bluuebunny/crossref_metadata_2025 huggingface dataset:
The Politics of Social Welfare: The BJP and the Discerning Voter
Authors: Kailash K. K.
Published: December 2024

Voting studies tell us that voters reward incumbents who take care of the economic self-interest of voters. However, is the relationship between services and votes simple and straightforward? Are there conditions when welfare provisioning does not convert into votes for the incumbent? Data from the National Election Studies 2024 appears to suggest that voters are discerning and concerned about access issues when it comes to welfare delivery. Voters do not cast their votes only on whether they received private (welfare) benefits but also consider factors such as their experience and well-being while accessing those goods and services. Examining the relationship between welfare services and voting, the article demonstrates that individual-level processes are politically significant enough to influence vote choices between the benefits and the votes. These findings could inform scholarly studies and policy debates on social service delivery and vote choice.
Predictive models for hydrocyclone performance parameters: Evaluating the impact of training functions using artificial neural network
Authors: Pathirikattu Aiswaria , Vakamalla Teja Reddy , Mangadoddy Narasimha
Published: December 2024

This study introduces a multilayer perceptron artificial neural network model to predict water split, cut size and sharpness of separation in hydrocyclone classifiers. The model is developed based on experimental data from 75, 100, 150 and 250 mm diameter hydrocyclones under different operating conditions and design parameters. The Levenberg–Marquardt training algorithm is found to be optimal based on the correlation coefficient and mean square error values. Pearson's correlation coefficient is used to assess the strength and direction between variables. The importance of input variables is estimated using the out-of-bag permuted predictor method. The ANN model employs 10, 10 and 8 hidden neurons achieving regression coefficients of R ∼ 0.92, R ∼ .99, R ∼ 0.90 and MSE values of 21.98, 38.915, 0.34 for water split, cut size and sharpness of separation, respectively. Comparative analysis indicates that the ANN model shows superior performance than empirical and semi empirical models.
Management of a Rare Complex Triad Injury of the Elbow Joint: Radial Head Fracture, Triceps Tendon Avulsion, and Rupture of the Medial Collateral Ligament
Authors: Shekhbihi Abdelkader , Masoud Mohammad , Reichert Winfried
Published: December 2024

Background:

Isolated triceps tendon injuries are infrequent, and their combination with a medial ligament avulsion is even rarer. Eccentric force on the triceps tendon following a fall on the outstretched hand, combined with a valgus torque at the elbow joint, exposes the medial side to stretching forces, potentially disrupting the ulnar collateral ligament (UCL). Furthermore, compressive forces on the lateral side could result in injury to the radial head. Currently, there is no standardized surgical approach for managing such combined injuries.

Indications:

The complex triad injury presented in this publication is debilitating and warrants primary surgical intervention to restore stability and function of the afflicted elbow.

Technique Description:

A slightly curved posterior skin incision is made, creating medial and lateral full-thickness skin flaps. The ulnar nerve is explored and tagged with a vessel loop for protection without a full release. Palpation of the medial joint capsule reveals a rupture of the medial collateral ligament. The radial head is palpated during forearm rotation. The fascia overlying the radial head is incised along with the annular ligament. The radial head fracture is debrided and provisionally fixed with a 1.6-mm K-wire and then stabilized with two 2.0-mm mini screws. The bony origin of the triceps tendon is scraped to remove debris. A V-shaped triceps tendon repair is performed using two 3.5-mm titanium Twinfix suture anchors. A Krackow-type suture is placed medially, laterally, and centrally on the tendon. The tendon is reduced and fixed with a 1.8-mm K-wire, which is then replaced by a button fixation. The UCL tear is identified as a humeral avulsion and repaired using two 3.5-mm titanium Twinfix suture anchors. The triceps fascia, annular ligament, and overlying fascia are then repaired, and the wound is closed in layers after thorough irrigation.

Results:

Repair of all 3 injuries was successfully accomplished through the same approach, with initial postoperative follow-up showing active free supination/pronation and passive flexion limited to 70°.

Discussion/Conclusion:

The described surgical technique provides a comprehensive approach to addressing the rare and complex injuries involving the radial head, triceps tendon, and medial collateral ligament. This article includes practical tips and tricks to ensure successful execution of the procedure.

Patient Consent Disclosure Statement:

The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.
Our versus their narcissist: Are narcissistic persons more popular in their ingroup than in a competing outgroup?
Authors: Dufner Michael , Zimmermann Johannes , Kraft Livia , Czarna Anna Z. , Maciej Sekerdej , Schmukle Stefan C.
Published: December 2024

In this registered report ( N = 423), we investigated in a competitive intergroup context to what extent the perception of targets scoring high in grandiose narcissism varies depending on whether they belong to one’s own group or to an opposing outgroup. In a laboratory study, members of newly formed groups had direct contact with another group and competed for scarce resources. Contrary to our hypothesis, perceivers did not ascribe targets scoring high in narcissistic admiration higher status when they belonged to their ingroup versus the outgroup. Also unexpectedly, they did not like targets scoring high in narcissistic rivalry better when they belonged to their ingroup. Instead, our findings indicate that narcissistic admiration was generally linked to more dominant-expressive behavior and that participants had a stronger inclination to interpret a specific behavior as aggressive when it was shown by a member of the outgroup, rather than a member of the ingroup.
Two decades of climate tipping points research: Progress and outlook
Authors: Armstrong McKay David I.
Published: December 2024

