bluuebunny/crossref_metadata_2025 huggingface dataset:
The development of the Egyptian 24-h movement guidelines for adults aged 50 years and older: an integration of sleep, sedentary behavior, and physical activity by the Egyptian Academy of Bone and Muscle Health
Authors: El Miedany Yasser , Toth Mathias , Plummer Susan , El Gaafary Maha , Mahran Safaa , Elwakil Walaa
Published: June 2024

Background

With the vision of healthy aging, the Egyptian Academy of Bone and Muscle Health followed an established guideline development process to create the Egyptian 24-h movement clinical guideline for adults aged 50 years and older adults. This guideline highlights the significance of movement behaviors across the whole 24-h day. Online databases (PubMed, Embase, and Cochrane Library) were searched for relevant peer-reviewed studies that met the a priori inclusion criteria.

Results

A total of 53 studies met the inclusion criteria. Leveraging evidence from the review of the literature led to the development of 27 statements answering the 5 key questions. Results revealed a major change in the previous basic understandings as it shifts away from focussing on a sole movement behavior to the combination of all the movement behaviors. Based on this, the final guideline was developed providing evidence-based recommendations for a “Healthy 24-Hour Day”, comprising a mix of light-intensity and moderate-to-vigorous-intensity physical activity, sleep, and sedentary behavior.

Conclusion

The developed guidelines are meant to help in the decision-making process and are intended for use by adults and older both nationally and internationally; also, for endorsement by the policy-makers. Dissemination and implementation efforts would impact positively on both health professionals and researchers and would also be useful to interested members of the public sector.
Women-led community institutions as a potential vehicle for the adoption of varieties and improved seed practices: an impact case from India
Authors: Hossain Mosharaf , Nayak Swati , Mohapatra Subhasmita , Trivedi Pooja , Waza Showkat A.
Published: June 2024

Rice–wheat rotation is the principal cropping system in South Asian countries. Increasing productivity under this cropping system in Northern India is not only a policy priority but also an important component towards ensuring food and nutritional security for the major portion of the Indian population. The objective of enhanced productivity is being pursued through innovative extension models focusing on the adoption of modern varieties and community-led seed production. The present experimental study (a randomized control trial) was conducted in Uttar Pradesh (India) to evaluate the efficacy of community institutions [e.g., women self-help group (WSHG)] based seed interventions in promoting the adoption of improved varieties amongst farmers. Besides, the impact on the implementation of quality seed production practices, adoption of seed quality measures, and participation in capacity-building trainings were also evaluated. The findings infer that implementing seed scaling programs through community institutions leads to a significantly higher rate of technological adoption than that executed through non-collectivized ways. Besides, farmers from WSHGs have more tendency towards learning new technologies and participating in training programs about improved crop management practices. The study also explains that WSHG-based programs are not a contributory factor in advancing farm technologies that are already in practice, such as seed cleaning and germination tests. This validated model can be suitably replicated for accelerated dissemination of seed-related innovations.
Preliminary results on effects of planting dates and maize growth stages on fall armyworm density and parasitoid occurrence in Zambia
Authors: Durocher-Granger Léna , Wu Gi-Mick , Finch Elizabeth A. , Lowry Alyssa , Yeap Yuen Ting , Bonnin J. Miguel , Offord Lisa , Kenis Marc , Dicke Marcel
Published: June 2024

