bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Linvoseltamab's BCMA Binding Epitope and Efficacy Against BCMA Mutations in Relapsed/Refractory Multiple Myeloma
Authors: Lee Ken , Zhou Yi , Franklin Matthew , Ullman Erica , Hermann Aynur , Kroog Glenn S. , Boyapati Anita , Rodriguez Lorenc Karen , Smith Eric , Lin John , Olson William , Sirulnik Leonardo Andres , Olson Kara
Published: December 2024

Patient outcomes in relapsed/refractory multiple myeloma (RRMM) have improved significantly with the adoption of BCMA targeted CAR-T and CD3 bispecific antibodies (bsAb). However, despite improvements in MM therapies, relapse remains an issue. Recent data from patients who relapsed following treatment with approved BCMAxCD3 bsAbs led to the identification of rare mutations in the extracellular domain of BCMA that can negatively impact the binding and cytotoxic activity of these molecules in vitro (Lee, H., et al, Nat Med. 2024). Linvoseltamab is a fully human BCMAxCD3 bsAb that demonstrated high and durable responses in RRMM. Here we characterize the binding epitope of linvoseltamab and evaluate its binding and activity on cells with identified BCMA mutations.

A 3.4 Å cryo-EM structure of the linvoseltamab Fab fragment bound to the BCMA extracellular domain shows that linvoseltamab features a long heavy chain CDR3, stabilized by a disulfide bond, which plays a major role in binding by inserting into a groove on the surface of BCMA. Linvoseltamab contacts a total of 16 BCMA residues which largely overlap with the reported epitopes of teclistamab and elranatamab (Lee, H., et al, Nat Med. 2024; Josic, M., et al, ASCO 2024). However, linvoseltamab also binds to the very N-terminal end of BCMA, suggesting that it is tilted toward the BCMA N-terminus with a distinct binding orientation.

Binding assays on cells expressing wild-type or mutant BCMA variants demonstrated that, unlike teclistamab and elranatamab, the BCMA R27P mutation had minimal impact on linvoseltamab binding. Additionally, utilizing a Jurkat NFAT-luc reporter assay system which measures BCMAxCD3 specific activation of T-cells, linvoseltamab mediated potent NFAT-luc activation in the presence of cells expressing BCMA-R27P. While the structural analysis showed linvoseltamab contacts BCMA R27, it is located at the edge of the binding interface and thus appears to not be crucial for binding. In addition, BCMA P33 does not contact linvoseltamab, consistent with the observation that the P33S mutation has no effect on linvoseltamab binding or activity. Cell binding and functional reporter bioassay and primary T cell cytotoxicity studies are underway for additional reported BCMA mutations.

This studyidentified a unique binding orientation for linvoseltamab and demonstrated that linvoseltamab retains its binding and functional activity even in the presence of an identified BCMA mutation (R27P) that negatively impacts other BCMAxCD3 bispecific antibodies. This suggests that linvoseltamab may be less susceptible to resistance mechanisms that involve these mutations, resulting in improved patient outcomes.
Optimal Duration of Anticoagulation for Unprovoked Venous Thromboembolism: A Threshold Decision Analysis Model
Authors: Youkhana Kimberley , Greenberg Charles , Djulbegovic Benjamin
Published: December 2024

Background: The optimal duration of long-term anticoagulation (AC) following an unprovoked venous thrombosis event (VTE) after the initial 3-6 months is unknown. Despite the providers careful consideration of the bleeding risk, probability recurrence off AC, and the patient's values and preferences (VP) about avoiding a recurrent VTE and bleed, the final decision remain subjective. When presented with the same patient, multiple providers may make different recommendations about the duration and intensity of AC. Using threshold decision analysis to model the effects of extended AC treatment we created and tested a model that quantifies the recommendations of the American Society of Hematology (ASH) thrombophilia for long-term AC over 10 years (10 Pr(VTE)).

Methods: We developed a threshold decision model incorporating VTE recurrence risk, AC efficacy, bleeding risks, and patient values and preferences (V&P). Key parameters included:

- VTE risk: 10% in year 1, then 5%/year

- AC efficacy: Relative Risk Reduction (RRR) = 0.85 [0.77 to 0.9]

- Bleeding risk: Low (0.5%/year) and High (1.5%/year)

- Major bleeding on AC: RR 2.17

- Relative value (RV): patient's weighting of VTE vs. bleeding risk

Results: The model calculates a threshold probability (T) at which AC benefits equal bleeding harms. AC is recommended when the probability of VTE without treatment (Pr(VTE)) exceeds the risk of bleeding. In most scenarios, the 10 Pr(VTE) consistently exceeded T, favoring long-term AC. This held true across various RV assumptions (RV=0.5, 1, 2) for both low and high bleeding risk scenarios. The only exception was in the high bleeding risk, worst-case scenario, where patients valuing avoiding bleeding twice as much as VTE (RV=2) might opt against long-term AC.

Conclusions: Based on current evidence of AC efficacy, bleeding risks, and estimated VTE recurrence rates, long-term AC appears to be the optimal management strategy for most patients with unprovoked VTE. Only in cases of high bleeding risk combined with strong patient preference for avoiding bleeding (RV>2) might discontinuation of AC be considered.