The potential for nonlinear ‘surprises’ in the climate system has been recognised since the 1960s. One such nonlinearity is a tipping point: when change in a system becomes self-sustaining once forced passed a threshold, triggering a state shift that is often abrupt and irreversible. Research on climate tipping points has flourished since 2005, recently culminating in the release of the Global Tipping Points Report at COP28 and calls for targeted assessment by the Intergovernmental Panel on Climate Change. Here I summarise progress in our growing understanding of climate tipping points and reflect on their implications for climate action and the outlook for future research.
Comparison of the Effects of Diaphragmatic Breathing and Pursed-lip Breathing Exercises on the Sleep Quality of Elderly Patients with Chronic Obstructive Pulmonary Disease (COPD): A Clinical Trial Study
Authors: Dodange Zahra , Darvishpour Azar , Ershad Mohamad Javad , Gholami-Chaboki Bahare
Published: December 2024

Background

Sleep-related disorders are common among older adults with chronic obstructive pulmonary disease (COPD). Breathing exercises, a key component of pulmonary rehabilitation programs, may improve sleep quality. However, there is a paucity of research on the impact of breathing exercises on sleep quality in elderly patients with COPD.

Objective

This study aimed to compare the effects of diaphragmatic breathing (DB) and pursed-lip breathing (PLB) exercises on sleep quality in elderly patients with COPD.

Design

Crossover clinical trial.

Methods

In this study, 60 elderly patients with COPD were randomly assigned to two groups: DB followed by PLB (Group 1) and PLB followed by DB (Group 2). Each exercise was performed for 4 weeks. Participants completed the Pittsburgh Sleep Quality Index (PSQI), Abbreviated Mental Test Score (AMTS), and COPD Assessment Test (CAT) questionnaires before training. Data were analyzed using descriptive and inferential statistics in SPSS version 21, with a significance level of 0.05.

Results

Both DB and PLB exercises significantly improved sleep quality in elderly patients with COPD ( P < 0.05). No significant difference was found between the two exercises. However, the sequence of exercises in Group 1 (DB followed by PLB) resulted in greater improvement in average sleep quality compared to Group 2.

Conclusion

This study demonstrates that DB and PLB exercises enhance sleep quality in elderly patients with COPD. These exercises are recommended as an effective non-pharmacological approach to improve sleep quality in this population.
The Impact of Fetal Hemoglobin Levels on Some Inflammatory Markers in Steady State Sickle Cell Anemia Patients
Authors: Akulue John Chuks , Ezekekwu Chinedu Anthony , Olaniyi John Ayodele , Ogundeji Peter Sunday , Akunwata Chima Uzoma
Published: December 2024

Background

Sickle cell anemia (SCA) is a multifaceted disease characterized by both acute and chronic inflammation. Even in the steady state; inflammatory oxidative stress gradually destroys tissues. Studies have shown that a higher fetal hemoglobin is associated with mild disease but there is no evidence of an association between inflammatory markers and HbF levels in our environment. The purpose of this study was to determine fetal hemoglobin levels and the plasma levels of some inflammatory markers in adult sickle cell anemia patients in steady state and to correlate these inflammatory markers with the fetal hemoglobin level.

Methods

This was a cross-sectional comparative study involving sickle cell anemia patients in steady state and apparently healthy hemoglobin AA individuals. Blood samples were collected and analysed for complete blood count using hematology autoanalyser. Interleukin 17 (IL-17), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein (CRP) were analysed using enzyme linked immunosorbent assay methods. Fetal hemoglobin (HbF) level was quantified using high performance liquid chromatography. Statistical analysis was done with SPSS software, version 25.

Results

One hundred participants comprising 50 adults with sickle cell anemia and 50 healthy controls (HbAA) adults, with age range 18-59 years, were studied.Platelets and white blood cell count were significantly higher while hematocrit was lower in SCA compared to the control population. HbF levels in SCA ranged from 2% to 21%. IL-17, IFN-γ, MCP-1 and CRP, were all significantly higher in patients with SCA compared to HbAA controls. There was a significant negative correlation between HbF and MCP-1 while the correlation of HbF with CRP, IL-17 and IFN-γ were not significant.There was a statistically significant negative correlation between HbF level and platelet count.

Conclusion

Patients with sickle cell anemia in steady state have higher levels of interleukin 17, interferon-gamma, monocyte chemoattractant protein-1 and C-reactive protein compared to HbAA individuals. Fetal hemoglobin has a significant negative relationship with monocyte chemoattractant protein-1 and platelet count in sickle cell anemia.
Functional Consequences of Chromosomal Alterations in Angioimmunoblastic T-Cell Lymphoma
Authors: Dachuan Huang , Chan Jason Yongsheng , Ong Choon Kiat , Lim Jing Quan
Published: December 2024

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of non-Hodgkin's lymphoma, representing a significant portion of peripheral T-cell lymphomas (PTCL). To elucidate the genomic landscape of PTCL, comprehensive genomic analysis was performed on 25 AITL and 19 PTCL- not otherwise specified (NOS) cases. Our findings reveal distinct genetic alterations in AITL, including a lower mutation burden and an enrichment of reactive oxygen species (ROS)-associated mutational signature (SBS18) when compared to PTCL-NOS. Besides recurrent somatic mutations in TET2 and RhoA, we have discovered frequent novel focal deletion on chromosome 8q24.21, impacting the PVT1 gene. Functional characterization demonstrated that this deletion activates the DNA damage pathway via CDKN1A/p21, potentially conferring a survival advantage to AITL cells under DNA damaging stress. These findings shed light on the molecular mechanisms underlying AITL development and highlight the potential clinical implications of chr8q24.21 focal deletion in this disease. Further studies with larger cohorts are warranted to validate these findings and explore their therapeutic implications.
Artificial Reasoning Approaches for Predicting Hemophilia a Severity
Authors: Rawal Atul , Ou Jiayi (Kelly) , Sauna Zuben E.
Published: December 2024

Background: Hemophilia A (HA) is an X-linked congenital bleeding disorder, which leads to deficiency of clotting factor VIII (FVIII). Even though it mostly affects males, and females are considered carriers, variants in F8 in females can result in HA. Many females go undiagnosed and untreated for HA and their bleeding complications are attributed to other causes. Predicting the severity of HA for female patients can provide valuable insights for treating conditions associated with the disease such as heavy bleeding.

