bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing a Patient-Derived Immortalized Erythroid Progenitor Cell Model to Investigate Disease Mechanisms and Lentiviral Gene Therapy Vector in Congenital Dyserythropoietic Anemia Type II
Authors: Taak Ravina , Babu Dinesh , Jamwal Manu , Palani Dhavapriya , Sharma Prashant , Bhatia Prateek , Bansal Deepak , Velayudhan Shaji R , Das Reena
Published: December 2024

Congenital dyserythropoietic anemias (CDAs) are rare inherited disorders characterized by ineffective erythropoiesis. Type II CDA (CDA II) is the most prevalent, caused by mutations in the SEC23B gene. Clinically, CDA II is manifest by mild to severe anemia, relative reticulocytopenia, jaundice, hepatosplenomegaly, and cholelithiasis. Bone marrow erythroblasts in these patients show erythroid hyperplasia and 10-30% binucleation or occasionally multinucleation. Previous in-vivo models using mice and zebrafish have not accurately replicated the disease phenotypes observed in humans.

In this study, we aimed to establish a patient-derived immortalized erythroid progenitor cell (iEPC) model to investigate disease mechanisms. We isolated peripheral blood mononuclear cells (PBMNCs) from two patients with clinical and pathological phenotypes consistent with CDA II, both of whom exhibited SEC23B mutations as identified by next-generation sequencing. One patient, compound heterozygous for mutations NM_006363.4:c.1043A>G and NM_006363.4:c.1898delC, displayed more severe symptoms and was transfusion-dependent, unlike the other patient, who was compound heterozygous for mutations NM_006363.4:c.1589G>A, and NM_006363.4:c.1905+3G>T and did not require transfusions.

Using a lentiviral vector, we transduced the PBMNCs with HPV E6/E7 genes and cultured them in erythroid progenitor expansion medium, successfully generating immortalized erythroid progenitors that were maintained for over 90 days. These iEPCs expressed erythroid markers CD71 and CD235a and were predominantly in the proerythroblast or basophilic erythroblast stages. The iEPCs could be differentiated into later stages of erythropoiesis using a cytokine-enriched medium. Despite typical expression kinetics of CD71, CD105, and CD235a during differentiation, the CDA II iEPCs showed reduced enucleation compared to a wild-type iEPC line, indicative of ineffective erythropoiesis.

Morphological analysis using Giemsa stain revealed binucleation in 20 to 30% of cells at the orthochromatic stage. Transmission electron microscopy showed a discontinuous double membrane in mature erythroblasts of both CDA lines. Western blot analysis confirmed reduced SEC23B expression in the CDA II lines. RNA sequencing of iEPCs pre- and post-differentiation identified novel pathways involved in disease pathogenesis. After transducing the iEPCs with a lentiviral vector expressing SEC23B, we observed a significant decrease in binucleated cells and an increase in terminally differentiated cells.

Our results demonstrate that iEPCs can be successfully generated from patients with rare red cell diseases and that CDA II disease modeling using iEPCs is viable for studying disease mechanisms and evaluating gene therapy vectors.
Treatment Outcomes for Patients with
TP53
-Mutated Mantle Cell Lymphoma: A Systematic Review and Meta-Analysis
Authors: Zhang Na , Xu Jiegang , Luo Chengxin , Zeng Dongfeng , Xu Shuangnian , Li Xi
Published: December 2024

Abstract

Background TP53 mutation, which is present in 10% to 20% of patients with mantle cell lymphoma (MCL), is the most poor predictor of early disease progression and death for MCL patients. Many clinical trials have been conducted to improve the therapeutic efficacy for these patients, but the best available treatment is still unknown. Thus, we conducted a systematic review and meta-analysis to evaluate the outcome of current various treatments for TP53-mutated (TP53m) MCL.

Methods EMBASE and MEDLINE were searched from inception to December 29, 2023 without language restriction. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies which reported the treatment outcomes for newly diagnosed or relapsed/refractory TP53m MCL patients were included. Outcomes included complete remission (CR) rate, overall response (OR) rate and overall survival (OS).

Results A total of 28 studies which met the inclusion criteria were included in this systematic review and meta-analysis. The treatment approaches for TP53m MCL patients in the included studies contained targeted therapy, targeted therapy combined chemotherapy, hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T-cell (CAR-T) therapy. The CR rate and OR rate for TP53m MCL patients with the current treatment was 68% (95%CI 57%-79%, I2=41%) and 79% (95%CI 65%-90%, I2=71%) respectively. For newly diagnosed TP53m MCL patients, targeted therapy was reported to be with the highest CR rate of 79% (95%CI 62%-93%, I2=3%) and the highest OR rate of 96% (95%CI 82%-100%, I2=10%). For relapsed/refractory TP53m patients, CAR-T therapy showed the highest CR rate of 84% (95%CI 64%-98%, I2=43%) and the highest OR rate of 95% (95%CI 73%-100%, I2=62%). The 1-year OS rate and 2-year OS rate for TP53m MCL patients with the current treatment was 63% (95%CI 52%-73%, I2=20%) and 53% (95%CI 38%-69%, I2=44%) respectively. For newly diagnosed TP53m MCL patients, 1-year OS rate and 2-year OS rate for allo-HSCT was 69% (95%CI 50%-83%, I2=54%) and 62% (95%CI 45%-77%, I2=0%), respectively. For relapsed/refractory TP53m MCL patients, 1-year OS rate was 43% (95%CI 10%-82%) for targeted therapy, 61% (95%CI 47%-73%) for CAR-T therapy, and 2-year OS rate was 44% (95%CI 32%-58%) for CAR-T therapy.