This model provides a framework for personalized decision-making, considering individual patient risks and preferences in determining the optimal duration of AC for unprovoked VTE.
Zanubrutinib Combined with R-CHOP in Patients of Newly Diagnosed DLBCL with p53 Expression: A Single-Arm Prospective Study
Authors: Zhang Liling , Li Qiuhui , Zhu Fang , Wu Gang , Chang Xiaona , Pan Huaxiong , Liu Tao , Liu Xinxiu
Published: December 2024

Introduction: p53 expression is associated with treatment failure and poor prognosis of diffuse large B-cell lymphoma (DLBCL). Bruton's tyrosine kinase (BTK) is a novel regulator of p53 activity and is involved in the cellular response to DNA damage. BTK inhibitors have shown high efficacy in mantle cell lymphoma and chronic lymphocyte leukemia with p53 alterations, and refractory and relapsed DLBCL. This study explored the efficacy and safety of zanubrutinib, a BTK inhibitor, combined with R-CHOP (ZR-CHOP) in patients of newly diagnosed DLBCL with p53 over-expression.

Methods: Newly diagnosed DLBCL patients with positive p53 protein expression (immunohistochemistry staining ≥50% of cells) were enrolled at the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from April 2022 to July 2024. ZR-CHOP regimen (zanubrutinib: 160 mg, bid, D1-21; rituximab: 375 mg/m², D1; cyclophosphamide: 750 mg/m², D2; doxorubicin: 50 mg/m², D2; vincristine: 1.4 mg/m², D2; prednisone: 100 mg/d, D2-D6) was administrated every 21 days for a total 6 cycles. Efficacy was evaluated using PET-CT/enhanced CT per Lugano 2014 criteria. The primary endpoint was the complete response rate (CRR), and secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs).

Results: A total of 16 patients were enrolled in the study until July 2024. The median age at diagnosis was 56 years (range 34-67), with 7 patients (43.7%) in Ann Arbor stage III-IV, 2 patients (12.5%) with an ECOG score ≥2, 8 patients (50.0%) with IPI score ≥2, and 5 patients (31.3%) with extranodal involvement. There were 13 cases (81.3%) of double expression of MYC and BCL2, and 15 cases (93.8%) of the non-GCB subtype. By the end of the follow-up period in July 2024, 14 patients were evaluable for efficacy, with an ORR of 100%. 12 patients (85.7%) achieved CR, and 2 patients (14.3%) achieved partial response (PR). With a median follow-up of 11.8 (0.5-20) months, the 1-year PFS and OS rates were 93.8% and 100%, respectively. In terms of safety, common grade 3-4 adverse events included anemia (4 cases), leukopenia (5 cases), neutropenia (4 cases), thrombocytopenia (1 case), and pulmonary infection (2 cases). There were no new safety signals observed.

Conclusions: The ZR-CHOP regimen is highly effective and safe for p53 over-expressed newly diagnosed DLBCL. It shows promise in improving the outcomes of p53-positive DLBCL patients.
Travel Time from Cancer Center Is Associated with Disparities in Non-Hodgkin Lymphoma Diagnosis Among People Living with HIV in Malawi
Authors: Harrington Meagan , Chirwa Amon , Kasonkanji Edwards , Simwinga Lusayo , Mumba Noel , Chikasema Maria , Kumwenda Phaleda , Painschab Matthew S , Fedoriw Yuri D.
Published: December 2024

Purpose: Kamuzu Central Hospital (KCH) in Lilongwe, Malawi, serves a population of around ten million from the country's Central and Northern regions. As one of just two centers in the country providing pathology and cancer care, the majority of the population is left with the burden of traveling long distances for diagnosis and treatment. HIV-associated non-Hodgkin lymphoma (NHL) is common in sub-Saharan Africa (SSA) due to the high prevalence of HIV in the region. Spatial barriers to care, particularly in relation to travel time, are not well defined in adults with HIV-associated malignancies in Malawi.

Methods: We included all patients with HIV-associated NHL from the KCH Lymphoma Study, a prospective observational cohort, from June 2013 to June 2023 (n=117). The location of study patients' residence was mapped using QGIS with further descriptive and survivorship analyses, including demographic and clinical characteristics, conducted in R. AccessMod 5 was used to produce models of travel time to KCH, using assumptions from previous literature.

Results: The diagnoses included in this analysis were diffuse large B cell lymphoma (DLBCL) (n=79), Burkitt lymphoma (n=22), plasmablastic lymphoma (n=13), and primary effusion lymphoma (n=3). Estimated travel time to clinic varied significantly (range: 20-618 minutes). 48% of patients were from Lilongwe district which makes up only 10% of the population of the catchment area. We noted a significant negative relationship between mean travel time to KCH and reported incidence of HIV-associated malignancies (correlation= -0.015; p=0.009). Travel time varied significantly when disaggregated by HIV status, with HIV+ART- individuals tending to be resident closer to the cancer center than HIV- or HIV+ART+ patients (p=0.005). In addition to disparities in diagnosis, HIV-associated NHL patients had worse progression-free survival as travel time to clinic increased (p=0.02), which remained significant after controlling for known prognostic markers including stage, performance status, and lactate dehydrogenase.