Objective: To predict the severity of HA in women based on F8 genotype and identify genotypes with a higher association for severe disease using artificial reasoning (AR) approaches.

Methods: Using multiple datasets of variants in the F8 and disease severity various repositories (e.g., My Life Our Future (MLOF)), we derived the sequence for the Factor VIII (FVIII) protein. Using the derived sequences, we used causal learning and artificial reasoning approaches such as ML classification models and Explainable AI (XAI) to predict the severity of HA in female patients and highlight genotypes with a higher association for severe HA.

Results: We apply causal learning to observational data to highlight the specific genotypes that have a direct cause-and-effect relation with severe HA in women. Utilizing different machine learning (ML) classification models, we validated our approach with predictive F1-scores of 0.88, 0.99, 0.93, 0.99 and 0.90 for all the validation sets. We picked the top-performing ML model to apply XAI via SHAP to identify genotypes with a higher association with severe HA.

Conclusion: AR-based approaches were successfully employed to predict HA severity in females based on variants in the F8. This study confirms previous research findings that ML can help predict the severity of hemophilia and provides new insights into genotypes with a higher association for severe disease. These results can be valuable for future studies in female patients with HA which is an urgent unmet need.
Comparative Retrospective Study of Therapies and Trends for Hospitalized Patients with New-Onset Immune Thrombocytopenia
Authors: Sherry Emily Grace , Lee Sophia , Auster Michael , Benkhadra Raed , Ocampo Miguel , Pandya Abhishek , Karnad Anand , Bowhay-Carnes Elizabeth
Published: December 2024

BackgroundImmune Thrombocytopenia is an autoimmune condition characterized by isolated thrombocytopenia and exclusion criteria. The U.S.'s incidence of ITP is 6.1 and greater in females, with bimodal distribution for ages 0-4 and 65+ years.1 ITP ranges in severity, with high economic cost (estimated U.S. expenditures of over $400 million).1 Despite ITP clinical updates, little research focused on hospitalized patients during first onset of ITP exists.AimsWe hope this study advances clinical practice for hospitalized patients with new-onset ITP.MethodsWe conducted retrospective chart review of adult patients with ITP treated at University Hospital or Mays Cancer Center between January 2020-January 2023, focusing on patients initially diagnosed inpatient. Data were reviewed in descriptive analysis.Results25 of 35 patients with inpatient onset/diagnosis of ITP were included. 20 had primary etiologies; 5 had secondary etiologies. Our group was largely Caucasian (13) and Hispanic (11).The majority were women (16) compared to men (9). One was pregnant; none had HIV. For these patients with first-onset of ITP while hospitalized, 6 received steroids, 1 received IVIG, 11 received both steroids and IVIG, and 7 had additional regimens (including observation, rituximab, splenectomy, plasmapheresis) during hospitalization. Platelet nadir and trends post-treatment days 1-3 were almost identical between the steroids-alone and steroids + IVIG group (Figure 1). Length of hospital stay after therapy onset was shortest for steroids + IVIG (4.9 days), followed by the steroids-alone (5.8 days), IVIG-alone (7 days), and other regimens (11.6 days) groups.Conclusion(s)In hospitalized patients with first-onset ITP, the first-line regimens of steroids-alone and steroids with IVIG had the best clinical results. Steroids-alone and steroids + IVIG yielded almost identical platelet responses, yet slightly longer hospitalization for steroids-alone group. We hope this study better informs our clinical practice of initial treatment of ITP inpatient. Further research increasing samples/population will amplify study power and generalizability.
Incidence and Outcomes of Post-Transplant Erythrocytosis in Kidney Transplant Recipients: A Cohort Study in a Southeast Asian Country
Authors: Wannaphut Chalothorn , Skulratanasak Peenida , Saetan Suparat , Aiumtrakul Noppawit , Ponvilawan Ben , Larpparisuth Nuttasith , Ratchawang Nartsiri , Owattanapanich Weerapat
Published: December 2024

Introduction: Post-kidney transplant erythrocytosis (PTE) is a common complication after kidney transplant, which can occur in 8-15% of transplant recipients. However, this condition, including the Thai population, has not been well studied in Southeast Asia.

Method: A single-center retrospective cohort was conducted among adult kidney transplant recipients who underwent transplantation between January 2010 and December 2020. Erythrocytosis is defined by hemoglobin levels > 16.5 g/dl in males and > 16.0 g/dl in females. We assessed the incidence and risk factors of PTE in this cohort and compared outcomes of PTE versus non-PTE patients.

