bluuebunny/crossref_metadata_2025 huggingface dataset:
BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer
Authors: Sriramulu Sushmitha , Thoidingjam Shivani , Chen Wei-Min , Hassan Oudai , Siddiqui Farzan , Brown Stephen L. , Movsas Benjamin , Green Michael D. , Davis Anthony J. , Speers Corey , Walker Eleanor , Nyati Shyam
Published: June 2024

Background

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment.

Methods

Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays.

Results

BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t1/2, ~8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade.

Conclusions

BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.
FoldPAthreader: predicting protein folding pathway using a novel folding force field model derived from known protein universe
Authors: Zhao Kailong , Zhao Pengxin , Wang Suhui , Xia Yuhao , Zhang Guijun
Published: June 2024

Protein folding has become a tractable problem with the significant advances in deep learning-driven protein structure prediction. Here we propose FoldPAthreader, a protein folding pathway prediction method that uses a novel folding force field model by exploring the intrinsic relationship between protein evolution and folding from the known protein universe. Further, the folding force field is used to guide Monte Carlo conformational sampling, driving the protein chain fold into its native state by exploring potential intermediates. On 30 example targets, FoldPAthreader successfully predicts 70% of the proteins whose folding pathway is consistent with biological experimental data.
The effect of an improved ICU physical environment on outcomes and post-ICU recovery—a protocol
Authors: Tronstad Oystein , Zangerl Barbara , Patterson Sue , Flaws Dylan , Yerkovich Stephanie , Szollosi Irene , White Nicole , Garcia-Hansen Veronica , Leonard Francisca Rodriguez , Weger Benjamin D. , Gachon Frédéric , Brain David , Lavana Jayshree , Hodgson Carol , Fraser John F.
Published: June 2024

Background

Intensive care medicine continues to improve, with advances in technology and care provision leading to improved patient survival. However, this has not been matched by similar advances in ICU bedspace design. Environmental factors including excessive noise, suboptimal lighting, and lack of natural lights and views can adversely impact staff wellbeing and short- and long-term patient outcomes. The personal, social, and economic costs associated with this are potentially large. The ICU of the Future project was conceived to address these issues. This is a mixed-method project, aiming to improve the ICU bedspace environment and assess impact on patient outcomes. Two innovative and adaptive ICU bedspaces capable of being individualised to patients’ personal and changing needs were co-designed and implemented. The aim of this study is to evaluate the effect of an improved ICU bedspace environment on patient outcomes and operational impact.

Methods

This is a prospective multi-component, mixed methods study including a randomised controlled trial. Over a 2-year study period, the two upgraded bedspaces will serve as intervention beds, while the remaining 25 bedspaces in the study ICU function as control beds. Study components encompass (1) an objective environmental assessment; (2) a qualitative investigation of the ICU environment and its impact from the perspective of patients, families, and staff; (3) sleep investigations; (4) circadian rhythm investigations; (5) delirium measurements; (6) assessment of medium-term patient outcomes; and (7) a health economic evaluation.

Discussion

Despite growing evidence of the negative impact the ICU environment can have on patient recovery, this is an area of critical care medicine that is understudied and commonly not considered when ICUs are being designed. This study will provide new information on how an improved ICU environment impact holistic patient recovery and outcomes, potentially influencing ICU design worldwide.

Trial registration

ACTRN12623000541606. Registered on May 22, 2023.https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385845&isReview=true.
Distinct effects of blood pressure parameters on Alzheimer’s and vascular markers in 1,952 Asian individuals without dementia
Authors: Lee Sungjoo , Kim Si Eun , Jang Hyemin , Kim Jun Pyo , Sohn Gyeongmo , Park Yu Hyun , Ham Hongki , Gu Yuna , Park Chae Jung , Kim Hee Jin , Na Duk L. , Kim Kyunga , Seo Sang Won
Published: June 2024

Background

Risk factors for cardiovascular disease, including elevated blood pressure, are known to increase risk of Alzheimer’s disease. There has been increasing awareness of the relationship between long-term blood pressure (BP) patterns and their effects on the brain. We aimed to investigate the association of repeated BP measurements with Alzheimer’s and vascular disease markers.

Methods

We recruited 1,952 participants without dementia between August 2015 and February 2022. During serial clinic visits, we assessed both systolic BP (SBP) and diastolic BP (DBP), and visit-to-visit BP variability (BPV) was quantified from repeated measurements. In order to investigate the relationship of mean SBP (or DBP) with Alzheimer’s and vascular markers and cognition, we performed multiple linear and logistic regression analyses after controlling for potential confounders (Model 1). Next, we investigated the relationship of with variation of SBP (or DBP) with the aforementioned variables by adding it into Model 1 (Model 2). In addition, mediation analyses were conducted to determine mediation effects of Alzheimer’s and vascular makers on the relationship between BP parameters and cognitive impairment.

Results

High Aβ uptake was associated with greater mean SBP (β = 1.049, 95% confidence interval 1.016–1.083). High vascular burden was positively associated with mean SBP (odds ratio = 1.293, 95% CI 1.015–1.647) and mean DBP (1.390, 1.098–1.757). High tau uptake was related to greater systolic BPV (0.094, 0.001–0.187) and diastolic BPV (0.096, 0.007–0.184). High Aβ uptake partially mediated the relationship between mean SBP and the Mini-Mental State Examination (MMSE) scores. Hippocampal atrophy mediated the relationship between diastolic BPV and MMSE scores.