Conclusion: Cancer care in Malawi is centralized, leading to diagnostic and treatment disparities. NHL patients who live further from KCH tend to face more challenges accessing diagnosis and treatment, particularly if they have comorbidities, such as HIV. Interestingly, the HIV+ ART- group tended to come from closer to KCH than other groups, implying that patients with curable lymphomas in more remote parts of the country are likely dying before they can be diagnosed and treated. Implementation science approaches are urgently needed to close the gap on both diagnostic and treatment disparities.
Identification of Ikaros As Novel Interaction Partner of Cyclin D1/CDK4 in MCL
Authors: Sun Xiaoyang , de Bra Stephan , Schmitz Tatjana , Tholen Stefan , Andrieux Geoffroy , Martens Uta Sabine Sabine , Boerries Melanie , Schilling Oliver , Duyster Justus , Miething Cornelius
Published: December 2024

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by cyclin D1 (CycD1) overexpression. CycD1 physiologically works as a cell cycle regulator in conjunction with CDK4/6, inducing cell cycle progression in G1/S phase. The role of CycD1 in oncogenesis is manyfold, including promoting proliferation, regulating DNA damage response and controlling migration and invasiveness, but many of the interacting proteins and the functional mechanisms underlying their interaction remain unexplored. We therefore aimed to systematically screen for novel CycD1-interacting proteins in MCL using proximity-dependent biotin identification (BioID).

Using an MCL mouse model based on the cooperation of CycD1 and c-myc, we established lymphoma lines from mice expressing CycD1 linked to a bacterial biotin ligase BioID2. The approach enables covalent biotinylation of proteins closely interacting with CycD1 after the addition of biotin. After optimization of the labeling procedure, CycD1-interacting proteins in the MCL cell line were tagged and enriched by streptavidin pull-down, followed by mass spectrometry analysis. The association of CycD1 with candidate proteins was verified by co-immunoprecipitation (Co-IP) and immunofluorescence co-localization and investigated functionally by shRNA knockdown and inhibitor treatment.

Among other candidates, we found the transcription factor Ikaros (Ikzf1) to be specifically interacting with CycD1. The interaction in a complex consisting of CycD1, CDK4, and Ikaros was verified by Co-IP in human MCL (hMCL) cells, and CycD1 and Ikaros were found to co-localize in the cell nuclei of hMCL cells. Knockdown of Ikaros and treatment with the Ikaros degrader lenalidomide and also the novel degrader CFT7455 induced apoptosis, G1-phase arrest and decreased CycD1 expression, indicating a direct effect of Ikaros on CycD1 levels. In ongoing experiments, we observed that CDK4 inhibition may affect the phosphorylation of specific amino acids in Ikaros, altering the nuclear localization and transcriptional activity of Ikaros.

In summary, we identified Ikaros as a novel interaction partner of CycD1/CDK4 in MCL. Our results indicate that Ikaros can transcriptionally regulate and stabilize CycD1, and in turn, CycD1-CDK4 may phosphorylate Ikaros and affect Ikaros transcriptional activity. This feedback loop may play an important role in the pathogenesis of MCL and could serve as a novel potential therapeutic target in MCL.
Safeguarding Lungs: Evaluating Pneumocystis Pneumonia Prophylaxis in Lymphoma Patients Receiving Rituximab-Inclusive Therapies
Authors: Sharma Anubhuti , Sharma Arundhati , Daid Simranpreet Singh , Sharma Vagisha , Agrawal Akriti , Rao Adishwar , Poulose Joyson
Published: December 2024

Background: Pneumocystis pneumonia (PCP) is an opportunistic fungal infection, which is frequently observed in immunocompromised patients. Although T-cell immunity is classically related to Pneumocystis defense, recent data support roles for B lymphocytes in the development of PCP in animals, and we have observed several cases of PCP in patients receiving rituximab. These observations prompted a systematic review and meta-analysis of our experience to see the efficacy of PCP prophylaxis (TMP-SMX) in lymphoma patients receiving rituximab. The efficacy of PCP prophylaxis in this population remains a subject of clinical interest.

Research Question: To evaluate the effect of PCP prophylaxis compared to no prophylaxis on the risk of developing PCP in lymphoma patients receiving rituximab.

Methods: We conducted meta-analysis including six retrospective cohort studies that compared the incidence of PCP in lymphoma patients receiving rituximab with and without prophylaxis. The cohort studies with incept up to January 2023 were retrieved from databases including PubMed, Google Scholar, EMBASE, PLOS ONE, Cochrane, and ClinicalTrials.gov. Data extraction was done using a spreadsheet, and data analysis was done using RevMan 5.4.1 for meta-analysis.

Results: The analysis included 2304 patients, with 571 receiving PCP prophylaxis and 1733 did not receive prophylaxis. Studies reporting results of PCP prophylaxis were included. Enrolled studies were quality assessed with Newcastle-Ottawa Scale. The incidence of PCP was significantly lower in the prophylaxis group (3 out of 571) compared to the no prophylaxis group (67 out of 1733). The pooled risk ratio (RR) was 0.23 [95% CI, 0.09 to 0.58], indicating a 77% reduction in the risk of PCP with prophylaxis.

Conclusion: The clinical course of cases of PCP in patients treated with rituximab can be quite fulminant, with significant mortality. Primary prophylaxis should be considered in patients at risk. PCP prophylaxis significantly decrease the risk of PCP in lymphoma patients receiving rituximab-based therapies, with a pooled risk ratio of 0.23.
Risk Determination in Pediatric Patients for Venous Thromboembolism
Authors: Loi Kyle , Brown Craig , Fan Qiyin , Kronfield Charlotte , McGrath Mary , Obi Andrea
Published: December 2024

Objective: Cases of hospital-acquired acute deep venous thrombosis (HA-DVT) and pulmonary embolism (HA-PE) within the pediatric population are rare. Risk assessment models (RAMs) are used to identify a patient's likelihood of developing venous thromboembolism (VTE). When VTE risk exceeds bleeding risk of low dose anticoagulants, patients are prescribed thromboprophylaxis. Within this study, we aim to highlight previously identified risk factors for pediatric HA-VTE by comparing three different RAMs: Caprini, Children's Hospital-Acquired Thrombosis (CHAT) Consortium Admission, and the Peds-Clot clinical Decision Rule (PCDR).