Fall armyworm (FAW),
Spodoptera frugiperda
(J.E. Smith), has become one of the main invasive species on earth since it was first found outside its native range in Africa in 2016. Integrated pest management (IPM) is a comprehensive tool that can help farmers managing pests while reducing the need of synthetic pesticides. Within an IPM strategy, proper time of planting is a critical management decision for farmers as planting too early or too late can lead to complete loss of the crop. Commonly, planting early to avoid peak infestation of FAW is recommended to farmers, however, no empirical data in Africa is available to sustain the advice. We studied the effects of planting dates of maize as well of maize growth stages on FAW density and on its local parasitoids in a field study. Three plots were setup (early, intermediate and late planting) and data was collected weekly in each plot. Plots were 20 m × 20 m to avoid small-plot effects, but the relatively large size of the plots was resource intensive and prevented replication. As such, this paper presents preliminary results due to the lack of true replicates across locations and years. Generalized Linear Models were used to model FAW density and parasitoids abundance and diversity. Our results showed an increase of egg masses over time from early to late planting. Additionally, parasitism probabilities were lower in the early planting treatment than for the intermediate and late plantings and decreased with increased maize maturity. Results on biodiversity of parasitoids show a less even trend for early and late whorl stages which are dominated by one or two species while maize reproductive stages show a more even distribution of species. Our preliminary research is the first to provide empirical evidence that planting early helps to avoid the peak activities of FAW moths. These findings provide important information for the sustainable management of FAW in Zambia with the aim to reduce chemical inputs and increase farmers’ incomes and livelihood.
Endostar combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone for locoregionally advanced nasopharyngeal carcinoma (LA-NPC): A phase III, prospective, randomised-controlled, multicenter clinical trial.
Authors: Kang Min , Ma Daiyuan , Gao Jianquan , Wang Fen , Yu Bin , Lu Ying , Zhang Yong , Wu Fang , Hu Kai , Zhang Tingting , Yang Zhendong , Ruan Lin , Qin Yutao , Wei Zhuxin , Meng Zhen , Dong Huan , Qin Yating , Zhou Ziyan , Yin Yuanxiu , Wang Rensheng
Published: June 2024

6002

Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for LA-NPC. However, approximately 30% of patients still fail to obtain a satisfactory effect. Endostar (Rh-endostatin), an anti-angiogenesis inhibitor, is well-tolerated and has been reported as a promising complement to CCRT. This trial aimed to evaluate the efficacy and safety of adding Endostar to CCRT for LA-NPC. Methods: In this prospective, randomized phase III study, patients with LA-NPC (stage III-IVb, 7th edition) were enrolled at 6 centers in China, and randomly assigned (1:1) to receive Endostar plus CCRT (CCRT+E group, n=150) or CCRT alone (CCRT group, n=150). Endostar (7.5 mg/m2/day, days 1-10, 15 days/cycle) was given continuously intravenously for 5 cycles (3 concurrent from 5 days before radiotherapy, and 2 adjuvant from the first day after the completion of radiotherapy). The primary endpoint was the progress-free survival (PFS) rate. The secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), local-regional relapse-free survival (LRRFS), the rate of complete response (CR) at 3 months after RT, and safety. Results: Between November 2016 and July 2020, 300 patients with LA-NPC were randomized (CCRT+E group, 150; CCRT group, 150). As of the data cutoff (December 2023), the median follow-up was 66 months. Intention-to-treat analysis showed that patients in the CCRT+E group achieved better CR rate at 3 months after RT (90.0% vs 80.7%, P=0.022). The 3-year PFS was 84.8% in the CCRT+E group, and 75.1% in the CCRT group (HR, 0.544; 95% CI, 0.336-0.879; Plog-rank=0.011). The 3-year OS was 89.2% vs. 85.3% (HR, 0.595; 95% CI, 0.361-0.982; Plog-rank=0.039). The 3-year DMFS was 89.7% vs. 80.5% (HR, 0.468; 95% CI, 0.266-0.821; Plog-rank=0.007). The 3-year LRRFS was 91.5% vs. 90.8% (HR, 0.808; 95% CI, 0.407-1.604; Plog-rank=0.541). Patients in the CCRT+E group and in the CCRT group had similar Grade 3-4 acute and late toxicity profile (61.7% vs. 65.3%, p=0.519 and 8.0% vs.7.3%, p=0.815). Conclusions: The addition of Endostar to standard CCRT significantly improved the 3-year PFS of LA-NPC patients with good safety profile. Clinical trial information: NCT02907710 .
Efficacy of nimotuzumab added to concurrent chemoradiotherapy after induction chemotherapy for patients with locally advanced nasopharyngeal carcinoma.
Authors: Wu Sangang , Wang Runjie , Yu Yifeng , Zhou Ping , Lian Chenlu , Wang Jun , Lin Qin
Published: June 2024