Conclusions Although targeted therapy or CAR-T therapy can achieve an relatively high response rate for newly diagnosed or relapsed/refractory TP53m MCL patients, survival was still poor for these patients and more effective treatment strategies need to be exploded.
Flavopiridol Restores Granulopoiesis in an Experimental Model of Severe Congenital Neutropenia
Authors: Dannenmann Benjamin , Nasri Masoud , Doll Larissa , Findik Betül , Bernhard Franka , Kandabarau Sergey , Klimiankou Maksim , Lengerke Claudia , Zeidler Cornelia , Welte Karl , Skokowa Julia
Published: December 2024

Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways that cause maturation arrest of granulocytic progenitors. The largest group of CN patients harbors autosomal dominant ELANE mutations (ELANE-CN).

We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of ELANE-CN and identified signaling pathways deregulated by ELANE mutations in iPSC-derived hematopoietic stem and progenitor cells, potentially leading to defective granulopoiesis. We further performed an in silico drug repurposing analysis of the transcriptomics data and selected flavopiridol, an FDA-approved pan-cyclin-dependent kinase inhibitor, as a potential therapeutic.

We found that treatment with low-dose flavopiridol (up to 10-fold lower than that usually used to treat cancer patients) rescued defective granulopoiesis in primary CD34+ cells of CN patients with different inherited gene mutations, including ELANE, HAX1, SRP54 and JAGN1, in vitro and in two zebrafish CN models in vivo (hax1-CN and jagn1b-CN) without any toxic effects on hematopoietic stem cells or granulocytes and leading to fully functional granulocytes.

We have previously shown that the expression levels of the transcription factor CEBPA are severely reduced in hematopoietic cells and myeloid progenitors of CN patients. Rescue of defective granulopoiesis by transduction of CD34+ cells from CN patients with CEBPA further supports its key role in the pathogenesis of CN. CEBPA is known to counteract CDK2 and CDK4 activity to induce granulopoiesis and we found that flavopiridol restored granulopoiesis caused by reduced CEBPA expression in vitro and in zebrafish embryos in vivo. These data provide insight into the mechanism of action of flavopiridol in rescuing defective granulopoiesis in CN.

Thus, we described for the first time a therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia.
SMARCC1 Controls the Oncogenic NOTCH1 Transcriptional Program in T-Cell Acute Lymphoblastic Leukemia
Authors: Shoumariyeh Khalid , Sun Xiaoyang , Poggio Teresa , Andrieux Geoffroy , Schmitz Tatjan , de Bra Stephan , Fotouhi Omid , Nizamuddin Sheikh , Martens Uta Sabine Sabine , Duyster Justus , Timmers Marc , Boerries Melanie , Miething Cornelius
Published: December 2024

Introduction: Mutations in NOTCH1 are highly prevalent in T-ALL and aberrant NOTCH1 signaling is required for maintenance of the leukemogenic state in T-cell progenitors. However, little is known about which interaction partners are functionally required for oncogenic NOTCH1 signaling. We therefore aimed to identify previously unappreciated molecular dependencies required for NOTCH1-driven T-ALL cells.

Methods: We performed an in vitro miR-E-based loss-of-function RNAi screen employing an shRNA-library targeting 340 genes of the NOTCH1-interactome in a murine model of human intracellular NOTCH1 (hICN1)-induced T-ALL (Tx17 cell line). To identify NOTCH1-specific depletors, the screen was also performed in two murine Notch1-negative cell lines, the pro-B-cell line BaF/3 and the T-cell lymphoma cell line EL4.

Results: We identified Smarcc1 as the top NOTCH1-specific candidate in our screen. Smarcc1 knockdown in Tx17 cells resulted in rapid depletion of shRNA-expressing cells and induction of apoptosis.These results were confirmed in the NOTCH1-dependent human T-ALL cell line JURKAT and by probing public data from the depmap portal, revealing a strong SMARCC1-dependency in the two most NOTCH1-dependent cell lines tested, JURKAT and PF-382. Pulldown of human SMARCC1 in Tx17 cells and proteomic analysis revealed binding of all known SWI/SNF complex members and Notch1. Retransplantation of Tx17 cells harboring Smarcc1 or neutral shRNAs and in vivo shRNA induction led to a significantly decreased spleen infiltration of Tx17 cells transduced with the Smarcc1 shRNA compared to a neutral shRNA. RNAseq analysis of Smarcc1 depleted cells indicated a differentiation switch from DP to CD4 SP cells, implicating Smarcc1 as a mediator of NOTCH1-induced differentiation blockade.

Conclusion: By functionally interrogating the molecular networks directly involved in NOTCH1 signaling in a murine model of hICN1-induced T-ALL, we identified Smarcc1 as a major contributor to oncogenic NOTCH1 signaling. Knockdown of Smarcc1 in NOTCH1-driven T-ALL cell lines resulted in apoptosis and rapid depletion of shRNA-expressing cells. Mechanistically, Smarcc1 binds NOTCH1 and regulates a NOTCH1-dependent transcriptional program. In ongoing investigations including CUT&RUN analysis, we are currently further probing the precise mechanism through which Smarcc1 maintains aberrant NOTCH1 signaling in T-ALL.
Radiopsy, Quantitative Wb-Mri Adc and Fat Fraction Sequences for Discrimination of Smoldering Multiple Myeloma and Multiple Myeloma: A Prospective Observational Study
Authors: Cerchione Claudio , Rossi Alice , Caroli Paola , Marchesini Matteo , Matteucci Federica , Cangini Delia , Barone Domenico , Nappi Davide , Bezzi Davide , Sarnelli Anna , Martinelli Giovanni , Normanno Nicola , Feliciani Giacomo
Published: December 2024

Purpose: To distinguish between Multiple Myeloma and High-Risk Smouldering Myeloma at staging using image-based biomarkers obtained from Whole Body-MRI (WB-MRI) Apparent Diffusion Coefficient (ADC) and Fat Fraction (FF) sequences.