Methods: This retrospective case-control study focused on pediatric patients between the ages of 12 and 22 admitted to a single institution from 2017 to 2022. Cases of acute VTE (defined as HA-DVT and/or PE) were matched to randomly selected controls 2:1 matched on length of stay. Total scores for Caprini, CHAT, and PCDR RAMs were calculated using clinical data extracted from chart review. Cases and controls were compared using chi2 and Mann-Whitney U test for categorical and continuous outcomes, respectively.

Results: The total incidence of acute VTE amongst adolescent and young adult inpatients was 0.2% (33/16,186). Cases were found to have a significantly higher BMI compared to controls (38.8±7.9 vs 22.4±6.2, p<0.001). No difference in age was found for cases compared to controls (mean age 17.2±2.2 vs 16.3±2.4, p=0.64). The PCDR scores were slightly different between cases and controls (2.32 vs 1.24, p=0.001) as were the modified Caprini scores (6.5 vs 2, p<0.001) whereas the CHAT predicted probability demonstrated a near ten-fold enrichment in risk amongst cases compared to controls (9.3% v. 0.8%, p=0.02). The risk factor determined to be significant across all RAM was the placement of a central venous catheter.

Conclusions: Cases for our study had an extremely low incidence rate, underscoring the importance of a robust risk assessment model capable of defining a high-risk population. Even amongst the highest risk population, (those who developed acute HA-VTE), the average calculated risk in the best-performing RAM was only found to be 9.3%. Currently available pediatric VTE RAMs may lead to overuse of thromboprophylaxis when broadly applied.
Exploring the Intersectionality of Marital Status and Sex on Survival Outcomes in Non-Hodgkin's Lymphoma
Authors: Akinyemi Oluwasegun Austine , Abobarin-Aofolaju Olufunmilayo , Abodunrin Faith , Adeoye Tayo , Adubi Oreoluwa , Fasokun Mojisola , Ikugbayigbe Seun , Odusanya Eunice , Michael Miriam , Hughes Kakra
Published: December 2024

INTRODUCTION: Non-Hodgkin's Lymphoma (NHL) survival is influenced by various factors, including marital status and sex. This study explores how these intersecting factors affect cancer-specific (CSS) and overall survival (OS) in NHL patients.

OBJECTIVE: To examine the intersection of sex and marital status on survival outcomes among individuals with NHL.

METHODOLOGY: We conducted a retrospective cohort study using SEER registry data for individuals aged 18-85 diagnosed with NHL. Cox regression models assessed the influence of marital status and sex on CSS and overall survival OS, adjusting for age, race, household income, disease stage, primary site, and treatment (chemotherapy, radiotherapy, surgery). Kaplan-Meier curves and log-rank tests compared survival distributions.

RESULT: The study analyzed 319,013 individuals with NHL from 2000 to 2020. Participants were predominantly white (73.0%) and female (54.7%), with 54.6% married and a median age of 66 years (IQR 55-76). Females exhibited a 33% higher hazard of death for cancer-specific survival (HR = 1.34, 95% CI: 1.30-1.38) and a 40% higher hazard for overall survival (HR = 1.40, 95% CI: 1.37-1.44). The interaction of marital status and sex significantly impacts both CSS and OS among individuals with NHL. Widowed individuals, regardless of sex, showed the highest risk of death; males had a cancer-specific hazard ratio (HR) of 2.50 (95% CI: 2.35-2.65) and overall HR of 2.31 (95% CI: 2.21-2.41), while females had a cancer-specific HR of 3.09 (95% CI: 2.87-3.31) and overall HR of 2.97 (95% CI: 2.82-3.12). Divorced and separated individuals also exhibited elevated risk. Notably, married males had the lowest hazard ratios, with cancer-specific HR of 1.07 (95% CI: 1.03-1.12) and overall HR of 0.87 (95% CI: 0.84-0.89).

CONCLUSION: This study highlights that marital status and sex significantly influence survival outcomes in NHL patients. Widowed individuals have the highest mortality risk, while being married is associated with better survival, especially for males. These findings emphasize the role of social support and gender-specific factors in NHL prognosis.
Disparity in Access to Myeloma CAR-T: A Geospatial Analysis of Distance to CAR-T Centers and Its Impact on Mortality
Authors: Daunov Michael , Gorham Benjamin , Ignatz-Hoover James J
Published: December 2024

Introduction

Novel therapy with chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized treatment options for patients with multiple myeloma (MM). However, disparities in access persist. One such disparity is related to access to CAR-T services, limited to specialized academic centers nationwide. We aimed to examine the disparity in access based purely on geographic distance to the nearest CAR-T center in the lower United States.

Methods

MM age-adjusted mortality per 100,000 persons organized by county was obtained from the NCI Cancer Atlas for both sexes and all races. A list of CAR-T centers was obtained from ide-cel and cilta-cel websites. These data were uploaded as Geographic Information System (GIS) layers using QGIS software. Distance from each county with available mortality data to nearest CAR-T center was then calculated. A comparison of mortality and distance from CAR-T center was performed for both ide-cel and cilta-cel using simple linear regression and Pearson bivariate correlations. Statistics were calculated using SPSS software.