Results: Of 399 kidney transplants, 84 (21%) developed PTE over a total follow-up time of 5.06 ± 2.16 years. The mean age was 44.36 ± 10.59 years, with 57.1% of male subjects. All PTE patients were asymptomatic during the clinical course of PTE. The median duration of PTE was 8.83 (5.55 - 18.17) months. In the multivariable analysis, male subjects were at a 1.92-time higher risk for PTE development than females (HR 1.92; 95%CI 1.16-3.20). Patients with pre-existing polycystic kidney disease (PKD) had a 3.87-time higher risk of developing PTE compared to those without PKD (HR 3.87; 95%CI 1.50-9.98). PTE patients significantly had a 50% lower risk for composite outcomes, including infection, new onset diabetes, transplant rejection, dialysis dependence, and death, compared to non-PTE groups (HR 0.50; 95%CI 0.27 - 0.9). Interestingly, none of the PTE patients underwent renal replacement therapy throughout the observation, while some non-PTE individuals became dialysis dependent.

Conclusion: Our study revealed the incidence rate of PTE was 0.05/person-year. PTE in Thai patients was strongly associated with male gender and pre-existing PKD. Patients with PTE tended to have higher eGFR. They had a significantly lower risk of developing composite outcomes, including infection, new-onset diabetes, rejection episodes, dialysis dependence, and mortality, compared to those without PTE.
Cytokine Release Syndrome: Trends with T Cell Engaging Bispecifics from a Systematic Review of Licensing Applications
Authors: Radtke Kendra , Bender Brendan C , Li Zao , Turner David C. , Roy Sumi , Belousov Anton , Li Chi-Chung
Published: December 2024

Effective prevention, mitigation, and management of cytokine release syndrome (CRS) is crucial in T cell engaging bispecific (TCE) development. We systematically reviewed the biologics licensing applications (BLAs) of 7 approved hematologic TCEs, gathering pan-molecule evidence on CRS clinical pharmacology. Mosunetuzumab and elranatamab had the lowest CRS risk among TCEs for non-hodgkin's lymphoma (NHL) (range 39-70%) and multiple myeloma (MM) (range 58-79%), respectively. Grade 2+ CRS was low for all approved molecules (ranged from 15% to 22%). All TCEs employed a 2 step priming approach, except blinatumomab (1 step; continuous infusion) and talquetamab bi-weekly (3 step), and were successful at mitigating CRS beyond the first full dose. Subcutaneous (SC) administration for CRS mitigation remains an inconclusive strategy across molecules; no TCEs are approved for intravenous and SC administration. Pharmacological characterization of CRS included cytokine dynamics and drug exposure-response (E-R) analysis for TCEs approved after 2021. IL-6 time profiles were reported for all TCEs along with IL-10 and IFN-y in 4/6 cases. Peak levels for one or more cytokines trended with dose-period CRS rates, but not consistently for all cytokines and molecules, further suggesting that the cytokine to CRS relationship is complex. Positive trends in CRS E-R were reported for 4/6 TCEs when the drug's maximum concentration (Cmax) or receptor occupancy were used as the exposure driver. E-R analyses were typically performed for each dose period through the first target dose. Covariates associated with CRS included baseline factors (disease status, treatment history, target level, effector cell status, age) and on-treatment factors (tocilizumab use, prior Cmax). Hospitalization is required for all TCEs except mosunetuzumab. Thus, further characterizing CRS and establishing a link between drug levels, biomarkers, and clinical events will not only aid TCE development but also benefit patients by reducing the need for intensive clinical interventions and hospitalization. Quantitative clinical pharmacology methods including mechanism- and empirical-based approaches will continue to be instrumental in TCE development, especially as regimens become more complex with combination and pretreatment integration.
What If the Erythrocyte Sedimentation Rate (ESR) Is Too Slow? New Parameters. New Explanations. New Applications
Authors: Darras Alexis , Qiao Min , Peikert Kevin , Hecksteden Anne , John Thomas , Stauffer Emeric , Muniansi Ingrid , Champigneulle Benoit , Pichon Aurelien , Furian Michael , Hancco Ivan , Brugniaux Julien V. , Nader Elie , Mühlbäck Alzbeta , Joly Philippe , Meyer Tim , Verges Samuel , Hermann Andreas , Connes Philippe , Wagner Christian , Kaestner Lars
Published: December 2024

The erythrocyte sedimentation rate (ESR) is one of the oldest diagnostic tools already known by the ancient Greeks. When blood is placed in a tube, a phase separation between blood plasma and the remaining part of the blood containing the cells appears. The distance between the top of the liquid and the phase boundary determines the sedimentation height. Fast sedimentation, typically the height measured after one hour, is an unspecific parameter indicating inflammation. However, there is more to ESR than a single value for the sedimentation height. We investigated the physical dynamics of the cell aggregation occurring during erythrocyte sedimentation and devised a novel explanation. The formation of rouleaux actually extends to the formation of a percolating gel. Therefore, it is not the aggregate size that determines ESR but the permeability of this gel. The collapse of this gel is the base of the ESR. Hence the process of erythrocyte sedimentation can be described by a set of parameters determined by this gel. In addition to differences in height, the delay time, the maximal sedimentation speed and the final compaction resemble the most important ones.

In contrast to common clinical practice, where only a fast ESR is associated with pathologic conditions, we identified diseases and circumstances when the ESR is significantly slower. This includes the ESR of Sickle Cell Disease (SCD) patients, Chronic Mountain Sickness (CMS) patients, patients suffering from the Neuroacanthocytosis Syndromes (NAS) on the one hand and endurance elite athletes and highlanders on the other hand.

