals are important for creating more lifelike and less disconcerting avatars. We propose a method for animating blood flow patterns, based on a data-driven physiological model that can be used to directly augment the appearance of synthetic avatars and photo-realistic faces. While the changes are difficult for participants to "see", they significantly more frequently select faces with blood flow as more anthropomorphic and animated than faces without blood flow. Furthermore, by manipulating the frequency of the heart rate in the underlying signal we can change the perceived arousal of the character.
Kinue Kamata, Yoshihiro Hatanaka, Hiromi Tanaka
et al.
AbstractOne of the often-used methods for in vitro evaluation of the blood compatibility of hemodialysis membranes is the circulation of human blood through a miniaturized hemodialyzer. The use of a rather small amount of human blood in its evaluation is one advantage of this method. However, because it is manufactured by a different process than actual ones, a miniaturized hemodialyzer membrane cannot always preserve the properties of actual hemodialyzers. To address this problem, we established a new experimental method that uses a relatively small amount of human blood and actual dialyzers. In this method, a test hemodialyzer and a control hemodialyzer filled with human blood obtained from the same donor is slowly rotated to prevent spontaneous blood cell sedimentation for 4 h at 37 °C. By use of this method, we were able to compare blood compatibility between a polysulfone (PS) membrane and a vitamin E (VE)-bonded PS membrane in terms of their relative antithrombotic, antioxidative, and anti-inflammatory properties. Consistent with many previous reports, the results clearly showed that compared with the PS membrane, VE-bonded PS membrane is more blood compatible. These findings suggest that our method is applicable, at least to in vitro blood compatibility evaluation of PS type dialysis membranes.
Infrared light scattering methods have been developed and employed to non-invasively monitor human cerebral blood flow (CBF). However, the number of reflected photons that interact with the brain is low when detecting blood flow in deep tissue. To tackle this photon-starved problem, we present and demonstrate the idea of interferometric speckle visibility spectroscopy (ISVS). In ISVS, an interferometric detection scheme is used to boost the weak signal light. The blood flow dynamics are inferred from the speckle statistics of a single frame speckle pattern. We experimentally demonstrated the improvement of measurement fidelity by introducing interferometric detection when the signal photon number is insufficient. We apply the ISVS system to monitor the human CBF in situations where the light intensity is $\sim$100-fold less than that in common diffuse correlation spectroscopy (DCS) implementations. Due to the large number of pixels ($\sim 2\times 10^5$) used to capture light in the ISVS system, we are able to collect a similar number of photons within one exposure time as in normal DCS implementations. Our system operates at a sampling rate of 100 Hz. At the exposure time of 2 ms, the average signal photon electron number is $\sim$0.95 count/pixel, yielding a single pixel interferometric measurement signal-to-noise ratio (SNR) of $\sim$0.97. The total $\sim 2\times 10^5$ pixels provide an expected overall SNR of 436. We successfully demonstrate that the ISVS system is able to monitor the human brain pulsatile blood flow, as well as the blood flow change when a human subject is doing a breath holding task.