6024

Background: To investigate the efficacy and toxicities associated with adding nimotuzumab to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LANPC) patients who received induction chemotherapy (IC). Methods: Patients with stage III-IVA nasopharyngeal carcinoma who received IC (TPF/TP/GP) and platinum-based CCRT between January 2017 and October 2021 were retrospectively included. We performed propensity score matching (PSM) to balance and control confounding factors, and the matching variables included gender, age, T stage, N stage, and Epstein-Barr virus (EBV) status. Patients were divided into two treatment groups: CCRT+nimotuzumab (200mg iv, weekly for 7 courses) and CCRT alone. Primary endpoints were overall survival (OS) and disease-free survival (DFS), the secondary endpoints were locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Results: We screened 242 patients in the analysis. After PSM, 121 (50.0%) and 121 (50.0%) had CCRT+nimotuzumab and CCRT alone, respectively. The 3-year OS was 95.4% and 88.0% in those with and without nimotuzumab treatment (P=0.041), and the 3-year DFS of the CCRT+nimotuzumab group was significantly better than that in the CCRT alone group (90.3% vs. 77.5%, P=0.003). Similar LRFS was found between those with and without nimotuzumab treatment (96.5% vs. 93.7%, P=0.297). The 3-year DMFS for CCRT+nimotuzumab versus CCRT alone was 92.9% versus 82.5% (P=0.008). No significant differences in major toxicities were found between the two treatment arms including hematologic toxicities, hepatoxicity, nephrotoxicity, gastrointestinal reactions, and mucositis (P>0.05). Conclusions: The addition of nimotuzumab to CCRT after IC in LANPC has shown promising results in treatment outcomes and acceptable toxicities.
The combination of patient-specific tumor and HPV sequencing to enable high-sensitivity detection of ctDNA in patients with HPV-associated oropharyngeal carcinoma.
Authors: Diplas Bill , Brown David N , Pei Xin , Chen Linda , Graybill Chiharu , Korn W. Michael , Westheimer Emily , Novaj Ardijana , Humm John , Shukla-Dave Amita , Schöder Heiko , Katabi Nora , Sherman Eric Jeffrey , Reis-Filho Jorge , Weigelt Britta , LEE NANCY Y. , Riaz Nadeem
Published: June 2024

6058

Background: Detection of Human papillomavirus (HPV) in plasma has been used to monitor treatment response in HPV-associated oropharyngeal carcinoma (OPC) but was found to have limited sensitivity in patients with low disease burden. We hypothesized that the combined detection of personalized tumor-specific alterations and HPV could provide a more sensitive approach for detecting circulating tumor DNA (ctDNA) and for disease monitoring in early-stage HPV-associated OPC patients. Methods: Patients with HPV-associated OPC (T0-2/N1-N2c) enrolled in a phase II chemoradiation (CRT) de-escalation trial (NCT03323563) were chosen for this study. The patients underwent resection of the primary tumor prior to CRT and a baseline plasma was drawn at this time. Additional plasma samples were collected weekly throughout CRT. Whole-exome and targeted HPV sequencing was performed on the primary resection to build a dictionary of somatic variants and for HPV typing, respectively. A dual PCM-HPV assay was developed based on the Invitae Personalized Cancer MonitoringTM (PCM) platform and used to evaluate the plasma samples. Tumor volume was measured by T2 MRI using a region of interest outlining the largest lymph node in the undissected neck. Results: 158 patients with T0-2/N1-N2c HPV-OPC were enrolled on the trial and the dual PCM-HPV assay was successfully designed for 111 patients targeting a median of 50 patient-specific mutations (range: 26-50). Preliminary analyses were performed on 71/111 patients (64.0%) with HPV16-associated tumors and available baseline plasma. 64/71 (90.1%) and 61/71 (85.9%) were ctDNA positive by PCM testing and HPV testing alone, respectively. Combining HPV plasma testing with PCM (PCM-HPV) improved the sensitivity to 68/71 (95.7%). This increased sensitivity was maintained when analyzing plasma samples collected weekly following CRT. The 3 patients with double negative HPV and PCM results at baseline had a lower tumor volume (p=0.05) and lower levels of genome instability (p=0.02) than those with ctDNA or PCM positive baseline plasma. HPV cfDNA levels are weakly correlated with tumor HPV genome copy number (r=0.16; p=0.001). Conclusions: The combined detection of personalized tumor-specific alterations and HPV provides a highly sensitive approach for detecting low disease burden in early stage HPV-associated OPC patients before and during treatment. [Table: see text]
Genomic and immune profiling of rare non-squamous sinonasal tumors.
Authors: Steuer Conor Ernst , Lubin Daniel , Adeyelu Tolulope Tosin , Bates James Edward , Shin Dong Moon , Patel Mihir R. , Schmitt Nicole C. , Stokes William A. , Bracken-Clarke Dara Mark , Abdulla Farah R. , Floudas Charalampos S. , Oberley Matthew James , Johnson Jennifer Maria , Wise-Draper Trisha Michel , Posner Marshall R. , Saba Nabil F.
Published: June 2024