Results

Based on NCI data, 747 US Counties had available mortality data for patients with multiple myeloma; 156 had available data by race. A total of 76 ide-cel and 55 cilta-cel sites were identified. For ide-cel, distance was correlated to age-adjusted mortality per 100,000 persons (r=.093, p=.011) and regression suggested that distance to nearest ide-cel site accounted for 0.9% of age-adjusted mortality (F=6.42, p=.011). For cilta-cel, distance was correlated to age-adjusted mortality per 100,000 persons (r=.122, p<.001) and regression suggested that distance to nearest cilta-cel site accounted for 1.5% of age-adjusted mortality (F=11.24, p<.001). When assessing disparity by race, non-Hispanic Blacks had a more age-adjusted mortality due to distance from CAR-T Center. For ide-cel, distance accounted for 2.5% of non-Hispanic Black age-adjusted mortality (F=3.929, p=.049). For cilta-cel, distance accounted for 6.4% of non-Hispanic Black age-adjusted mortality (F=10.404, p=.002).

Conclusions

Using geospatial analysis, we identified that a county's distance to CAR-T center had a statistically significant impact on age-adjusted multiple myeloma mortality. This impact was more pronounced for Non-Hispanic Black patients, of particular interest as MM is more likely to affect the Black patient. As more patients become eligible for CAR-T therapy, the benefit of living near a CAR-T center will likely grow. Distance to CAR-T centers may form a new interface with a patient's social determinants of health, creating a new health care disparity in MM.
A New Severe Congenital Neutropenia Syndrome Associated with Autosomal Recessive COPZ1 Mutations
Authors: Borbaran Bravo Natalia , Deordieva Ekaterina , Doll Larissa , ElGamacy Mohammad , Dannenmann Benjamin , Azevedo Joana , Iannuzzo Alberto , Delafontaine Selket , Lehners Moritz , Kolodziej Marius Sebastian Theo , Hernandez Alvarez Birte , Hellmuth Anna-Sophia , Ritter Malte , Findik Betül , Zakharova Viktoria , Bräuning Sandro , Kandabarau Sergey , Lengerke Claudia , Feil Robert , Meyts Isabelle , Delon Jérôme , Templin Markus F. , Sturm Marc , Rieß Olaf , Zeidler Cornelia , Welte Karl , Shcherbina Anna , Klimiankou Maksim , Skokowa Julia
Published: December 2024

We have identified a new inherited bone marrow (BM) failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense mutation were found in three patients from two unrelated families. While two affected siblings with a stop-codon COPZ1 mutation suffered from congenital neutropenia (CN) that involves other hematological lineages, and non-hematological tissues, the patient with a missense COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated COPZ1 protein was predicted to display diminished interaction with its COPI complex partner, COPG1. These findings were consistent with the observed block in retrograde protein transport from the Golgi to the ER in human fibroblasts carrying truncated COPZ1. Human CD34+ cells with truncated or missense COPZ1 had significantly impaired granulocytic differentiation and in zebrafish embryos, truncated Copz1 also resulted in defective myelopoiesis. Intracellularly, truncated COPZ1 downregulated JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways while inducing STING, interferon-stimulated genes, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species (ROS) levels in CD34+ cells. Missense COPZ1 deregulated interferon and JAK/STAT signaling but less than the truncated protein. Finally, treatment with the small molecule HIF1α activator IOX2 or transduction of cells with COPZ2 cDNA restored defective granulopoiesis in COPZ1-mutated CD34+ cells, offering potential therapeutic options.
Attenuated processing of vowels in the left temporal cortex predicts speech-in-noise perception deficit in children with autism
Authors: Fadeev Kirill A. , Romero Reyes Ilacai V. , Goiaeva Dzerassa E. , Obukhova Tatiana S. , Ovsiannikova Tatiana M. , Prokofyev Andrey O. , Rytikova Anna M. , Novikov Artem Y. , Kozunov Vladimir V. , Stroganova Tatiana A. , Orekhova Elena V.
Published: December 2024

Background

Difficulties with speech-in-noise perception in autism spectrum disorders (ASD) may be associated with impaired analysis of speech sounds, such as vowels, which represent the fundamental phoneme constituents of human speech. Vowels elicit early (< 100 ms) sustained processing negativity (SPN) in the auditory cortex that reflects the detection of an acoustic pattern based on the presence of formant structure and/or periodic envelope information (f0) and its transformation into an auditory “object”.

Methods

We used magnetoencephalography (MEG) and individual brain models to investigate whether SPN is altered in children with ASD and whether this deficit is associated with impairment in their ability to perceive speech in the background of noise. MEG was recorded while boys with ASD and typically developing boys passively listened to sounds that differed in the presence/absence of f0 periodicity and formant structure. Word-in-noise perception was assessed in the separate psychoacoustic experiment using stationary and amplitude modulated noise with varying signal-to-noise ratio.

Results

SPN was present in both groups with similarly early onset. In children with ASD, SPN associated with processing formant structure was reduced predominantly in the cortical areas lateral to and medial to the primary auditory cortex, starting at ~ 150—200 ms after the stimulus onset. In the left hemisphere, this deficit correlated with impaired ability of children with ASD to recognize words in amplitude-modulated noise, but not in stationary noise.