Conclusions

Each BP parameter affects Alzheimer’s and vascular disease markers differently, which in turn leads to cognitive impairment. Therefore, it is necessary to appropriately control specific BP parameters to prevent the development of dementia. Furthermore, a better understanding of pathways from specific BP parameters to cognitive impairments might enable us to select the managements targeting the specific BP parameters to prevent dementia effectively.
The circular bioeconomy: a driver for system integration
Authors: Schipfer Fabian , Burli Pralhad , Fritsche Uwe , Hennig Christiane , Stricker Fabian , Wirth Maria , Proskurina Svetlana , Serna-Loaiza Sebastian
Published: June 2024

Background

Human and earth system modeling, traditionally centered on the interplay between the energy system and the atmosphere, are facing a paradigm shift. The Intergovernmental Panel on Climate Change’s mandate for comprehensive, cross-sectoral climate action emphasizes avoiding the vulnerabilities of narrow sectoral approaches. Our study explores the circular bioeconomy, highlighting the intricate interconnections among agriculture, forestry, aquaculture, technological advancements, and ecological recycling. Collectively, these sectors play a pivotal role in supplying essential resources to meet the food, material, and energy needs of a growing global population. We pose the pertinent question of what it takes to integrate these multifaceted sectors into a new era of holistic systems thinking and planning.

Results

The foundation for discussion is provided by a novel graphical representation encompassing statistical data on food, materials, energy flows, and circularity. This representation aids in constructing an inventory of technological advancements and climate actions that have the potential to significantly reshape the structure and scale of the economic metabolism in the coming decades. In this context, the three dominant mega-trends—population dynamics, economic developments, and the climate crisis—compel us to address the potential consequences of the identified actions, all of which fall under the four categories of substitution, efficiency, sufficiency, and reliability measures. Substitution and efficiency measures currently dominate systems modeling. Including novel bio-based processes and circularity aspects might require only expanded system boundaries. Conversely, paradigm shifts in systems engineering are expected to center on sufficiency and reliability actions. Effectively assessing the impact of sufficiency measures will necessitate substantial progress in inter- and transdisciplinary collaboration, primarily due to their non-technological nature. In addition, placing emphasis on modeling the reliability and resilience of transformation pathways represents a distinct and emerging frontier that highlights the significance of an integrated network of networks.

Conclusions

Existing and emerging circular bioeconomy practices can serve as prime examples of system integration. These practices facilitate the interconnection of complex biomass supply chain networks with other networks encompassing feedstock-independent renewable power, hydrogen, CO2, water, and other biotic, abiotic, and intangible resources. Elevating the prominence of these connectors will empower policymakers to steer the amplification of synergies and mitigation of tradeoffs among systems, sectors, and goals.
Farm animal welfare regulatory preferences and food choice: survey evidence from the US
Authors: Boaitey Albert
Published: June 2024

Public support is critical for the incorporation of farm animal welfare (FAW) standards into national food policies. Multiple pathways, e.g., market-based policies, political mandates, and donations to animal charities, exist for the public to influence these standards. The challenge often remains that citizens may express significantly different regulatory preferences from consumers thereby disproportionally overburdening the latter. For food, this consumer–citizen role is directly linked to dietary choice. Although a large body of research has examined the determinants of dietary choice on the one hand, and FAW policy preferences, on the other, no attempt has been made to address these issues side by side. This study explores the preferences for FAW regulatory mechanisms and strategic behavior among dietary groups. Preferences for private labeling, political mandates, and donations to charities in support of and against conventional agriculture are examined. Data are from an online survey of 1020 residents conducted in the US. The results show a proclivity among segments of the public who do not consume livestock products for political mandates and the tendency to behave strategically. Regulatory preferences are embedded within distinct human value orientations. Urban—non-urban, generational and gender divides in regulatory preferences are also identified. These insights are relevant for the ongoing development of FAW standards given the portfolio of mechanisms at the disposal of stakeholders.
The walnut-derived peptide TW-7 improves mouse parthenogenetic embryo development of vitrified MII oocytes potentially by promoting histone lactylation
Authors: Wei Yaozong , Pan Bo , Qin Jianpeng , Cao Beijia , Lv Tianyi , Ye Jiangfeng , Ning Ao , Du Kunlin , Chen Xiangyi , Zou Shuqi , Zang Shengqin , Yu Guozhi , Song Tianzeng , Liang Qiuxia , Zhou Guangbin
Published: June 2024

Background

Previous studies have shown that the vitrification of metaphase II (MII) oocytes significantly represses their developmental potential. Abnormally increased oxidative stress is the probable factor; however, the underlying mechanism remains unclear. The walnut-derived peptide TW-7 was initially isolated and purified from walnut protein hydrolysate. Accumulating evidences implied that TW-7 was a powerful antioxidant, while its prospective application in oocyte cryopreservation has not been reported.