Significant differences can be detected between healthy controls and the patients listed using the aforementioned parameters. However, diagnostic value is only given if a clear discrimination between patients and healthy controls is possible. We found such discrimination for NAS patients with 8% false negative and 11% false positive among healthy controls. For differential diagnosis, we also tested patients with neurodegenerative diseases different from NAS, namely Parkinson's disease patients, Huntington's disease patients and amyotrophic lateral sclerosis patients. None of them showed a difference in the ESR compared to healthy controls, but all of them presented a significant difference to NAS patients.

Considering the low expenses required for ESR measurements and that they are automated in many central laboratories on the one hand and the difficulty and often very late diagnosis of NAS (sometimes years after the onset of symptoms), we recommend an ESR screening for NAS (slow sedimentation) as a routine in the frame of ordinary health checks of adults.
Phase II Clinical Trial on Chidamide, Rituximab and High-Dose Methotrexate (C-R-HDMTX) in Newly Diagnosed Primary CNS Lymphoma
Authors: Chen Guang-Liang , Jin Jia , Sun Hui , Liu Yizhen , Zhang Qunling , Xia Zuguang , Cao Junning , Hong Xiaonan , Lv Fangfang
Published: December 2024

Abstract

Background:

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma variant confined to the central nervous system. Current treatment primarily uses high-dose methotrexate (MTX) with rituximab, but incomplete responses and relapse are common. Chidamide, an oral histone deacetylase (HDAC) inhibitor, can cross the blood-brain barrier, achieving therapeutic concentrations in cerebrospinal fluid. In addition, it enhances MTX efficacy by promoting its polyglutamylation and regulating key genes. This study investigates the potential of combining chidamide with rituximab and high-dose MTX (C-R-HDMTX) in PCNSL treatment.

Methods:

This single-center, open-label, phase II trial administered C-R-HDMTX every three-week for six courses unless disease progression, death, or intolerable toxicity. The primary endpoint was complete remission (CR) rate. Progression-free survival (PFS) was also assessed. Treatment included chidamide (20 mg orally, twice weekly for two weeks, followed by a one-week break), rituximab (375 mg/m² IV, day 1), and MTX (3.5 g/m² IV, day 2) per 21-day cycle. Responses were evaluated using the international PCNSL collaborative group (IPCG) criteria after 2-4 cycles.

Results:

Between September 7, 2020, and August 26, 2023, ten patients (7 males, 3 females) were enrolled. The median age was 62 years (range, 50-76). Overall, 8 patients had non-germinal center B-cell-like (non-GCB) subtype, 2 patients had GCB subtype. Nine patients were evaluable for efficacy. Six patients exhibited multiple enhancing lesions. The overall response rate at the end of induction was 89%, with a CR rate of 78% (7/9 patients). With a median follow-up of 16.5 months (range 11.0-46.5)，the median PFS was 13 months, with the longest ongoing at 46.5 months. The median OS was not achieved. Grade 3/4 hematologic toxicities included neutropenia and thrombocytopenia (20% each). Common non-hematologic adverse events were mild, including hypocalcemia (80%), hyponatremia and elevated AST (50% each), and increased ALT (30%).

Conclusions:

The C-R-HDMTX regimen demonstrated high efficacy and manageable toxicity in PCNSL patients, warranting further investigation as a potential treatment option for this aggressive lymphoma.

Clinical trial information: NCT04516655
Novel Nilotinib Tablet Formulation: Pharmacokinetic Characterization and Effects of Food
Authors: Mauro Michael J. , Radich Jerald P. , Jain Paras , Sequeira David , Douer Dan
Published: December 2024

Introduction: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor with demonstrated efficacy in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML). Use of the drug is limited by a boxed warning and a specific dosing regimen that increases treatment complexity. The prescribing information for nilotinib capsules states that they should be administered on an empty stomach and with no food consumed for ≥2 hours (h) before and ≥1 h after dosing. A novel reduced-dose tablet formulation of nilotinib has been developed to provide equivalent bioavailability (BA) under fasted conditions and minimize the effect of food on pharmacokinetics (PK).

Objective: To characterize the PK profile of a novel film-coated tablet formulation of nilotinib, assess the effects of food on nilotinib relative BA, and compare its PK profile to that for nilotinib capsules.

Methods: The PK of nilotinib capsules (300 or 400 mg) and/or novel film-coated tablets (142 or 190 mg) were evaluated in 6 open-label, randomized, single-dose, crossover studies that enrolled a total 384 healthy volunteers. Nilotinib tablets were administered under prandial conditions defined as: (1) fasting, (2) high-fat meal: fasting for 10 h overnight and administration of study drug 2 h after the start of a high-fat, high-calorie, non-vegetarian breakfast, and (3) low-fat meal: fasting for 10 h overnight and administration of study drug 2 h after the start of a low-fat, low-calorie breakfast. Comparison of the PK profiles and formal statistical evaluation was conducted for bioequivalence (BE) of the nilotinib tablet to nilotinib capsule for all of these conditions.

Results: In the fasted state, BE was established for a 142 mg dose of nilotinib tablet with the 300 mg dose nilotinib capsule and for the 190 mg dose of nilotinib tablet with 400 mg dose nilotinib capsule. Nilotinib tablets (142 mg and 190 mg dose) administered in both fed conditions resulted in higher maximum plasma concentrations (Cmax) and areas under the time vs. plasma concentration curve from administration extrapolated to infinity (AUC0-inf) than the observed fasted state. For nilotinib tablets, the increases in Cmax and AUC0-inf were 55% and 59%, respectively for the 190 mg dose when delivered with a low-fat meal and 66% and 64% when delivered with a high-fat meal. The respective values for 400 mg nilotinib capsules delivered with a low-fat meal were 122% and 101% and those for administration with a high-fat meal were 275% and 210%.