e18008

Background: Sinonasal tumors (SNT) are rare tumors and make up less than 3% of all head and neck malignancies. The majority of SNTs have squamous cell histology and less common histologies remain understudied. We present a comprehensive analysis of genomic and immune profiles of rare SNTs that can help identify avenues for prognostic biomarkers and future targeted treatments. Methods: Non-squamous SNT samples (n =124) were profiled through Next Generation Sequencing (NGS) of DNA (592-genes; NextSeq or WES; NovaSeq) and RNA (WTS; NovaSeq) at Caris Life Sciences (Phoenix, AZ). Centralized pathology review was carried out to confirm histological subtypes. PD-L1 expression was tested by IHC (22c3, positive (+) >=1%; SP142, positive (2+)/ >=5%). Deficient mismatch repair/microsatellite instability (dMMR/MSI-H) was accessed by IHC/NGS. Immune cell fraction of the tumor microenvironment (TME) was estimated by quanTIseq, and gene expression profiles (transcript per million, TPM) were analyzed for transcriptional signatures predictive of response to immunotherapy. Mann-Whitney U and ChiSquare/Fisher-Exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Results: Non-squamous SNT samples included 35.5% (n = 44) adenoid cystic (ACC), 19.4% (n = 24) adenocarcinoma (AD), 10.5% (n = 13) undifferentiated carcinomas (SNUC), and 34.6% (n = 43) Esthesio/Olfactory Neuroblastomas (ENB). Notably, molecular features associated with each histological subtype are reported in the table. Furthermore, analysis of the inferred immune infiltrates showed that ENB had significantly higher fractions of NK cells (ACC: 5.6% vs AD: 4.6% vs SNUC: 4.4% vs ENB:10.5%, p <0.00001), CD8 T cells (0.1% vs 0.88% vs 0.22% vs 1%, p < 0.0001), CD4 T cells (0.4% vs 1.9% vs 0.03% vs 3.6%, p < 0.00001) and dendritic cells (4.5% vs 3.4% vs 2.6% vs 7.3%, p<0.00001) compared to the other sinonasal tumors. M1 macrophage (ACC: 2.6% vs AD: 1.9% vs SNUC: 1.1% vs ENB: 1.1%, p = 0.047) and Treg fractions (ACC: 2.0% vs AD: 1.6% vs SNUC: 1.2% vs ENB: 0.6%, p<0.00001) were significantly higher in ACC. There was also significantly increased expression of immune checkpoint genes in ENB compared to AD ( PD-1: 0.8 vs 0.5 TPM, p = 0.022) and in ENB compared to ACC ( HAVCR2: 3.4 vs 2.9 TPM, p = 0.047). Conclusions: To our knowledge, this is the largest study characterizing the genomic and immune alterations in non-squamous SNTs. Our findings offer potential for future targeted and immune therapeutic applications in these rare diseases. [Table: see text]
Economic evaluation of the novel PD-1 inhibitor toripalimab in recurrent or metastatic nasopharyngeal carcinoma: Cost-efficiency and expanded access modeling versus pembrolizumab.
Authors: Abraham Ivo , Pondel Marc , MacDonald Karen
Published: June 2024