Result

Here, we found that parthenogenetic activation (PA) zygotes derived from vitrified MII oocytes showed elevated ROS level and delayed progression of pronucleus formation. Addition of 25 μmol/L TW-7 in warming, recovery, PA, and embryo culture medium could alleviate oxidative stress in PA zygotes from vitrified mouse MII oocytes, furtherly increase proteins related to histone lactylation such as LDHA, LDHB, and EP300 and finally improve histone lactylation in PA zygotes. The elevated histone lactylation facilitated the expression of minor zygotic genome activation (ZGA) genes and preimplantation embryo development.

Conclusions

Our findings revealed the mechanism of oxidative stress inducing repressed development of PA embryos from vitrified mouse MII oocytes and found a potent and easy-obtained short peptide that could significantly rescue the decreased developmental potential of vitrified oocytes, which would potentially contribute to reproductive medicine, animal protection, and breeding.
The probable direction of impact at Dhala impact structure, India deciphered from microfracture intensity and X-ray diffractometry: a new potential impact direction indicator
Authors: Behera Swastik Suman , Tiwari Sonal , Pandey Ambrish Kumar , Agarwal Amar , Ojha Arun Kumar
Published: June 2024

The most widely used method of determining impact direction employs asymmetric ejecta distribution around the crater. However, the active terrestrial landscape seldom preserves the pristine ejecta blanket, making it challenging for this analysis to be carried out. The deeply eroded Dhala impact structure, formed during the Proterozoic, is devoid of an ejecta blanket. We, therefore, utilize the variation in the full width at half maxima (FWHM) of the quartz (100) peak in X-ray diffraction (XRD) spectra and the P10microfracture intensity in the monomict breccia to estimate the probable downrange direction of the Dhala impact structure. The monomict breccia rocks of the Dhala impact structure have experienced low shock pressures (< 10 GPa) and are highly fractured, making them the ideal target lithology for our study. Previous studies have used XRD extensively for strain analysis in synthetic materials and rocks. Microfracture intensity acts as an indicator for the degree of fracturing or brittle damage in the rocks, with the maximum shock-induced damage being concentrated in the downrange direction. The results from the XRD are consistent with the microfracture intensity analyses and indicate that the probable direction of impact was from southwest to northeast, with northeast being the downrange direction. Furthermore, we suggest that the degree of fracturing and X-ray diffractometry can be used to identify the downrange direction of an impact crater.

Graphical Abstract
Dual-frequency to five-frequency real-time precise point positioning using new BDS-3 PPP-B2b service
Authors: Yang Haochen , Ren Xiaodong , Liu Mingxiu , Zhang Xiaohong
Published: June 2024

BeiDou global navigation satellite system (BDS-3), a developed GNSS by China, has the ability to support five different signals, including B1I, B3I, B1C, B2a, and B2b. Meanwhile, BDS-3 has officially provided the satellite-based precise point positioning (PPP) service through the B2b signal (PPP-B2b) since 2021. It’s necessary to conduct a comprehensive analysis on multi-frequency PPP with PPP-B2b corrections. In this study, a multi-frequency undifferenced and uncombined PPP model (UDUC) using PPP-B2b corrections was employed to investigate dual-frequency to five-frequency real-time PPP performance. The results show that compared with the conventional dual-frequency solutions, multi-frequency solutions can improve both the convergence performances and positioning accuracy of PPP-B2b service, especially during the convergence stage. The quad-frequency and five-frequency solutions can achieve the best positioning performance. The static solutions of multi-frequency PPP models reach the centimeter-level accuracy after convergence. In kinematic mode, the convergence time of the five-frequency PPP results is reduced by 23.5% compared with the dual-frequency results. The root mean square (RMS) errors of the five-frequency PPP in the E, N, and U components are 7.1 cm, 4.8 cm, and 12.4 cm, which are improved by 6.8%, 11.5%, and 5.5%, respectively.

Graphical Abstract
Co-designing a participatory evaluation of older adult partner engagement in the mcmaster collaborative for health and aging
Authors: Abousifein Marfy , Falbo A. Tina , Luyckx Joyce , Abelson Julia , Ganann Rebecca , Vrkljan Brenda , Carusone Soo Chan
Published: June 2024

Engagement of patients and the public in health research is crucial for ensuring research relevance and alignment with community needs. However, there is a lack of nuanced evaluations and examples that promote collaborative and reflective learning about partnerships with partners. The aim of this paper is to provide a case example of a participatory evaluation of the engagement of older adult partners in an aging-focused research centre. We outline our process of co-planning and implementing an evaluation of the McMaster Collaborative for Health and Aging’s engagement strategy through the use of multiple methods, including a standardized tool and qualitative approaches. The team chose to explore and capture the engagement experiences and perspectives of the older adult partners within the Collaborative using a survey (the Public and Patient Engagement Evaluation Tool (PPEET)), an art-based method (photovoice), and a focus group. We present a brief summary of the findings but primarily focus this paper on the experiences of using each methodology and tool, with an emphasis on promoting dialogue on the benefits, limitations, and challenges. We reflect on the process of co-planning and the integration of both standardized tools and qualitative approaches to adopt a holistic approach to evaluating partnership within the Collaborative. Ultimately, this case example aims to provide practical guidance for other research groups navigating the complexities of partnership engagement and evaluation, thereby promoting meaningful partnerships in research.
Remote feedback in endovascular simulation training: a mixed-methods study
Authors: Roche Adam F. , Moneley Daragh , Lawler Tim , Boyle Emily , Gosi Greg , O’Callaghan Adrian , Cahir Caitriona , O’Keeffe Dara , Condron Claire M.
Published: June 2024

Background

There is an increasing need to increase simulation-based learning opportunities for vascular surgery residents in endovascular skills training. This study aims to explore the effectiveness of remote expert instructional feedback of endovascular simulation-based education, as a means of increasing training opportunities in this area for vascular surgery residents.