Methods and Materials: From January 2021 to March 2024, we enrolled consecutive myeloma patients at staging into an observational prospective trial and divided them into two groups based on International Myeloma Working Group (IMWG) criteria: High-risk Smouldering Multiple Myeloma (SMM, group 1) and Multiple Myeloma (MM, group 2). All patients underwent WB-MRI using the Myeloma Response Assessment and Diagnosis System (MY-RADS). We use the term “Radiopsy” to indicate the quantification and modelling of image characteristics nearby the biopsy site to predict patient status. An experienced radiologist placed a cylindrical, 5 cc VOI nearby the biopsy site and 5 more identical VOIs on distant sites such the pelvis bone and on D11 and L5 vertebrae. The dataset was split into a training and test set with a 70:30 ratio. LASSO algorithm was used to select the most predictive features and build logistic regression models, which were then validated using the test set. Receiver operating curves (ROC) and area under the curve (AUC) were used as metrics for models' performance assessment. Radiopsy models were tested on distant biopsy site to predict disease invasion.

Results: The study included 102 patients (46 males, mean age 63 ± 12 [SD]) with 60 diagnosed with MM and 42 with SMM. 144 quantitative features were extracted from the VOI at the biopsy site WB-MRI ADC and FF sequences for each patient. Radiopsy model showed a median AUC of 0.85 (0.79-0.95) in the training phase and a median AUC of 0.65 (0.55-0.80) in the test phase. The best predictive model had an AUC of 0.95 and 0.75 in the training and test phase, respectively. The models used to predict patient status at biopsy site were also predictive in distant VOIs.

Conclusions: Radiopsy models can distinguish between MM and SMM with good performance nearby the biopsy site. Radiopsy can be used to predict disease invasion on distant sites where biopsy is not possible or not feasable

Clinical Relevance/Application: This observational prospective trial showed that using quantitative features extracted from WB-MRI ADC and FF sequences can help distinguish between high-risk SMM and MM at staging, thus potentially enhancing diagnostic accuracy.
Metabolic Tumor Volume after Two Cycles of Chemotherapy in Patients Treated for Advanced-Stage Hodgkin Lymphoma: Analysis of the German Hodgkin Study Group Phase III HD18 and HD21 Trials
Authors: Ferdinandus Justin , Kaul Helen , Schneider Gundolf , Fuchs Michael , Eich Hans Theodor , Baues Christian , Rosenbrock Johannes , Roth Katrin S , Drzezga Alexander , Van Heek Lutz , Dietlein Markus , Borchmann Peter , Kobe Carsten
Published: December 2024

Introduction:

PET-guided treatment is standard of care to treat patients diagnosed with advanced-stage classical Hodgkin Lymphoma (AS-cHL) in several countries. Here, we investigate the role of metabolic tumor volume (MTV) for the response assessment of patients treated for AS-cHL.

Methods:

The investigator-initiated phase III trials HD18 (NCT00515554) and HD21 (NCT02661503) randomized patients between 18-60 years with newly diagnosed AS-cHL to receive BEACOPP (HD21 standard arm, HD18) or BrECADD (HD21 experimental arm). All patients received two cycles of chemotherapy followed by response assessment after two cycles (PET-2). MTV after two cycles (MTV-2) encompassed all lymphoma tissue with standard uptake value > 4. To exclude confounding of PET-guided treatment, we first analyzed MTV-2 in patients treated in control arms of HD18 who received 6 cycles of BEACOPP irrespective of PET-2 (C6-Cohort). Cox-regression models and Kaplan Meier estimates were used to analyze impact of MTV-2 on progression-free survival (PFS). Findings were validated in the full ITT cohorts of HD18 and HD21.

Results:

A total of 645 patients were included in the C6-Cohort, of these 471 (64.6%) were rated as DS1-3 in PET-2 and 569 (88.2%) had no residual MTV-2. Compared to patients with DS1-3 (5y-PFS 93.5%; CI95: 91.2-95.9), Patients with measurable MTV-2 had significantly inferior PFS (5y-PFS 77.5%; HR 3.62, CI95: 1.94-6.76), while patients without detectable MTV-2 and DS4 had similarly high PFS (5y-PFS 89.3%; HR 1.65; CI95: 0.8-3.38). In line with these results, in the analyzed ITT cohorts of HD18 (n = 1756) and HD21 (n= 1211), patients with DS4 but with completely resolved MTV-2 had similar outcomes as patients with DS1-3 (HD18: HR 1.12, CI95: 0.69-1.80; HD21: HR 1.03, CI95: 0.55-1.95), whereas patients with measurable MTV-2 featured higher risk of progression (HD18: HR 2.98, CI95: 1.92-4.64; HD21: HR 4.44, CI95: 2.78-7.09). Results were similar in both trial arms of HD21 (BEACOPP vs. BrECADD) and frequency of measurable MTV-2 was similar in HD18 post-amendment and HD21.