Conclusions

These results suggest that perceptual grouping of vowel formants into phonemes is impaired in children with ASD and that, in the left hemisphere, this deficit contributes to their difficulties with speech perception in fluctuating background noise.
Evolutionary literacy as a catalyst for sustainable futures: connecting biological evolution education and education for sustainability
Authors: Pessoa Patrícia , Lopes J. Bernardino , de Lima Joelyn , Pinto Alexandre , Søgaard Jørgensen Peter , Sá-Pinto Xana
Published: December 2024

In the face of growing societal, public health and environmental challenges linked to the functioning of the biosphere, strong evolutionary literacy emerges as indispensable to plan and achieve sustainable futures. However, research on evolution education has mainly focused on the content taught in classrooms, leaving its application to sustainability issues largely unexplored. Given this, in this paper, we suggest an integrated view of biological evolution education and sustainability education. For that, we argue for the pivotal role of evolutionary literacy to address diverse sustainability issues and for the development of key competencies in sustainability, namely systems thinking and anticipatory competencies. To support the implementation in classrooms, we propose educational strategies to promote evolutionary literacy, systems thinking and anticipatory competencies through socioscientific issues linked to sustainability topics. Finally, we identify future research needed at the intersection of evolution education and education for sustainability to effectively promote evolutionary literacy and the development of key competencies in sustainability. With this, we aim to contribute to further enhancing education for sustainability through the lens of evolution.
Impact of DNA extraction, PCR amplification, sequencing, and bioinformatic analysis on food-associated mock communities using PacBio long-read amplicon sequencing
Authors: Baer Mareike , Höppe Lisa , Seel Waldemar , Lipski André
Published: December 2024

Background

Long-read 16S rRNA gene amplicon sequencing has a high potential for characterizing food-associated microbiomes. The advantage results from sequencing the full-length (1,500 bp) gene, enabling taxonomic resolution at species level. Here we present a benchmarking study using mock communities representative of milking machine biofilms and raw meat, revealing challenges relevant to food-associated habitats. These were varying species abundances, reliable intra-genus differentiation of species, and detection of novel species with < 98.7% sequence identity to type strains. By using mock communities at different levels of preparation − as mixed whole cells, mixed extracted DNA, and mixed PCR products − we systematically investigated the influence of DNA extraction using two different kits, PCR amplification of 16S rRNA genes, sequencing, and bioinformatics analysis including reference database and gene copy number normalization on bacterial composition and alpha diversity.

Results

We demonstrated that PacBio ccs-reads allowed for correct taxonomic assignment of all species present within the mock communities using a custom Refseq database. However, choice of percent identity values for taxonomic assignment had a strong influence on identification and processing of reads from novel species. PCR amplification of 16S rRNA genes produced the strongest bias on the observed community composition, while sequencing alone reproduced the preset composition well. The PCR bias can in part be attributed to differences in mol% G + C content of 16S rRNA genes resulting in preferred amplification of low mol% G + C-containing taxa.

Conclusions

This study underlines the importance of benchmarking studies with mock communities representing the habitat of interest to evaluate the methodology prior to analyzing real samples of unknown composition. It demonstrates the advantage of long-read sequencing over short-read sequencing, as species level identification enables in-depth characterization of the habitat. One benefit is improved risk assessment by enabling differentiation between pathogenic and apathogenic species of the same genus.
Effectiveness of non-pharmacological interventions in managing symptom clusters among lung cancer patients: a systematic review
Authors: Chen Qiuhong , Li Yonglin , Lin Yiyang , Lin Xiujing , Arbing Rachel , Chen Wei-Ti , Huang Feifei
Published: December 2024

Background

Non-pharmacological interventions, as complements to pharmacological treatments, are widely employed for managing symptom clusters in patients with lung cancer. Although numerous systematic reviews and meta-analyses have explored the effects of these interventions, most studies have centred on the broader cancer population and specific symptom clusters. This review aims to consolidate existing non-pharmacological interventions and assess their effectiveness in managing symptom clusters among lung cancer patients.

Methods

A comprehensive literature search, encompassing eight databases from inception to October 1, 2024, was conducted. Two independent reviewers carried out the study selection, quality assessment, and data extraction. Methodological quality was evaluated using the Cochrane Risk-of-Bias 2 tool and the Risk of Bias in Non-randomized Studies of Interventions. The findings were synthesized narratively based on intervention type and supplemented by meta-analysis using RevMan 5.4 software. The study protocol was registered with PROSPERO (CRD42023467406).

Results

This systematic review comprised 15 relevant studies involving 1,692 patients, published between 2011 and 2024. The analysis revealed the effectiveness of psychological, educational, and complementary or alternative medicine interventions in alleviating the severity of most symptom clusters. However, the efficacy of exercise-based and multimodal interventions remained inconclusive. The meta-analysis demonstrated a positive impact of non-pharmacological interventions on depression compared with the control conditions (SMD = -0.30, 95% CI [-0.46, -0.15], p < 0.01, I2 = 6%). Additionally, the educational intervention subgroup showed low heterogeneity and effectively improved fatigue (SMD = -0.50, 95% CI [-0.68, -0.33], p < 0.01, I2 = 0%).