Methods

A mixed-methods study design was adopted. Twelve vascular surgery residents from Ireland were tasked with completing two endovascular renal artery procedures: one with in-person expert feedback and the other with remote instruction. Participants ranged in experience levels from second year to final year of residency. Following the training activities, interviews and a questionnaire were employed to gather information on the usefulness of remote feedback.

Results

There was no significant difference reported by participants using a post-event validated questionnaire between remote and in-person feedback. During the interviews, participants expressed mixed feelings about the presence of the educator while practicing, but they eventually saw no limiting factors to their practice when the trainer provided remote feedback. When receiving performance feedback remotely, clear communication and a shared knowledge of the task development are critical to success.

Conclusions

We believe these findings can inform the design and development of remote learning and assessment of endovascular skills training and ultimately provide increased opportunities for more skills practice for vascular surgical residents.
New insights into the DNA extraction and PCR amplification of minute ascomycetes in the genus Laboulbenia (Pezizomycotina, Laboulbeniales)
Authors: Van Caenegem Warre , Haelewaters Danny
Published: June 2024

Molecular studies of fungi within the order Laboulbeniales (Ascomycota, Pezizomycotina) have been hampered for years because of their minute size, inability to grow in axenic culture, and lack of reliable and cost-efficient DNA extraction protocols. In particular, the genus Laboulbenia is notorious for low success with DNA extraction and polymerase chain reaction (PCR) amplification. This is attributed to the presence of melanin, a molecule known to inhibit PCR, in the cells. We evaluated the efficacy of a standard single cell-based DNA extraction protocol by halving the recommended amount of reagents to reduce the cost per extraction and adding bovine serum albumin (BSA) during the multiple displacement amplification step to reverse the effect of melanin. A total of 196 extractions were made, 111 of which were successful. We found that halving the reagents used in the single cell-based extraction kit did not significantly affect the probability of successful DNA extraction. Using the halved protocol reduces cost and resource consumption. Moreover, there was no significant difference in the probability of successfully extracting DNA based on whether BSA was added or not, suggesting that the amount of melanin present in cells of the thallus has no major inhibitory effect on PCR. We generated 277 sequences from five loci, but amplification of the internal transcribed spacer region, the mitochondrial small subunit rDNA, and protein-coding genes remains challenging. The probability of successfully extracting DNA from Laboulbeniales was also impacted by specimen storage methods, with material preserved in > 95% ethanol yielding higher success rates compared to material stored in 70% ethanol and dried material. We emphasize the importance of proper preservation of material and propose the design of Laboulbeniales-specific primers to overcome the problems of primer mismatches and contaminants. Our new insights apply not only to the genus Laboulbenia; Laboulbeniales generally are understudied, and the vast majority of species remain unsequenced. New and approachable molecular developments will benefit the study of Laboulbeniales, helping to elucidate the true diversity and evolutionary relationships of these peculiar microfungi.
Clinical efficacy of two different doses of rituximab as a treatment option in adult patients with chronic immune thrombocytopenia
Authors: El-Saied Dina G. , Dwidar Amany M. , Abdelaty Mona Mahrous
Published: June 2024

Background

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with a high incidence of chronicity among adults. Rituximab is recommended as a treatment option for chronic ITP with the best long-term effect compared with other therapies. However, the optimal dose of rituximab remains unclear. We retrospectively compared the response rate, incidence of relapse, and other clinical outcomes in 34 chronic ITP patients who received rituximab in different doses. Patients were divided into two groups according to rituximab dose (the low-dose group, 100 mg/week for 4 weeks, and the standard-dose group, 375 mg/m2 weekly for 4 weeks).

Results

Females represented 72.2% and 56.3% of patients in the low dose and the standard dose groups, respectively. The overall response in all patients was 88.2%. By the end of the second month of treatment, 77.8% achieved partial remission and 11.1% achieved complete remission in the low-dose group versus 68.8% and 18.8% in the standard-dose group. Similar incidence of sustained complete response after 6 months of treatment, 83.3% after low dose rituximab and 81.2% after the standard dose (p = 1.000). The incidence of relapse was similar between both groups.