Conclusion:

Complete resolution of MTV after two cycles of first-line chemotherapy for AS-cHL occurs in a vast majority of patients and associates with favorable prognosis, irrespective of DS. Approximately 10% had measurable MTV-2 (i.e. any lesion with SUV > 4) and face high risk of progression. Our results advocate implementation of quantitative biomarkers to refine response assessment in AS-cHL.
Inferior Survival of Chronic Phase Chronic Myeloid Leukemia Patients in Public Health System Compared to Social Security and Private Systems in Perú: A Real-Life Study
Authors: Pizarro-Perea Marlies , Samanez-Figari Cesar , Mallma Soto Victor Ivan , Arteta Cecilia , Diaz Bardales Carol , Calderon Hafid , Calle Cindy , Carbone Ethan , Castillo Claudia , López Córdova Naty , Huaman Veronica , Menacho Estefany , Molina Maribel , Sanchez Jorge , Seminario Victor E , Jiménez Tornero Gledy , Vargas Olga , Vera Maria Alejandra , Untama José L.
Published: December 2024

Background: The prognosis and survival of Chronic myeloid leukemia (CML) patients have improved in the last decades. Peru is a developing country without a national register of Cancer, where CML patients are seen in three different healthcare systems with some disparities, the objective of this study is to compare the clinical characteristics of patients with CML at diagnosis and survival by healthcare system.

Methods: We performed a real-life observational retrospective study collecting epidemiological and clinical data of newly diagnosed CML patients from three different settings: public health (PH), social security (SS) and private (P). All the patients were treated according to the guidelines and resources of each center and the data was obtained from their respective database.

Results: We obtained data from 785 CML patients older than 14 years who were treated in three different healthcare systems since 2010: 297 patients at public health (PH), 424 at social security (SS) and 64 at private (P), respectively.

At the time of CML diagnosis, fewer patients were diagnosed in chronic phase (PC) at PH system (82.5%) compared to 95.4% and 95.3% at SS and P systems, respectively.

A total of 531 chronic phase (CP) patients had completed data and were evaluated. At Public system we found younger patients (mean age 41.3yo vs 47.9yo and 51yo for PH, SS and P), major M/F ratio (2.21 vs 1.65 and 1.13 for PH, SS and P), lower Hb levels (9.5 vs 10.17 and 11.3 g/dL for PH, SS and P systems), higher WBC (231 vs. 201 and 189 x 109/L for PH, SS and P).

About risk scores, fewer patients had high-risk Sokal score in P system (32.6%) in comparison with SS (54.8%) and PH (59.8%). In contrast, more pts had high-risk ELTS score in PH system (38.6%) compared to SS (23.6%) and P (18.4%).

Because of similarities we pooled the survival data of P and SS system and compared with PH, we found an inferior OS at PH compared to P and SS: 5y OS and 10y OS at PH was 81.5% and 72.1% in contrast to 91% and 81.9% for combined P and SS (Log-rank p 0,02).

Conclusion: The CML patients at public health system had more advanced phases of disease, were younger and had more adverse characteristics at diagnosis, and it correlates with inferior OS. This study could be used to promote national measures of public health to improve the outcome of CP CML patients in our country.
Impact of Molecular Aberrations on Discordance Among Modalities of Blast Enumeration for Risk Stratification in Myelodysplastic Neoplasms
Authors: Steiner Laurenz , Kaur Navkirandeep , Jann Johann-Christoph , Fabarius Alice , Metzgeroth Georgia , Meggendorfer Manja , Hofmann Wolf-Karsten , Jawhar Mohamad , Nowak Daniel , Streuer Alexander
Published: December 2024

Introduction: To determine prognosis and treatment of myelodysplastic neoplasms (MDS), adequate risk stratification is a crucial element in handling MDS patients. In the Revised International Prognostic Scoring System (IPSS-R), cytogenetical data and the amount of blasts in the bone marrow (BM) smear have substantial weight. With platelet count, hemoglobin level and absolute neutrophil count as explicit parameters and defined risk categories for evaluating karyotypes, morphology-based blast enumeration remains a relatively subjective part of risk scoring. BM cytology (BM-c), BM histology (BM-h) and BM flow cytometry (BM-f) are widely used to determine the amount of blasts in MDS patients. In the cohort of MDS patients treated since 2012 in our institution, we found significant blast count discordance among these three modalities, impairing overall survival (OS) of discordant (dis) patients. Previous research has shown remarkable impact of molecular genetic aberrations on OS in MDS. Therefore, we went out to define such markers which may help to discriminate discordant diagnostic cases.

Methods/Results: We analyzed molecular genetic data of 145 MDS patients and compared the blast counts in the three modalities to determine concordant (con, n=83, 57%) and dis samples (n=62, 43%). Although there were no significant differences between these two groups regarding age, sex, hemoglobin level, platelet count and IPSS-R karyotype risk groups (all p > 0.05), a pronounced difference in overall survival of low-risk MDS patients according to IPSS-R was observed (con vs. dis, median OS 72 vs. 35 months, p = 0.036). In dis cases, further analysis showed significantly more mutations regarding -7/7q deletion (9 vs. 1 cases, p = 0.04) and BCOR (6 vs. 0 cases, p = 0.03). In case of the splicing factor mutations SF3B1 (6 vs. 16 cases, p = 0.003) and U2AF1 mutations (2 vs. 7 cases, p = 0.04), significant differences in favor of concordant samples were found. Interestingly, when low-risk con and dis patients were re-stratified using IPSS-M, OS was markedly higher and differences in OS between con and dis patients vanished (72 vs. 146 months, p = 0.46).