Conclusions: Reduced-dose nilotinib film-coated tablets (142 and 190 mg) provide exposures comparable to 300 and 400 mg nilotinib capsules in the fasted state. The PK profile for nilotinib film-coated tablets also results in much smaller increases in exposure vs. the capsules when the drug is taken with food.
Artificial Intelligence-Based Algorithm for the Diagnosis of Idiopathic Multicentric Castleman's Disease in a Lower-Middle Income Country
Authors: Brandão Antonio Adolfo Guerra Soares , De Farias Danielle Leão Cordeiro , Konopelko Michał , Amtmański Wojciech , Mroz Mikolaj , Jurczuk Aleksandra , Majewski Maciej , Szukalski Lukasz , Basak Grzegorz , Verboski Bianca Milena , de Assunção Caio Lopes , Lis Karol , Dabrowski Michal Jerzy , Dudziński Marek
Published: December 2024

Introduction

Idiopathic multicentric Castleman's disease (iMCD) is an ultra rare lymphoproliferative disorder difficult to diagnose due to its rarity (prevalence of 6.9-9.7 cases per million in the United States) and the lack of awareness among physicians. Median time between symptoms onset and the diagnosis of iMCD in Brazil is estimated to be 18 months. We propose that an artificial intelligence (AI)-based algorithm working on electronic health records may help to identify patients suspected of Castleman disease that were missed during medical evaluation.

Methods

Firstly, symptoms listed in the CDCN iMCD criteria [Fajgenbaum DC, et al. Blood. 2017;129(12):1646-57] were defined by medical terms. Medical definition contained ICD - 10 codes, lab test results and phrases that may be found in the medical texts (descriptions of imaging tests, interviews, epicrisis). SPACY models with in house developed regular expressions (regex) were used to identify phrases (entities) assigned to symptoms in the unstructured medical texts. Entity context defined as negation, family relation, historical or hypothetical event was determined by the BERTH model that went through additional training on the Saventic database. Patients were ranked based on the symptoms they possessed. Patients were ranked only when lymphadenopathy was identified and patients already diagnosed with iMCD (four cases) were excluded. Physicians with expertise in iMCD led the review of patients' charts with the highest score.

Results

594 953 patients' charts from a tertiary Brazilian hospital were screened by the algorithm and iMCD clinical and/or laboratory features were identified in 102 patients, which had higher probability of having iMCD. Of those, 12 had mimicker conditions with overlapping iMCD features and three others required further assessment.

Conclusion

This AI driven tool was able to identify patients who have iMCD features. Screening with this tool found at least three candidates for additional evaluation. In the future, algorithms like the one we present may facilitate screening for iMCD.
Hemgn Upregulation By Gfi1 through PU.1 Repression Contributes to Gfi1's Anti-Apoptotic Activity
Authors: G C Binod , Dong Fan
Published: December 2024

Gfi1 is a transcriptional repressor that plays a critical role in hematopoiesis. The repressive activity of Gfi1 is mediated mainly by its SNAG domain that interacts with and thereby recruits the histone demethylase LSD1 to its target genes. An important function of Gfi1 is to protect hematopoietic cells against stress-induced apoptosis, which has been attributed to its participation in the posttranscriptional modifications of p53 protein, leading to suppression of p53 activity. In this study, we show that Gfi1 upregulated the expression of Hemgn, a nuclear protein, through a 16-bp promoter region spanning from +47 to +63 bp relative to the transcription start site (TSS), which was dependent on its interaction with LSD1. We further demonstrate that Gfi1, Ikaros and PU.1 bound to this 16-bp region. However, while Ikaros activated Hemgn and collaborated with Gfi1 to augment Hemgn expression, it was not required for Gfi1-mediated Hemgn upregulation. In contrast, PU.1 repressed Hemgn and inhibited Hemgn upregulation by Gfi1. Notably, PU.1 knockdown and deficiency, while augmenting Hemgn expression, abolished Hemgn upregulation by Gfi1. PU.1 (Spi-1) has been shown to be repressed by Gfi1. We show here that PU.1 repression by Gfi1 preceded and correlated well with Hemgn upregulation. Hemgn has been shown to be induced in response to DNA damage and inhibit DNA damage-induced apoptosis. Our data further demonstrate that Gfi1 and DNA damage acted in collaboration to augment Hemgn expression in a p53-independent manner. Notably, Hemgn knockdown partially abolished the protective effect of Gfi1 on DNA damage-induced apoptosis in both p53-expressing and p53-deficient cells. In contrast, partial restoration of Hemgn expression in the lineage negative (Lin-) bone marrow cells from Gfi1-/- mice diminished their hypersensitivity to DNA damage. Together, our date strongly suggest that Gfi1 upregulates Hemgn by repressing PU.1 and that Hemgn upregulation contributes to the anti-apoptotic activity of Gfi1 in a p53-independent manner.
Pre-Clinical Evaluation of AZD5492, a Novel CD8-Guided T Cell Engager, for B-Non Hodgkin Lymphoma Indications
Authors: Lawrence Rachel , Cayatte Corinne , Izuzquiza Fernandez Macarena , Rata Scott , Ciucci Thomas , Lin Wen , Lara Abigail , Jafarzadeh Nazli , Foreman Taylor , Payne Sterling , Shandilya Harini , Sambamurthy Nisha , Luo Haibin , Stebbings Richard , Dovedi Simon , Gorgun Gullu , Mato Anthony , Cemerski Saso , Cobbold Mark , Younes Anas
Published: December 2024

Introduction

Non-Hodgkin lymphomas (NHL) include diverse neoplasms of the lymphoid compartment, with the majority originating from the B-cell lineage. Bispecific CD20xCD3 T cell engagers (TCEs), both monovalent and bivalent, have shown promising rates of ORRs and CRs in the clinic leading to several FDA approvals for the treatment of R/R DLBCL and FL. However, these treatments are still associated with significant toxicities, including CRS and ICANS, limiting their therapeutic window and potential for clinical combinations.