Conclusions

Psychological and educational interventions have proven effective in managing symptom clusters in lung cancer patients. However, further research is needed to explore the effects of exercise, multimodal approaches, and complementary or alternative medicine. To enhance symptom management, future research could focus on core symptom clusters.
Challenges of modern work environments and means of overcoming them in the context of psychosocial risk assessments
Authors: Pavlista Valeria , Angerer Peter , Diebig Mathias
Published: December 2024

Background

Modern work environments constitute an underrepresented part of psychosocial risk assessments at work. Little is known about whether there is an increased stress load at all and what possible improvements could be made in such a case.

Methods

Modern work environments were assessed in an online questionnaire in 33 companies across a period of more than 4 years. A total of 3431 employees participated in the study. Both quantitative and qualitative data was applied to obtain a differentiated picture.

Results

Increased stress caused by modern work environments was an issue for around a third of the sample. 31.6% of the participants at least sometimes struggled to balance work and private life. Quite a few of the participants (36.3%) worked sometimes or more outside regular working hours. For 32.4% of participants, the workload has increased due to new technologies, but for 30.4% it has not. The majority (81.4%) feel they can work productively in home offices. The data from 178 completed free text fields on improving modern work environments from the employees’ perspective was analysed. Many named suggestions relate to improvements in time management.

Conclusion

This study provides both detailed insights into various aspects of modern work environments and offers solutions to counteract possible negative consequences. Assessing modern work environments in psychosocial risk assessments would be a valuable addition to its completeness.
Barriers and facilitators to effective pain management in elderly Arab patients: a nursing perspective through a qualitative study
Authors: Shaban Mostafa , Shaban Marwa Mamdouh , Mohammed Huda Hamdy , El-kest Hend Reda Ali
Published: December 2024

Background

Effective pain management in elderly patients is crucial for quality of life, yet cultural and institutional factors can significantly impact care delivery, particularly in Arab healthcare settings.

Aim

To explore the barriers and facilitators to effective pain management in elderly Arab patients from the perspective of nurses.

Methods

A qualitative descriptive study was conducted with 12 registered nurses from various departments at Tanta University Hospitals, Egypt. Data were collected through semi-structured interviews, observations, and document analysis. Content analysis was used to identify themes and subthemes.

Results

Five main themes emerged: (1) Cultural Barriers to Pain Expression, including stoicism and religious beliefs; (2) Institutional Barriers to Pain Management, such as resource limitations and time constraints; (3) Facilitators to Effective Pain Management, including family support and nurse adaptability; (4) Interdisciplinary Collaboration, emphasizing teamwork and education; and (5) Emotional and Professional Rewards for nurses. Cultural factors often led to underreporting of pain, while institutional constraints hindered thorough assessments. Nurse adaptability and family support, when present, facilitated better pain management.

Conclusion

The study reveals complex interplay between cultural, institutional, and professional factors influencing pain management in elderly Arab patients. Findings suggest the need for culturally sensitive pain assessment tools, enhanced nurse education in pain management, and policies promoting family-centered care and interdisciplinary collaboration.

Implications

Results can inform the development of culturally appropriate pain management strategies and policies in Arab healthcare settings, potentially improving care quality for elderly patients.
Values of welfare technologies: a qualitative study of how employees in Swedish care for older adults understand and justify the use of new technology
Authors: Lydahl Doris , Davidsson Anna
Published: December 2024

Background

In Swedish care for older adults, the use of welfare technology − for example, medicine-dispensing robots and GPS alarms − stimulates ongoing evaluations and negotiations. National policy documents, as well as previous research, indicate that these technologies are expected to improve the quality and efficiency of care but also involve potential or experienced challenges in providing high-quality care and the conditions for care workers − often portrayed as a conflict between political and caring organizational values. More research is thus needed on how the use of welfare technology is justified at central and municipal government levels as well as within care-providing organizations. This article aims to identify how the introduction and use of welfare technology is justified by employees and in policy documents pertaining to welfare technology in Swedish care for older people.

Methods

Qualitative interview data involving 37 individuals were collected in municipalities in southern Sweden. The interviewees were managers, administrative staff, and licensed practical nurses working in home care services or special housing for older adults, offering care 24/7. Policy documents and agreements of significance for Swedish welfare technology policy were analysed. The analysis focused on values promoted as significant for the provision of care and related to the use of welfare technology. Justifications and values were analysed as belonging to different ‘worlds of worth’, as either shared or conflicting, and contextually situated.

Results

The documents reflect values regarding, for instance, efficiency, independence, good working conditions, optimised use of human resources, and time to tend to relationships. The employees justified the use of welfare technologies with reference to optimisation and efficiency, activation and participation, dignity and freedom, social relationships, and good working conditions. These values represent three different worlds of worth − the industrial world, the civic world, and the domestic world − and are situated in employees’ everyday work practices.