Conclusion

Our findings demonstrate that both regimens had no statistically significant differences in overall response, relapse rate, and time to reach response. The low dose of rituximab is comparable to the standard high dose in efficacy and safety for the treatment of chronic ITP patients and can be a good option in centers with limited resources.
Impact of JAK2 allele burden on MF outcome in the era of ruxolitinib.
Authors: Braish Julie , Bose Prithviraj , Pemmaraju Naveen , Pierce Sherry , Sasaki Koji , Estrov Zeev , Patel Keyur P. , Kantarjian Hagop M. , Masarova Lucia
Published: June 2024

6514

Background: Myelodepleted myelofibrosis (MF), characterized bycytopenias, lower JAK2V617F allele burden (JAK2%) and shorter benefit from JAKi ruxolitinib (RUX), has worse survival (OS) compared to myeloproliferative MF. Lower JAK2% and inferior OS is more typical for primary MF (PMF) vs MF from essential thrombocythemia or polycythemia vera (PPV/PET-MF). We sought to investigate the impact of JAK2% (</≥ 50%), cytopenias and the use of RUX in outcome of PMF/PPV-PET-MF patients from our center. Methods: 601 medical charts of JAK2 mutated patients with MF (known JAK2%) were retrospectively reviewed. We divided patients based on the absence (-) or presence (+) of cytopenias (hemoglobin < 10 g/dL or platelets < 100 x10^9/L) and leukocytosis (WBC ≥ 25 x10^9/L) into: Gr1 = (-)/(-) [absence of both]; Gr2 = (-)/(+) [proliferative]; Gr3 = (+)/(-) [cytopenic]; Gr4 = (+)/(+) [cytopenic and proliferative]) and evaluated OS per JAK2 </≥ 50% and PMF vs PPV/PET-MF. We assessed the tolerance of RUX ≥3 years. We used descriptive statistics, Kaplan-Meier curve with log-rank test and regression analysis for demographics, estimation of OS and its comparison. OS was censored at the time of stem cell transplantation. Results: Median age of the entire cohort was 75 years (64% males). Patients with JAK2 <50%, more likely PMF, had more anemia and thrombocytopenia, higher blasts, less leukocytosis, and smaller splenomegaly. JAK2 </≥ 50% did not discriminate OS of the entire group, PMF or PPV/PET-MF (median OS of ~ 45 months for each; only PPV/PET-MF with 64 months). OS of Gr1-4 according to JAK2 </≥ 50% and PMF/ PPV/PET-MF and combined OS of patients with comparable outcome (A-D) are shown in the table. The final groups with distinct outcomes included: A+B) non-cytopenic PET/PPV-MF and PMF irrespectively of proliferation and JAK2% - with one exception of non-cytopenic, proliferative PMF with JAK2 ≥50% - had median OS of 70 months (range, 54-86); D) cytopenic and proliferative PMF with any JAK2% and PPV/PET-MF with JAK2 < 50% of median OS 19 months (range, 13-25), and C) the rest of the cytopenic patients and non-cytopenic, proliferative PMF with JAK2 ≥50% with a median OS of 36 months (range, 32-42). Among the 3 final groups, similar proportion of patients were exposed to RUX during their follow-up: 36% (A+B), 31% (B) and 28% (C), respectively (p =0.13). The most patients in (A+B) group were able to tolerate RUX for ≥3 years (p =0.036). All patients had improved OS with RUX (data to be presented). Conclusions: Cytopenias and/or proliferation, rather than JAK2 </≥50%, define the outcome of PMF and PPV/PET-MF patients. [Table: see text]
Achievement of therapeutic levels using dose-reduced peg-asparaginase in adult patients with acute lymphoblastic leukemia.
Authors: Goldberg Leah Ann , Kapadia Anjani , Palmer Andrew , Shah Syed Abdul Mannan , Rahmani Youshanlouei Hamed , DuVall Adam , Stock Wendy , Dworkin Emily , Patel Anand Ashwin
Published: June 2024

6530

Background: Peg-asparaginase (PEG) doses range from 2000-2500 IU/m2 in pediatric-inspired regimens for acute lymphoblastic leukemia (ALL). Pediatric PEG dosing in adolescents and young adults (AYAs) has resulted in improved outcomes, but PEG-associated toxicities increase with age and often limit its use. Therapeutic dosing is determined by asparagine (ASP) depletion for 14 days after dose; L-asparaginase levels can act as a surrogate marker of ASP depletion. We previously showed dose reduced PEG (defined as <2000 IU/m2) results in high rates of therapeutic L-asparaginase 7 days post PEG (Derman et al, Leuk Lymphoma 2020). Here we describe prolonged duration of ASP depletion and comparable toxicities after dose reduced PEG in adults with ALL. Methods: Patients ≥18 years with ALL or lymphoblastic lymphoma (LBL) who received PEG from 1/1/2008 to 9/28/2023 were identified for retrospective chart review. Those with ≥1 PEG trough level (defined as 10-20 days after dose) were included. The primary endpoint was therapeutic PEG levels (≥0.1IU/mL L-asparaginase) at 7 and 14 days post administration, with secondary endpoint being induction grade 3+ toxicities (CTCAE v.5.0). Results: 49 patients met inclusion criteria, of which 48 received PEG during induction. Median age was 34.7 (range 18-66), 67% were male and 53% had B-cell ALL. 17 (35%) received an induction dose ≤ 500 IU/m2, 22 (46%) received 501 to ≤1000 IU/m2 and 9 (19%) received >1000 IU/m2. Induction median dose was 1000 IU/m2. Among those with PEG trough levels, 79% were therapeutic after induction; of note, 4 patients were transitioned from PEG to Erwinia asparaginase due to silent inactivation. During induction, 23 (48%) patients had ≥1 grade 3+toxicity, including 5 (10%) with hepatotoxicity, 1 (2%) with pancreatitis, and 2 (4%) with a thrombotic event. There was no statistical relationship between dose level and toxicities (p=.8). Conclusions: This study demonstrates durability of therapeutic L-asparaginase levels and ASP depletion that persists 14 days despite dose reduction. There were decreased rates of hepatotoxicity and comparable rates of pancreatitis and thrombotic events compared to rates reported in CALBG 10403 (C10403) (Stock et al, Blood 2019), which utilized standard pediatric dosing. In addition, our cohort’s median age was significantly older than those treated on C10403. This suggests PEG dose reduction may offer similar therapeutic ASP depletion with comparable or reduced toxicities. Dose reduction should be studied prospectively in AYAs with ALL. [Table: see text]
Outcomes of patients with bone marrow fibrosis in de novo and secondary acute myeloid leukemia.
Authors: Urrutia Samuel , Kantarjian Hagop M. , Ravandi-Kashani Farhad , Jabbour Elias , Kanagal-Shamanna Rashmi , Loghavi Sanam , Patel Keyur P. , Montalban-Bravo Guillermo , Short Nicholas James , Daver Naval Guastad , Borthakur Gautam , Dinardo Courtney Denton , Kadia Tapan M. , Masarova Lucia , Bose Prithviraj , Pemmaraju Naveen , Garcia-Manero Guillermo , Sasaki Koji
Published: June 2024