e18015

Background: Toripalimab, a novel anti-PD-1 antibody recently approved in the US as a breakthrough therapy in combination with gemcitabine and cisplatin (GemCis) for first-line treatment of adults with metastatic or recurrent locally advanced nasopharyngeal carcinoma (R/M NPC), is a category 1, NCCN-recommended preferred regimen. Although not FDA-approved for this indication, other PD-1 inhibitors, including pembrolizumab, are NCCN-recommended in combination with GemCis (category 2A but without direct evidence). The wholesale acquisition cost (WAC) of toripalimab at market entry is 80% that of pembrolizumab. This simulation modeling evaluates the cost-efficiency of toripalimab+GemCis versus pembrolizumab+GemCis in R/M NPC and the budget-neutral expanded access to the toripalimab regimen enabled by savings. Methods: Utilizing WAC drug costs and treatment administration costs, we modeled the cost-efficiency over a treatment duration equivalent to the toripalimab JUPITER-02 trial median PFS of 21.4 months (m). Without trial evidence for pembrolizumab+GemCis in R/M NPC, we assumed that such a regimen would be comparable to toripalimab+GemCis in median PFS. We also assumed that 31 cycles of PD-1 inhibitor (with GemCis in cycles 1-6) are administered over a median PFS of 21.4m. Using the cost-efficiency savings, we simulated the potential for budget-neutral expanded access to toripalimab treatment. A second model utilizing an ex ante toripalimab average sales price (ASP) of 80% of pembrolizumab ASP was estimated. Results: The WAC model estimated the toripalimab regimen to cost $292,316 (all agents over 21.4m or 31 cycles) while the pembrolizumab regimen costs $361,229, for savings of $68,913 per patient. These savings enable 7.7 additional toripalimab maintenance cycles to be purchased on a budget-neutral basis for every patient treated. For every 4.24 patients treated with toripalimab+GemCis instead of pembrolizumab+GemCis, one additional patient can be treated with the full toripalimab regimen (all agents) for 21.4m. Extrapolated to the 2024 US incident R/M NPC population of 1207 patients, if 50% of patients are treated with toripalimab+GemCis instead of pembrolizumab+GemCis savings of $41,589,183 provide access to 4,513 additional toripalimab maintenance cycles or 142 full toripalimab regimens (all agents for 21.4m) budget-neutrally. Similar results were demonstrated in the ASP model. Conclusions: With a market entry WAC that is 20% lower than pembrolizumab, toripalimab can generate approximate savings of $69,000 per patient over the median PFS treatment duration of 21.4m. If 50% of R/M NPC incident patients are treated with toripalimab, savings provide access to the full toripalimab+GemCis regimen to an additional 142 patients—effectively raising the treatment rate to 62% at no additional cost.
METTL3 as a potential predictive biomarker for immunotherapy response in metastatic head and neck cancer.
Authors: Arumugam Paramasivam , Jayaseelan Vijayashree Priyadharsini , Ramasubramanian Abilasha
Published: June 2024

e18019

Background: Head and neck squamous cell carcinoma (HNSCC) that has metastasized presents a significant challenge for cancer treatment, requiring innovative approaches to predict immunotherapy response. Methyltransferase-like 3 (METTL3), a key component of the m6A RNA methylation machinery, has been shown to have various roles in cancer, including its potential impact on immunotherapy responses. In this study, we aim to explore the expression and related function of METTL3 in metastatic HNSCC. Methods: We investigated the expression level and its clinicopathological significance of METTL3 using The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) datasets. Further validation of the METTL3 mRNA and protein expression were carried out with real-time PCR and Western blot on tissues from 112 cases of HNSCC patients. In addition, the functional role of METTL3 was investigated in vitro studies. The treatment response prediction values of METTL3 in metastatic HNSCC were calculated using ROC-plotter. Results: Our investigation revealed a significant overexpression of METTL3 in HNSCC tissue samples than in normal tissues ( p < 0.001). The high expression of METTL3 was significantly correlated with nodal metastasis, advanced cancer stages, and higher tumor grades in HNSCC samples, indicating that METTL3 plays an important role in driving HNSCC progression and aggressiveness. The functional study revealed intricate connections between METTL3 and immune regulatory genes expression, highlighting its potential to influence the tumor immune microenvironment. Silencing or pharmacological inhibition of METTL3 by METTL3 inhibitor STM2457 reduced tumorigenic activity through decreasing PD-L1 expression. ROC-plotter calculations showed that the high METTL3 expression predicted powerful immunotherapy (AUC=0.588, p=6.3e-06) in metastatic HNSCC patients. Conclusions: In conclusion, METTL3 appears to be a promising predictive biomarker for the response to immunotherapy in patients with metastatic HNSCC. This research provides valuable insights into the multifaceted role of METTL3 and promising therapeutic response predictor in metastatic HNSCC.
A phase II umbrella clinical trial of advanced salivary gland cancer based on molecular typing.
Authors: Ji Dongmei , Guo Yanjing , Liu Xin , Yang Yanan , Sang Youzhou , Chen Guangliang , Dong Shu , Wang Yulong , He Xiayun , Ying Hongmei , Lu Xueguan , Wang Yu , Hu Chaosu , Ji Qinghai , Zhang Lu
Published: June 2024