Conclusion: Our study reveals molecular genetic features that impact the assessment of blasts by the classically used modalities BM-c, BM-h and BM-f. Samples mutated in BCOR or with -7/7q deletion showed a distinct tendency towards blast discordance, while splicing factor mutations were mostly found in con patients. As previously shown, blast discordance is relevant for OS of patients and may significantly alter therapeutic decisions, highlighting that especially in discordant cases molecular data should be considered.
Interim PET-Adapted De-Escalation Chemotherapy Regimen for Advanced Stage Classical Hodgkin Lymphoma Using Brentuximab Vedotin, Pembrolizumab, Doxorubicin, and Dacarbazine: Phase 2 Safety and Efficacy Study
Authors: Lee Hun Ju , Ravizzini Gregory , Aboismail Eslam , Wixom Jenna , Henderson Jared , Fayad Luis E. , Ahmed Sairah , Nair Ranjit , Westin Jason R. , Iyer Swaminathan P , Nze Chijioke , Al Zaki Ajlan , Vega Francisco , Wang Michael , Flowers Christopher R. , Malpica Luis
Published: December 2024

Background:

Brentuximab vedotin (Bv), Nivolumab (N) and Pembrolizumab (P) have revolutionized the management of advanced stage classical Hodgkin Lymphoma (AS cHL). Significant improvements in both safety and efficacy have been observed with the Echelon-1 (E1) and SWOG S1826 studies. In GHSG HD18 & HD21, PET adapted strategy showed that the numbers of cycles could be reduced without affecting impact on the efficacy. Pembrolizumab followed by AVD in frontline AS cHL with minimal immune mediated adverse events (IMAE)(Allen et al Blood Advances 2023). This study incorporates pembrolizumab into the Bv+AD regimen based on the lower incidence of IMAE observed with pembrolizumab and utilizes a PET-adapted strategy to reduce chemotherapy exposure for patients with a negative interim PET scan. NCT05922904

Objectives:

This study aims to assess the safety and efficacy of PET-Adapted de-escalation of chemotherapy regimen after achieving interim PET negative.

Methods:

Study is enrolling patients with newly diagnosed stage I/II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Subjects will receive three cycles of BvP+AD (Bv 1.2 mg/kg capped at 100kg), pembrolizumab 400 mg [P], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]). Pembrolizumab was administered in Q6 week dosing intervals (C1D1, C2D15, C4D1 and C5D15), whereas the rest of the regimen were administered Q2 weeks. Interim PET scan was performed after cycle 3. Subjects achieving PET negativity defined as Deauville scores (DS) of 1 or 2 or 3 with > 90% reduction in total metabolic tumor volume (TMTV) will continue in the de-escalation arm. Subjects on the de-escalation arm will complete three additional cycles of only BvP. Subjects with positive interim PET defined as DS of 4, 5 or 3 < 90% reduction of TMTV would proceed with the standard arm to complete three additional cycles of BvP+AD, for a total of six cycles.

The primary efficacy endpoint is CR rate at the end of therapy (EOT). Key secondary endpoints include safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression are assessed using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. TMTV was calculated using Lesion cut off SUV of 4.0, by MIM software Version 7.4.
Trial eligibility, treatment patterns and outcome for venetoclax-based therapy in AML: a prospective cohort study
Authors: Wolach Ofir , Levi Itai , Nachmias Boaz , Tavor Sigal , Amitai irina , Ofran Yishai , Ganzel Chezi , Zuckerman Tsila , Okasha Doaa , Hellmann Ilana , Tadmor Tamar , Dally Najib , Canaani Jonathan , Stemer Galia , Grunspan Moshe , Berger Adi Jacob , Frankel Neta , Berelovich Jenia , Bleterman Alexandra , Barak Moran , Cohen Raanan , Moshe Yakir
Published: December 2024

Venetoclax (Ven) plus hypomethylating agents are considered standard-of-care for patients with acute myeloid leukemia (AML) judged ineligible for intensive chemotherapy (IC). Real-world studies complement clinical trials, since patterns of patient selection, treatment-exposure and post-remission management may vary. This prospective observational multi-center study included 209 newly diagnosed IC-ineligible patients with a median age 75 years (interquartile range, 71-81 years). A high proportion of patients had secondary AML (53.7%), adverse-risk disease (35.3%), and complex karyotype (15.5%). At a median follow-up of 22.5 months (range 0.1-43), median overall-survival (mOS) was 11.7 months (95% Confidence Interval [CI] 9.9,15.4). Composite complete remission (CRc) was achieved in 65.2% (CR 44.4%; CRi 20.8%). Of responding patients, 21.1% underwent stem-cell transplantation. When stratified based on VIALE-A original eligibility criteria, mOS was 17.8 months for patients meeting eligibility criteria and 10.7 months for patients who did not (p=0.027). AML ontogeny (p=0.024), reduced kidney function (p=0.001), Charlson co-morbidity index (CCI; p=0.0017), ELN-risk (p=0.01) and body-mass index (p=0.0298) were significantly associated with OS. Multivariant Cox-regression analysis confirmed independent association of OS with AML ontogeny (p=0.012), CCI (p=0.033) and ELN-risk (p=0.019). Patients enrolled in the latter half of the study period demonstrated improved OS compared to those enrolled earlier (p=0.026). This prospective observational study highlights outcomes of patient subgroups, including those excluded from registration trials. (clinicaltrials.gov: #NCT03987958).
Prognostic impact of patient-reported symptoms in multiple myeloma
Authors: Abdallah Nadine , Bohra Arwa , Mammadzadeh Aytaj , Buadi Francis , Kapoor Prashant , Dispenzieri Angela , Gertz Morie , Hayman Suzanne , ElHaj Mohammed , Dingli David , Cook Joselle , Binder Moritz , Lin Yi , Kourelis Taxiarchis , Warsame Rahma , Thompson Carrie , Menser Terri , Rajkumar S. Vincent , Kumar Shaji
Published: December 2024