6538

Background: The outcomes of patients with de novo acute myeloid leukemia (AML) with bone marrow fibrosis (MF) have not been systematically studied. Our objective was to define the prognosis of patients with AML and multiple degrees of bone marrow fibrosis, efficacy of therapy, and survival outcomes. Methods: We retrospectively evaluated 2302 patients diagnosed with AML at a single center from 2007 to 2023 and annotated clinicopathologic characteristics and outcomes. Results: We identified 492 (21%) with AML and MF. We found 344 (69.9%) had MF 0-1 and 148 (30.1%) had MF 2-3. Median age was 67 (IQR: 57-73). Fifty-five (11.1%) had a history of myeloproliferative neoplasm (MPN). Patients with MF 2-3 were associated with complex cytogenetics (39.2%), JAK2 mutations (25.7%), and lower incidence of IDH2(16.9%) or CEBPA(15.5%) mutations (Table). For patients with MF 0-1, median overall survival (mOS) was 14.2 months compared to 7.5 months for those with MF 2-3 (p<0.005). Survival in patients with MPN history was 9.4 months compared to 12.4 months in patients with de novo AML. In a multivariate analysis, MF 2-3 (HR 2.00 95%CI 1.59-2.51), non-diploid cytogenetics (HR 1.29, 95%CI 1.33-1.69), and number of co-morbidities (HR 1.26 95%CI 1.10-1.43) were prognostic for shorter mOS. Sixty-four percent were treated with low-intensity chemotherapy (LIC), 36.1% with intensive chemotherapy (IC). Complete remission (CR)/CR with incomplete count recovery (CRi) rates were 63.5% for IC vs 37.9% for LIC (p=0.007). Four-week mortality after induction was 5.8% with IC, 8.4% with LIC (p = 0.809). In patients aged 60 and older, with MF 2-3, intensive therapy did not result in improved survival (6.5 months vs 7.0 months, p = 0.19). Conclusions: Patients with AML and MF 2-3 have worse outcomes irrespective of MPN history. For patients aged 60 and above, intensive chemotherapy does not result in improved survival. [Table: see text]
Impact of protein energy malnutrition on hospitalized patients with acute myeloid and lymphoid leukemia: A United States population-based cohort study.
Authors: Syal Arshi , Arya Yajur , Casipit Bruce Adrian , Obomanu Elvis , Heller Gordon , Dourado Claudia M. , Leighton John Charles
Published: June 2024

6548

Background: Acute leukemia poses a significant burden to the society and the healthcare system. Advances in chemotherapeutics and hematopoietic stem cell transplantation (HSCT) have increased survival in these patients. Protein energy malnutrition (PEM) frequently complicates the clinical picture in patients with cancer, however data on the impact of PEM in patients with acute myeloid and lymphoid leukemia is limited. Methods: We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with acute leukemia (myeloid and lymphoid) and PEM using appropriate ICD-10 diagnostic codes. We stratified patients with acute leukemia based on the presence or absence of PEM. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of <0.05 was considered statistically significant. The aim of this study was to investigate the impact of PEM on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charge among patients with acute leukemia. Results: We identified a total of 30995 hospitalized patients with acute leukemia, of which 13.06% (4050/30995) had comorbid PEM. The overall in-hospital mortality among patients with acute leukemia was 8.95% (2775/30995). Among those with co-morbid PEM, the mortality rate was significantly higher at 12.47% (505/4050, p<0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, PEM was found to be an independent predictor of increased in-hospital mortality (adjusted OR 1.50; 95% (confidence interval [CI], 1.18 -1.91); p=0.001), longer LOS (coefficient 10.50; CI 8.59 -12.41; p<0.001), and higher total hospitalization charge ($208,308; CI $147,516- $269,100; p<0.001). Conclusions: Our analysis demonstrated that PEM was widely prevalent in hospitalized patients with acute leukemia and significantly worsened outcomes including increased in-hospital mortality, LOS, and cost of healthcare utilization. A proactive approach for prevention and early management of cancer associated malnutrition is required. Further prospective multicentric studies are needed to better describe these associations.
A prospective phase II randomized clinical study of folic acid in the intervention of radiation esophagitis induced by concurrent chemoradiotherapy in lung cancer.
Authors: Zhang Hao , Zhu Yiying , Ouyang Weiwei , Su Shengfa , Ma Zhu , Li Qingsong , Yang Wengang , Chen Xiaxia , Lu Bing
Published: June 2024