Methods

We engineered a first-in-class CD8-guided TCE, AZD5492, for B-NHL malignancies. AZD5492 is an asymmetric, trispecific monoclonal IgG1 antibody which harbors two Fab binding domains to CD20, one VHH binding domain to TCR, one VHH binding domain to CD8 co-receptor. AZD5492 binding, cytolytic activity, and efficacy were extensively interrogated in vitro and in vivo, in murine models and in non-human primates (NHP).

Results

The VHH domains of AZD5492 allow preferential engagement of CD8+ T cells through CD8/TCR binding, leading to the formation of an artificial immunological synapse with CD20+ target cells, T-cell activation and target B cell killing. Compared to conventional CD20xCD3 TCEs, which equally engage and activate CD4+ and CD8+ T cells, AZD5492 drives potent B cell killing through preferential engagement of CD8+ T cells, with reduced CD4+ T cell activation and associated cytokine production. In NSG humanized mice engrafted subcutaneously or intravenously with B cell tumors, AZD5492 conferred potent and dose-dependent anti-tumor efficacy. When compared to conventional bivalent CD20xCD3 TCEs, comparable anti-tumor efficacy was achieved with significantly less systemic cytokine production. Importantly, repeated dosing of AZD5492 was also evaluated in cynomolgus monkey for up to 1 month and induced a marked and prolonged decrease in CD19+ and CD20+ B cells in the blood and in tissues (lymph nodes, spleen, and bone marrow). Transient cytokine increases were observed post-first dose of AZD5492 but was not associated with notable toxicity. Overall, AZD5492 was well tolerated in cynomolgus monkeys and a NOAEL was established at 3 mg/kg.

Conclusions

AZD5492 represents a first-in-class T cell engager for the treatment of B cell lymphomas. Compared to conventional CD3-based T cell engagers, AZD5492 anti-tumor activity in murine models was associated with low cytokine release and this favorable safety profile was recapitulated in NHP. AZD5492 has therefore the potential to significantly improve therapeutic index. AZD5492 IND has been approved by the FDA and a FIH study in patients with R/R NHL and CLL is ongoing.
The Effect of Alpha-Thalassemia on HbA1c Levels
Authors: Kerdsinchai Pasiri , Tantiworawit Adisak , Manosroi Worapaka , Niprapan Piangrawee , Punnachet Teerachat , Hantrakun Nonthakorn , Piriyakhuntorn Pokpong , Rattanathammethee Thanawat , Hantrakool Sasinee , Chai-Adisaksopha Chatree , Rattarittamrong Ekarat , Norasetthada Lalita , Charoenkwan Pimlak
Published: December 2024

Abstract

Background: Beta-thalassemia patients have shown that HbA1c levels are lower in patients and correlate with lower hemoglobin (Hb) levels. The findings are possibly due to the shortening of red blood cell lifespan and elevated fetal hemoglobin (Hb F) levels. Alpha-thalassemia is common in Southeast Asia. Patients with alpha-thalassemia also experience chronic hemolytic anemia that may affect HbA1c levels.

Objective: To investigate the effect of alpha-thalassemia on HbA1c levels and the correlation between Hb and HbA1c levels.

Methods: This cross-sectional study enrolled patients with alpha-thalassemia and a control group from September 2022 to April 2024 from the Tertiary care University Hospital. Thalassemia patients and control subjects were confirmed through hemoglobin typing (HPLC) and PCR for alpha-thalassemia. Inclusion criteria included individuals aged ≥ 15 years with confirmed non-diabetes mellitus status by fasting blood sugar (FBS) and hemoglobin A1c level (HbA1c). Exclusion criteria included anemia resulting from other hemoglobinopathies and anemia from other causes. An analysis of variance (ANOVA) test was employed for the statistical analysis, dependent on the distribution of data. Linear correlation analysis was employed to explore the association between anemia and HbA1c levels in the HbH disease group.

Results: A total of 158 patients were enrolled, comprising 56 control patients, 72 HbH disease patients, and 30 patients with alpha-thalassemia trait 1. Patient characteristics, including sex, fasting blood glucose, creatinine, and GFR, did not differ significantly between the groups. The mean ± SD of HbA1c compared between the control, alpha-thalassemia 1 trait, and HbH disease groups was 5.3% ± 0.4 mmol/mol, 5.3% ± 0.4 mmol/mol, and 4.1% ± 0.6 mmol/mol, respectively (P < 0.001). Significant differences in the mean HbA1c level ± SD [95% CI] were observed between the HbH disease and control groups (-1.25 ± 0.09 mmol/mol [95% CI -1.44 to -1.05] P < 0.001), whereas no significant difference was found in the alpha-thalassemia trait 1 group compared with the control group (0.06 ± 0.09 mmol/mol [95% CI -0.11 to 0.24] P= 0.476). Furthermore, no statistically significant linear correlation was observed between the degree of anemia and HbA1c levels in the HbH disease group.