Patient-reported outcomes (PROs) are associated with treatment outcomes in multiple myeloma (MM) in the clinical trial setting. However, most PRO tools are time consuming, which hinders use in routine practice. Our institution incorporated a “Hematology Patient-Reported Symptom Screen” (HPRSS), a 3-item questionnaire for fatigue, pain, and quality of life (QOL). The main objective of this study was to evaluate the impact of these symptoms on progression-free survival (PFS) and overall survival (OS) in a real-world cohort of patients with newly diagnosed MM. This retrospective study included patients with MM diagnosed between April 2011 and December 2017, seen at Mayo Clinic (Rochester, MN), who completed the HPRSS. Patients rated their symptoms on a scale from 0 to 10. Clinically relevant symptoms were defined as scores ≥5 for pain and fatigue, and ≤5 for QOL. At diagnosis, 735 patients had scores for all domains. The median follow-up was 8.1 years. Age was associated with increased odds of fatigue and decreased QOL. Female sex and comorbidities were associated with fatigue and pain. Higher disease stage, anemia, lytic lesions, and increased plasma cell burden were associated with fatigue, pain, and decreased QOL. Clinically relevant fatigue, pain, and decreased QOL were associated with decreased PFS and OS. On multivariate analysis including age, International Staging System III, high-risk cytogenetics, and postinduction transplantation, fatigue and decreased QOL were independently associated with decreased OS. A composite HPRSS score stratified patients into 3 groups with distinct OS. Patient-reported symptoms are prognostic in patients with newly diagnosed MM. The prognostic values of fatigue and decreased QOL are independent of age, disease stage, and transplant status.
Effects of different supervised and structured physical exercise on the physical fitness trainability of children and adolescents: a meta-analysis and meta-regression
Authors: Pinho Carolina Dertzbocher Feil , Bagatini-PhD Natália Carvalho , Lisboa Salime Donida Chedid , Mello Júlio Brugnara , Cunha Giovani dos Santos
Published: December 2024

Background

Physical fitness has been considered an important health indicator. Several factors can impact the increase in physical fitness in children and adolescents, including chronological age, sex and BMI, in addition to training variables such as weekly frequency, session and intervention duration, and types of exercises performed. To know the importance of variables that can impact physical fitness, it is important for health professionals to identify the most efficient way of prescribing physical exercises for children and adolescents. The aim is review and meta-analyses of the effects of supervised and structured physical exercise on the physical fitness trainability of children and adolescents.

Methods

Relevant articles were searched in the PubMed, Cochrane Library, Embase and Scopus platform databases and selected based on the following criteria: children and adolescents aged between 7 and 17 years who performed any type of structured physical exercise compared to a control group without exercise and evaluating physical fitness (strength or muscular power, cardiorespiratory fitness (CRF) or speed. The results are reported in accordance with PRISMA 2020.

Results

Eighty studies were included with a total of 5769 participants. Strength exercises (ES: 1.073; 95% CI, 0.612–1.533; P < 0.001; I2: 74%), concurrent (ES: 1.054; 95% CI, 0.255–1.853; P < 0.010; I2: 72%) and sports (ES: 0.573; 95% CI, 0.015 to 1.132; P < 0.044; I2: 34%) seem to be the most effective in increasing muscular strength. Aerobic activities (ES: 0.400; 95% CI, 0.258–0.542; P < 0.001; I2: 74%), sports (ES: 0.271; 95% IC, 0.148–0.394; P < 0.001; I2: 15), or HIIT (ES: 0.668; 95% IC, 0.333–1.003; P < 0.001; I2: 29%) resulted in increased CRF (ES: 0.514; 95% IC, 0.220–1.808; P < 0.001; I2: 66%). The practice of physical exercise increased muscular power (ES: 0.241; 95% CI, 0.053–0.429; P = 0.012; I2: 0%). The practice of HIIT impacts MAS gains (ES: 0.048; 95% CI, 0.050 − 0.026; P = 0.029; I2: 44%).

Conclusion

Supervised and structured physical exercise can improve muscular strength (15–35%), CRF (5.4–8.5%), muscular power (5.6–11.8%), and MAS (5.4%) trainability in children and adolescents. Sex, BMI of the subjects and type of exercise performed (aerobic activities, exclusive to strength, HIIT or sports) should be considered when prescribing the exercise.
Acute airway inflammation following controlled biodiesel exhaust exposure in healthy subjects
Authors: Sandström Thomas , Bosson Jenny A. , Muala Ala , Kabéle Mikael , Pourazar Jamshid , Boman Christoffer , Rankin Gregory , Mudway Ian S. , Blomberg Anders , Friberg Maria
Published: December 2024

Background

Exposure to standard petrodiesel exhaust is linked to adverse health effects. Moreover, there is a mounting request to replace fossil-based fuels with renewable and sustainable alternatives and, therefore, rapeseed methyl ester (RME) and other biofuels have been introduced. However, recent toxicological research has indicated that biodiesel exhaust may also induce adverse health-related events.

Aim

To determine whether exposure to 100% RME biodiesel (BD100) exhaust would cause an acute airway neutrophilic recruitment in humans.

Methods

Fourteen healthy subjects underwent exposure to diluted BD100 exhaust and filtered air for 1-h, in a blinded, random fashion. Bronchoscopy with endobronchial mucosal biopsies, bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed six hours after exposure. Differential cell counts and inflammatory markers were determined in the supernatant and biopsies were stained immunohistochemically.