e20004

Background: To investigate the efficacy and safety of folic acid intervention in lung cancer patients with radiation esophagitis caused by concurrent chemoradiotherapy. Methods: It was a randomized, controlled, single-center clinical trial of 82 patients with stage N2~N3 lung cancer including SCLC and NSCLC were prospectively included. All patients were randomly divided into experimental and control group according to 1:1, and patients were required to receive radiation therapy for lung lesions and mediastinal metastatic lymph nodes (More than 2 cycles of chemotherapy were completed during the same period of radiotherapy or take targeted drugs at the same time, the cumulative radiation dose of chest lesions should exceed 40Gy). The experimental group took folic acid tablets 30mg/day orally at the beginning of radiotherapy until the end of radiotherapy, while the control group did not receive any drug intervention.When two groups appeared radiation esophagitis, the grading criteria for RTOG should be evaluated first, then according to the guidelines of symptomatic treatment.Esophageal toxicity was evaluated during radiotherapy, and improved RTOG and NCI-CTC ratings were performed weekly at the onset of radiation esophagitis and thereafter until 1 week after the end of radiotherapy. Results: The incidence of radiation esophagitis in the experimental group was low during the observation period, and the occurrence time of radiation esophagitis could be delayed in the experimental group, but there was no statistical significance between the two groups ( P=0.456). After folic acid intervention, the symptoms of pain and dysphagia of radiation esophagitis in the experimental group were significantly decreased, especially the RTOG grade and NCI-CTC improvement grade decreased significantly 2 weeks after the occurrence of radiation esophagitis( P=0.007, P=0.009). In the experimental group, it was found that the greater the change of hemoglobin before and after radiotherapy, the occurrence time of radiation esophagitis was about delayed, which was statistically significant(r=0.348, P=0.040).The correlation analysis of the control group showed that the change of body mass index was positively correlated with the onset time of radiation esophagitis(r=0.372, P=0.020);The lower the hemoglobin content after radiotherapy and the larger the hemoglobin difference before and after radiotherapy, the higher the highest incidence of radiation esophagitis(r= -0.454, P=0.004;r= -0.343, P=0.032). Conclusions: Oral folic acid can delay the onset of radiation esophagitis due to concurrent chemoradiotherapy and promote the recovery of radiation esophagitis to a certain extent,but can not interfere with the occurrence of radiation esophagitis.This trial is registered in Clinical Trials(NCT0529636). Clinical trial information: NCT0529636 .
Osimertinib related cardiotoxicity in patients with non-small cell lung cancer.
Authors: Mensah Samuel Akaakole , Alruwaili Waleed , Ahmad Syed , Patel Brijesh , Almubarak Mohammed
Published: June 2024

e20011

Background: There have been cases of cardiotoxicity induced by osimertinib in patients with non-small cell lung cancer (NSCLC). Limited data exists for a comprehensive cardiotoxicity profile analysis for osimertinib in NSCLC patients. Methods: Data was retrospectively collected from electronic medical records for all patients who were started on osimertinib for NSCLC at West Virginia University Health System between 7/2016 and 1/2024. Prevalence of heart failure (HF), atrial fibrillation, and prolonged QT before and after starting osimertinib were calculated. Corrected QT interval was calculated using the Fredericia formula. QT prolongation was defined as a QTc >500 milliseconds (ms). Results: A total of 116 participants with NSCLC on osimertinib were included in the analysis with median age of 52.2 years, 69.8% female, and mean 1.52 years of follow-up. The study population was 93.1% of white race, and significant comorbidities within the overall population included hypertension (70.7%), hyperlipidemia (53.4%), tobacco use (38.8%), coronary artery disease (18.1%) and diabetes mellitus (15.5%) (Table). Out of 85 patients with no specified prior cardiac abnormalities, 29.4% developed new onset cardiac abnormalities (Table). The median QTc increased from 429 ms to 444 ms after starting osimertinib, and 8.8% of patients had QTc >500 ms. Conclusions: Osimertinib is used in NSCLC and appears to be associated with an increase in cardiac abnormalities. A direct causal relationship between osimertinib use and cardiotoxicity has not yet been established. Given the strong association between this medication exposure and the observed cardiac toxicities, use of osimertinib may entail closer cardiac monitoring of electrocardiogram and echocardiographic abnormalities. [Table: see text]
Association of N-adhesin and focal adhesion kinase with frequency of tumor spread through the airspace (STAS) in stage I lung carcinoma and correlation with recurrence.
Authors: Liu Hongbing , Meng Yunchang
Published: June 2024