Conclusion: In summary, HbH patients demonstrated notably lower HbA1c levels than the control group while levels were similar between the alpha-thalassemia trait 1 and control group.
CD38 Expression As an Additional Prognostic Marker in Mantle Cell Lymphoma
Authors: D'Addona Matteo , Pezzullo Luca , Giudice Valentina , De Novellis Danilo , Ferrara Idalucia , Fontana Raffaele , Guariglia Roberto , Luponio Serena , Mettivier Laura , Martorelli Maria Carmen , Gigantiello Andrea , Morini Denise , Rizzo Michela , Buonanno Maria Teresa , Ciancia Giuseppe , Gorrese Marisa , Serio Bianca , Selleri Carmine
Published: December 2024

Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by a t(11;14)(q13;q32) occurring in pre-B cells and determining uncontrolled cell proliferation. MCL cell immunophenotype is typically CD19+CD20+CD5+CD22+CD24+CD79a+CD43+FMC7+BCL2+CD10-CD11c-CD23-CD200-BCL6-CyclinD1+SOX11+; however, neoplastic clones could aberrantly express adhesion molecules that can augment tumor aggressiveness.

In this study, we evaluated the prognostic impact in MCL of several surface markers currently used for immunophenotyping in other B-cell lymphomas.

In this retrospective observational real-life study, a total of 46 newly diagnosed MCL patients (M/F, 35/11; mean age, 67 years old; range, 44-87 years) were enrolled from 2000 to 2023 followed at the Hematology Unit, University Hospital of Salerno, Italy. Most patients (n = 41, 89%) had advanced (III-IV) disease, and high MIPI score (94% of subjects). Ki-67, an immunohistochemistry proliferation marker, was increased in 59% (expression >30%) and in 4% was decreased (≤30%). Flow cytometry immunophenotyping was performed on bone marrow and/or peripheral in all subjects using the following antibody panels: CD19, CD20, CD5, CD23, CD10, CD11c, CD43, CD103, CD200, SmIg, CD22, CD79, FMC7, CD27, CD49d, CD38, CD25, CD56, CD16, CD2.

In our cohort, CD38 was frequently absent in MCL patients (positivity in N = 8, 17%; negativity in N = 16, 36%) patients. However, CD38- subjects tended to have a shorter overall survival (OS) compared to those patients with CD38 expression (median OS, 14 months vs not reached, CD38- vs CD38+ patients; P = 0.0591), as well as for progression-free survival (PFS) (median PFS, 26 months vs not reached, CD38- vs CD38+ patients; P = 0.0391), especially in patients aged 65 or older (median OS, 238 months vs 14 months, younger CD38- vs older CD38- MCL patients; P = 0.1252). Moreover, we investigated the impact of CD38 expression in patients that have Ki-67 expression between 30 and 70%. Despite falling in the high-risk MIPI categories because the patients have Ki-67 expression >30%, CD38+ MCL patients showed better clinical outcomes compared to CD38- subjects with Ki-67 expression between 30-70% (median OS, not reached vs 14 months, respectively; P = 0.0055; and median PFS, not reached vs 14 months, respectively; P = 0.0127).

In conclusions, CD38 negativity is frequent in MCL; however, this condition could be associated with worse outcomes, especially in older patients (>65 years old) and in subjects with intermediated Ki-67 expression (30-70%). Therefore, our results indicated that CD38 could be a potential prognostic biomarker in MCL and could be included in current prognostic scoring systems for better risk stratification.
Ultra-Low Dose Radiotherapy Combined with Orelabrutinib Improves the Complete Response Rate of Treatment for Localized Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma
Authors: Yang Shaoxin , Zhao Chong , Zhou Yixiong , Shi Jun
Published: December 2024

Background: Extranodal marginal zone B-cell lymphoma (EMZL) is the most common lymphoma of the ocular adnexa (OA). Although radiotherapy is still the first-line treatment for localized OA-EMZL (stage I/II), the toxic effects of standard dose radiotherapy cannot be ignored. While reduced doses of radiotherapy can lessen these toxic effects, they also lower the complete response (CR) rate. We aim to use prospective trials to improve this CR rate while reducing the toxic effects of radiotherapy.

Methods: This is a single-arm, open clinical trial. Nine patients were diagnosed with OA-EMZL through surgery. These patients had Ann Arbor stage I/II with residual lesions. They received an ultra-low dose of radiation therapy, with each dose of 2 Gy administered twice, for a total of 4 Gy. Concurrently, the patients received oral orelabrutinib, 150 mg daily, every 4 weeks as a course of treatment, and the efficacy and adverse reactions were evaluated. During the treatment process, the patients continued to take oral orelabrutinib for four courses.

Results: One patient had involvement of both eyes, while the remaining eight had monocular involvement. Eight patients had lesions located in the orbit, and one had lesions in the orbit and lacrimal gland. Currently, five of the patients have completed treatment and all achieved CR, while the remaining four cases are still under treatment. Three patients achieved CR after three courses, and two patients achieved CR after four courses. Additionally, the lesions in the patients still undergoing treatment have shrunk compared to before treatment. During treatment with orelabrutinib, one patient experienced mild leukopenia and one patient experienced mild thrombocytopenia. There were no early toxic effects, such as dermatitis, xerophthalmia, conjunctivitis, watering eyes in eight patients. Moreover, dry eye was not aggravated in one patient due to lacrimal gland resection.

Conclusion: The combination of ultra-low dose radiotherapy and orelabrutinib in the treatment of OA-EMZL not only improves the effectiveness of treatment but also significantly reduces the toxic effects of radiotherapy, providing a new approach for the treatment of localized OA-EMZL.