Results

Compared with filtered air, BD100 exhaust exposure increased bronchial mucosal endothelial P-selectin adhesion molecule expression, as well as neutrophil, mast cell and CD68 + macrophage numbers. An increased influx of neutrophils and machrophages was also seen in BW.

Conclusion

Exposure to biodiesel exhaust was associated with an acute airway inflammation that appeared similar to preceding petrodiesel exposure studies. The present findings, together with the recently reported adverse cardiovascular effects after similar biodiesel exposure, indicate that biodiesel is not free of toxicity and may affect human health.
A temporary hospital intensive care unit: a preparedness concept to increase intensive care capacity
Authors: Østerås Øyvind , Almeland Stian , Landsdalen Håvard , Gjerde Stig , Sommerfelt-Pettersen Jan Knudtzon , Flaatten Hans
Published: December 2024

Introduction

Norway faced the possibility of the most significant strain on its intensive care capacity in decades during the COVID-19 pandemic. All Regional Health Authorities in Norway were instructed to prepare for an increase in Intensive Care Units (ICU) capacity demands. To address the surge in demand for critical care, a gymnasium within Haukeland University Hospital premises was planned to be used as a 20-bed temporary ICU. A team-based care approach was trained, where non-ICU nurses received specialized training to support ICU procedures. Maintaining up-to-date medical devices and consumables stored for preparedness through a planned rotation system that feeds into daily use are important. While shortages of medical equipment, hospital beds, and intensive care facilities may occur, personnel shortages are likely to be more significant.

Conclusions

The concept demonstrates promising potential in enhancing preparedness and maintaining critical care surge capacity during pandemics or mass casualty incidents.
Improving productivity of citramalate from CO2 by Synechocystis sp. PCC 6803 through design of experiment
Authors: Faulkner Matthew , Andrews Fraser , Scrutton Nigel
Published: December 2024

Background

Cyanobacteria have long been suggested as an industrial chassis for the conversion of carbon dioxide to products as part of a circular bioeconomy. The slow growth, carbon fixation rates, and limits of carbon partitioning between biomass and product in cyanobacteria must be overcome to fully realise this industrial potential. Typically, flux towards heterologous pathways is limited by the availability of core metabolites. Citramalate is produced in a single enzymatic step through the condensation of the central metabolites pyruvate and acetyl-CoA; improvements in citramalate productivity can, therefore, be used as a measure of overcoming this limitation. Furthermore, citramalate is a useful biomaterial precursor and provides a route to renewable methyl methacrylate and poly(methyl methacrylate), which is often traded as Perspex or Plexiglas.

Results

Here, we describe a phenomenon where the concerted optimisation of process parameters significantly increased citramalate production in Synechocystis sp. PCC 6803. Design of experiment principles were used to determine the optima for each parameter and the interplay between multiple parameters. This approach facilitated a ~ 23-fold increase in citramalate titre from initial unoptimised experiments. The process of scale-up from batch cultures to 0.5, 2, and 5 L photobioreactors is described. At the 2-L scale, citramalate titres from carbon dioxide reached 6.35 g/L with space–time yields of 1.59 g/L/day whilst 5-L PBRs yielded 3.96 ± 0.23 g/L with a productivity of 0.99 ± 0.06 g/L/day. We believe the decrease in productivity from 2-L to 5-L scale was likely due to the increased pathlength and shading for light delivery reducing incident light per cell. However, changes in productivity and growth characteristics are not uncommon when scaling up biotechnology processes and have numerous potential causes.

Conclusions

This work demonstrates that the use of a process parameter control regime can ameliorate precursor limitation and enhance citramalate production. Since pyruvate and/or acetyl-CoA give rise to numerous products of biotechnological interest, the workflow presented here could be employed to optimise flux towards other heterologous pathways. Understanding the factors controlling and thus increasing carbon partitioning to product will help progress cyanobacteria as part of a carbon–neutral circular bioeconomy. This is the first study using design of experiment to optimise overall carbon fixation rate and carbon partitioning to product, with the goal of improving the performance of a cyanobacterium as a host for biological carbon capture.
Impact of systemic inflammation and disease activity on the incidence of interstitial lung disease in patients with rheumatoid arthritis – a nested case-control study within the German biologics register RABBIT
Authors: Ramien Ronja , Rudi Tatjana , Alten Rieke , Krause Andreas , Schneider Matthias , Schaefer Martin , Strangfeld Anja , Meissner Yvette
Published: December 2024

Background

To investigate the association between the development of incident interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and the disease activity of RA with its various components, especially C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).

Methods

We analysed data from RA patients, observed in the German biologics register RABBIT between 2001 and 2021. In a nested case-control study, patients with a reported incident ILD diagnosis during follow-up were matched 1:5 to patients without ILD. Matching criteria were sex, age, RA duration, date of enrolment and observation time. Defined by a directed acyclic graph (DAG), we adjusted the conditional logistic regression models for rheumatoid factor, smoking, chronic obstructive pulmonary disease and tuberculosis/chronic viral infections to investigate the impact of disease activity/systemic inflammation. Mean and categorized values were analysed within 12 months prior to ILD and during the entire observation time. Additionally, two sensitivity analyses were performed, using validated ILD cases only and considering ILD cases with an observation time of more than 12 months.