e20020

Background: Spread through air spaces (STAS) is one of the many modes of lung cancer dissemination. Aberrant activation of epithelial-mesenchymal transition (EMT) has been associated with enhanced tumor cell migration and invasiveness, a process that is accompanied by a decrease in adhesion molecules that maintain contact between epithelial cells, leading to cell separation and increased cell motility. Our objectives were to investigate the effect of adhesion molecule expression levels on STAS occurrence and postoperative recurrence in patients undergoing radical resection for stage I lung carcinoma. Methods: We examined the association of adhesion molecules with STAS as the primary endpoint and the Disease-Free Survival (DFS) as a secondary endpoint. E-cadherin, P-cadherin, N-cadherin, focal adhesion kinase (FAK), epithelial cell adhesion molecule (EpCAM) neural cell adhesion molecule 1 (NCAM1), vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule-1 (ICAM-1) were analyzed by immunohistochemistry in patients undergoing radical resection for stage I lung carcinoma. Associations between those adhesion molecules expression levels and STAS were determined by using the chi-square test and logistic regression model. DFS was analyzed by using the log-rank test and Cox proportional risk model. Results: As of January 1, 2024, 12 of 60 patients undergoing radical resection for stage I lung carcinoma had a disease recurrence. All of 60 patients’ tissue specimens were retrospectively analyzed, and there were no significant differences between patients with STAS-positive(n=30) and STAS-negative(n=30) in baseline clinicopathologic features, except for histological growth patterns, and lymphovascular invasion.Higher incidence of STAS was significantly associated with low expression of E-cadherin (P=0.002), high expression of N-cadherin (P=0.018) and FAK (P=0.027), and males (P=0.026), independent of tumor size, age, and clinical stage. Multivariate analysis showed that STAS (P=0.025), low E-cadherin/high N-cadherin (P=0.038), low E-cadherin/high FAK (P=0.025), and high N-cadherin/FAK (P=0.003) were significantly correlated with a higher risk of recurrence. In addition, females (P=0.034), and high N-cadherin/FAK (P=0.032) were associated with a high risk of recurrence in patients with STAS. Conclusions: Low expression of e-cadherin, high expression of N-cadherin and FAK were independent predictors of higher incidence of STAS. Tumors with low E-cadherin/high N-cadherin, low E-cadherin/high FAK, and high N-cadherin/FAK expression were important predictors of recurrence in patients with stage I lung carcinoma. Additionally, high N-cadherin/FAK expression in tumors provides information about a higher risk of recurrence in STAS-positive stage I lung carcinoma.
Comparative genomic analysis of circulating tumor cells and primary tissues in early-stage lung cancer: Unveiling signatures of metastatic potential.
Authors: Lee Jinsu , Sung Hyejin , Park Jeemin , Ji Soojeong , Kim WooJung , Jung Sojin , Cho Sukki
Published: June 2024

e20021

Background: Recent studies substantiate the circulating tumor cells (CTCs) as biological markers for the cancer progression and metastasis. Nevertheless, isolating CTCs is challenging due to their relatively low abundance in the bloodstream. The innovative CTC detection and characterization method, iDXGate TO by BeyondDx, has overcome these challenges, facilitating the seamless identification of genomic alterations, deepening understanding of the functions of CTCs in cancer progression. Methods: In this study, a total of 50 patients diagnosed with early-stage lung cancer, without a history of anticancer therapy at Seoul National University Bundang Hospital from August 2023 to December 2023 participated to compare the genomic alterations between primary cancer tissue and CTCs. Resected tumor tissues and whole blood were collected during surgery, and DNA was freshly extracted and transferred. iDXGate TO, designed specifically for early-stage lung cancer, employs EpCAM, EGFR, and HER2 Biomarkers for targeted capture of circulating tumor cells (CTCs). Targeted sequencing was performed on the genomic DNA extracted from both cancer tissues and CTCs of each patient. Out of the CTC samples, 16 were excluded due to insufficient DNA. Results: Detailed analysis involved sequencing data from 34 CTC samples and 50 tissue samples. CTCs exhibited 100% (34/34) likely pathogenic alterations, compared to 42.00% (21/50) in tissues. Predominant genomic alterations in CTCs included MSH6 (100.0%), FANCE (91.2%), CDK12 (85.3%), HNF1A (85.3%), AXIN2 (82.4%), and FLCN (79.4%). Tissues were frequently associated with EGFR (40.0%), TP53 (34.0%), FAT1 (18.0%), LRP1B (16.0%), NOTCH3 (16.0%), and KMT2D (16.0%). Alterations in MSH6, FANCE, and CDK12 underscore the critical role of DNA repair mechanisms in CTCs, contributing to genomic instability. Alterations in HNF1A suggest implications in metabolic regulation, influencing the tumor microenvironment. Alterations in AXIN2 and FLCN hint at involvement in Wnt signaling and cellular growth regulation, potentially contributing to tumorigenesis. Conclusions: The iDXGate TO selectively identifies tumor-specific circulating tumor cells (CTCs) and explores a new realm of liquid biopsy through molecular and phenotypic integrated analysis. Detection of altered genes in CTCs highlights the molecular heterogeneity. Further exploration of these genetic alterations could offer valuable insights into the underlying mechanisms propelling cancer progression. Additionally, CTCs could serve as pivotal biomarkers for real-time monitoring of tumor evolution, potentially guiding the development of targeted therapies tailored to the specific genomic landscape of CTCs.