Conclusions

Values presented by employees and in policy documents are shared rather than conflicting. However, employees emphasise values associated with the domestic world, downplaying industrial values. We argue that politicians and civil servants should consider the situated judgements made by employees and develop more bottom-up strategies. This requires an acknowledgement of the existing values hierarchy, where values of optimisation and efficiency are held in high esteem but to accommodate higher values rather than as end goals.
Supplementation of laying hens’ feed with Schizochytrium powder and its effect on physical and chemical properties of eggs
Authors: kiran Ifra , Umbreen Huma , Nisa Mahr un , Al-Asmari Fahad , Zongo Eliasse
Published: December 2024

Biofortification enhances dietary quality and nutritional value using traditional marine microalga species, particularly docosahexaenoic acid (DHA), which is an essential n-3 fatty acid for human health. Eggs are natural fortified candidates. This study aimed to investigate the effect of dietary Schizochytrium powder on egg productivity, egg nutritional content, and fatty acid levels in laying hens. Hy-Line Brown laying hens (n = 150) were uniformly assigned to five groups for 52 days. The control group received no supplements, whereas the other four experimental groups were provided with varied amounts of schizochytrium powder. The experimental feed contained isonitrogenous (16.60%) and isocaloric metabolizable energy, 36.69 MJ/kg components. No significant differences were observed (p > 0.05) on different parameters such as average daily feed intake, feed conversion ratio, egg weight, and shell thickness. Enriching eggs significantly increased α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and DHA levels (p < 0.001), while decreasing the n-6/-3 ratio in a dose-dependent manner, ensuring high quality and biological efficacy. A plateau point was maintained throughout the study period. In the first two weeks, increased DHA levels were observed in egg yolks when microalgae concentrations were elevated by 1%. The study found that powdered Schizochytrium limacinum served as a substitute for DHA in enhancing eggs with n-3 fatty acids.
Siwu decoction mitigates radiation-induced immune senescence by attenuating hematopoietic damage
Authors: Huang Mingyue , Ye Anping , Zhang Haoyu , Ru Yi , Bai Zhijie , Zhang Yanyan , Gao Yue , Ma Zengchun
Published: December 2024

Background

To investigate the long term effects of ionizing radiation (IR) on hematopoietic stem/progenitor cells (HSPCs), immune tissues and cells, and the effects of Siwu decoction (SWD) on immune senescence mice.

Methods

C57BL/6 J mice were exposed to 6.0 Gy 60Co γ irradiation. After 8-weeks of IR, SWD (5, 10, 20 g/kg/d) was administered for 30 days. The changes of HSPCs in bone marrow (BM) and T, B type lymphocyte and natural killer (NK) cells in spleen were detected by flow cytometry. The changes of peripheral blood cells were also examined. Hematoxylin–eosin staining were used to detect the pathological lesions of hippocampus, spleen and thymus tissues. Absolute mouse telomere length quantification qPCR assay kit was used to measure the telomere length of BM cells. The expression of factors associated with inflammation and aging such as p16, β-galactosidase in spleen, thymus and BM was determined.

Results

Administration of SWD could increase the proportion of LSK (Lin−, Sca-1 + , c-Kit−), multipotent progenitor cells and multipotent progenitor cells and decrease the proportion of common myeloid progenitors and granulocyte–macrophage progenitors in BM. The proportion of B cells and NK cells in spleen and the content of white blood cells, red blood cells, hemoglobin, lymphocytes and eosinophils in peripheral blood were increased, at the same time, the proportion of neutrophils and monocytes was reduced by SWD. The pathological lesions of hippocampus, spleen and thymus were improved. The expression of p16 and β-galactosidase in spleen, thymus and BM was reduced and shortening of the telomere of BM cells was inhibited after administration. In addition, SWD could reduce the content of Janus activated kinase (JAK) 1, JAK2 and signal transducer and activator of transcription 3 (STAT3) in BM and spleen.

Conclusions

SWD could slow down IR-induced immune senescence by improving hematopoietic and immunologic injury. SWD might reduce the inflammation level of BM hematopoietic microenvironment by acting on JAK/STAT signaling pathway, while the immune damage of mice was improved by affecting the differentiation of HSPCs. The remission of hematopoietic and immunologic senescence was further demonstrated at the overall level.

Graphical Abstract
Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer
Authors: Han Eunkyung , Choi Hye Yeon , Kwon Hyun Jung , Chung Yul Ri , Shin Hee-Chul , Kim Eun-Kyu , Suh Koung Jin , Kim Se Hyun , Kim Jee Hyun , Park So Yeon
Published: December 2024

Background

The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their clinicopathological and prognostic significance with a special focus on the spatial distribution of TILs in TNBCs.

Methods

We analyzed TNBC samples through PanCancer Immune Profiling using NanoString nCounter assays to identify immune-related genes that are expressed differentially in relation to TIL levels and evaluated protein expression of selected markers through immunohistochemical staining on tissue microarrays. For a comprehensive assessment of the expression of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell markers, a CTL-NK score was devised based on CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL levels.

Results

Gene expression analysis revealed significant upregulation of CTL and NK cell-associated genes including GNLY, KLRC2, and GZMB in TIL-high TNBCs. Immunohistochemical validation confirmed that TNBCs with higher TILs had a greater amount of CD56+, CD57+, GNLY+, and GZMB+ TILs not only in absolute number but also in proportion relative to CD4+ or CD8+ TILs. High TIL and its subset (CD4+, CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL) infiltration correlated with favorable clinicopathological features of tumor. In survival analysis, high CTL-NK score was found to be an independent prognostic factor for better disease-free survival (DFS) of the patients. Furthermore, uniformly high TIL infiltration was linked to better DFS, whereas cases with heterogeneous TIL infiltration showed no difference in survival compared to those with uniformly low TIL infiltration.

Conclusion

Our study showed that CTL and NK cell-associated gene expression and protein levels differ significantly according to TIL levels and that CTL-NK score and distribution of TILs within tumors have a prognostic value. These findings emphasize the importance of CTLs and NK cells as well as the spatial uniformity of TIL infiltration in clinical outcome of TNBC patients, providing valuable insights for refining prognostic assessments and guiding immunotherapeutic strategies.