Results

We identified 139 RA patients with incident ILD and matched them to 686 controls. In 94 cases the diagnosis could be validated, and 98 cases had a follow-up of > 12 months. The averaged DAS28 composite score (including ESR or CRP) was not associated with developing RA-ILD (odds ratios 1.16 [95% confidence interval: 0.97–1.40] and 1.06 [0.86–1.29], respectively). However, single measures of inflammation, log ESR (1.86 [1.35–2.57]) and log CRP (1.55 [1.21–1.97]), were significantly associated with an increased RA-ILD risk. A higher risk for ILD was also revealed for persistently high inflammation. Other DAS28 components showed no significant associations with RA-ILD. These results were consistent for values over the entire observation time of a patient and within 12 months prior to the ILD. Sensitivity analyses confirmed these findings.

Conclusion

Higher levels of systemic inflammation, as indicated by ESR and CRP, but not joint counts or patient’s global assessment, were significantly associated with the occurrence of incident ILD in patients with RA. As possible predictor for the development of RA-ILD, systemic inflammation should be monitored closely and independently of joint count results.
Toxicology study of a tissue anchoring paclitaxel prodrug
Authors: Chinthapatla Rukesh , Stephens Jazz Q. , Neumann-Rivera Isabel B. , Henderson Nichol M. , Nie Minhua , Haynes Hannah R. , Pierce Joshua G. , Meritet Danielle M. , Brudno Yevgeny , Oh Annie
Published: December 2024

Background

Local drug presentation made possible by drug-eluting depots provides benefits for a vast array of diseases, including cancer, microbial infection, and wound healing. Drug-eluting depots provide sustained drug release of therapeutics directly at disease sites with tunable kinetics, remove the need for drugs to access disease sites from circulation, and reduce the side effects associated with systemic therapy. Recently, we introduced an entirely novel approach to local drug presentation named Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs enables local drug presentation without any material carriers, capitalizing on innate tissue structures to anchor drugs at the site of administration.

Methods

In this report, we comprehensively evaluate the local and systemic toxicological profile of a paclitaxel version of TRAPs in mice by clinical observations, body weight monitoring, histopathological evaluations of injection sites and major organs, as well as blood and urine analyses.

Results

We find that intradermal administration of TRAP-paclitaxel does not induce substantial toxic effects. Localized inflammatory responses were observed at the injection sites and secondary minimal, non-specific inflammation was observed in the liver. All other organs displayed unremarkable histological findings.

Conclusions

These findings support the potential of TRAP-paclitaxel as a promising candidate for localized cancer treatment, offering high-concentration drug delivery while mitigating scarring and adverse side effects.
Silicoflagellate assemblages in the North Pacific surface sediments: an application of the modern analog method to reconstruct the glacial sea surface temperature in the Japan Sea
Authors: Okazaki Yusuke , Onodera Jonaotaro , Tanizaki Kyohei , Nishizono Fumiaki , Egashira Kazuki , Tomokawa Asuka , Sagawa Takuya , Horikawa Keiji , Ikehara Ken
Published: December 2024

Recent silicoflagellate distributions have been examined in 195 surface sediment samples from the North Pacific to establish the silicoflagellate assemblage dataset from surface sediments across the North Pacific for paleo sea surface temperature (SST) reconstruction. The relative abundance data of all seven silicoflagellate taxa identified in this study were used for the modern analog method to reconstruct past SST. The SST reconstruction based on the silicoflagellate modern analog technique was applied to the two sediment cores from the Japan Sea. With the development of ice sheets, the Japan Sea experienced a low salinity isolation event during the Last Glacial Maximum (LGM: 19 ka–26.5 ka), which hampers the SST reconstruction employing geochemical proxies such as alkenone and Mg/Ca thermometry. The reconstructed glacial SST between 25 and 15 ka was ~ 5 °C in the northern and southern Japan Sea, indicating significant southward migration of the glacial subpolar front. The timings of the deglacial SST rises were ~ 14 ka at the south core site and ~ 10 ka at the north core site, indicating a latitudinal lag. This lag likely reflects a gradual increase in the fluxes of the Tsushima Warm Current from the East China Sea through the Tsushima Strait. Compilation of the silicoflagellate assemblages in the North Pacific surface sediments used for the modern analog technique to reconstruct past sea surface temperature (SST), revealing the Japan Sea SST during the last glacial maximum ~20 ka ago.
Older adults’ recognition of medical terminology in hospital noise
Authors: Bent Tessa , Baese-Berk Melissa , Puckett Brian , Ryherd Erica , Perry Sydney , Manley Natalie A.
Published: December 2024

Word identification accuracy is modulated by many factors including linguistic characteristics of words (frequent vs. infrequent), listening environment (noisy vs. quiet), and listener-related differences (older vs. younger). Nearly, all studies investigating these factors use high-familiarity words and noise signals that are either energetic maskers (e.g., white noise) or informational maskers composed of competing talkers (e.g., multitalker babble). Here, we expand on these findings by examining younger and older listeners’ speech-in-noise perception for words varying in both frequency and familiarity within a simulated hospital noise that has important non-speech information. The method was inspired by the real-world challenges aging patients can face in understanding less familiar medical terminology used by healthcare professionals in noisy hospital environments. Word familiarity data from older and young adults were collected for 800 medically related terms. Familiarity ratings were highly correlated between the two age groups. Older adults’ transcription accuracy for sentences with medical terminology that vary in their familiarity and frequency was assessed across four listening conditions: hospital noise, speech-shaped noise, amplitude-modulated speech-shaped noise, and quiet. Listeners were less accurate in noise conditions than in a quiet condition and were more impacted by hospital noise than either speech-shaped noise. Sentences with low-familiarity and low-frequency medical words combined with hospital noise were particularly detrimental for older adults compared to younger adults. The results impact our theoretical understanding of speech perception in noise and highlight real-world consequences of older adults’ difficulties with speech-in-noise and specifically noise containing competing, non-speech information.