e18062

Background: Salivary gland cancers (SGCs) exhibit high heterogeneity in molecular and genomic characteristics, which provides a basis for targeted therapies of SGCs. Until recently, the gene targets of precision therapy drugs mainly included HER2, NTRK, TROP2, androgen-receptor (AR), etc. Herein, we report the preliminary result of a single-center, open-label, phase II umbrella clinical trial evaluating the efficacy and safety of molecular subtype-guided precision therapy for advanced salivary gland cancer (NCT05924256). Methods: Patients (pts) diagnosed as advanced SGC were recruited into 3 arms according to genetic subtypes. Pts with HER2 mutation/amplification or HER2 overexpression (IHC 3+ or IHC 2+/ISH+) will be assigned to arm 1 and receive SHR-A1811(anti-HER2) 4.8 mg/kg i.v. on day 1 of each 21-day cycle. IHC AR+ pts will be assigned to arm 2 and will receive rezvilutamide 240mg p.o. qd plus leuprolide 3.75mg s.c. on day 1 of each 28-day cycle. Pts with HER2 negative and AR negative will be assigned to arm 3 to receive SHR-A1921(anti-TROP2) 3.0 mg/kg or 4.0 mg/kg i.v. on day 1 of each 21-day cycle. A Simon’s two-stage optimal design was applied to each arm. The primary endpoint was the objective response rate (ORR) per RECIST1.1. Secondary endpoints included adverse events (AEs), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), etc. Results: Between Aug 2, 2023, and Jan 21, 2024, 21 pts were enrolled (arm 1/2/3: 9/5/7 pts, respectively). All pts were included in the safety set. In arm 1, of 6 evaluable pts, the unconfirmed ORR and DCR accounted for 100.0% and 100.0%, respectively. The most common treatment-related adverse events (TRAEs) in arm 1 were decreased lymphocyte count, neutrophil count, and decreased appetite (44.4% each). In arm 2, of 5 evaluable pts, the unconfirmed ORR and DCR were 20.0% and 100.0%, respectively. Rash, alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased (20% each) were the most common TRAEs. In arm 3, of 6 evaluable pts, the unconfirmed ORR and DCR were 33.3% and 66.7%, respectively. In this arm, the most common TRAEs were stomatitis and vomiting (42.9% each). Conclusions: This molecular subtype-guided precision therapy for advanced salivary gland cancer showed promising results with acceptable toxicity. Clinical trial information: NCT05924256 .
A first-in-human phase 1, multicenter, open-label study of CB-012, a next-generation CRISPR-edited allogeneic anti-CLL-1 CAR-T cell therapy for adults with relapsed/refractory acute myeloid leukemia (AMpLify).
Authors: Daver Naval Guastad , Maiti Abhishek , Sallman David Andrew , Roboz Gail J. , Solh Melhem M. , Milano Filippo , Strickland Stephen Anthony , Eghtedar Alireza , Kanner Steven Brian , Ledergor Guy , Marcy Donna , Garner Elizabeth , Francica Brian J. , Shaw McKay , Bird Kalin , Rattan Jennifer , Zudaire Enrique , Portella Socorro , Vachhani Pankit , Park Jae H.
Published: June 2024

TPS6586

Background: CAR-T cell therapies have shown significant clinical benefit in treating adults with many hematologic malignancies. In acute myeloid leukemia (AML), a challenge in the development of CAR-T cell therapies has been the limitation of suitable target antigens since many are also expressed on hematopoietic stem cells (HSCs). The target antigen C-type lectin-like molecule-1 (CLL-1) has emerged as an attractive therapeutic target due to its expression on AML mature blasts and leukemic stem cells and its absence on HSCs. CB-012 is an allogeneic CAR-T cell therapy that targets CLL-1. CB-012 is derived from healthy donor T cells by using Cas12a CRISPR hybrid RNA-DNA (chRDNA) technology to introduce 5 genome edits: (1) TRAC gene knockout (KO), which eliminates T cell receptor expression to reduce the risk of graft-versus-host disease, (2) site-directed insertion of a fully human anti-CLL-1 CAR into the TRAC locus, (3) KO of PD-1 to enhance antitumor activity by reducing T cell exhaustion, (4) β2-microgobulin ( B 2M) gene KO, which eliminates HLA class I presentation to mitigate host T cell-mediated rejection, and (5) site-directed insertion of a B2M–HLA-E-peptide fusion into the B 2M locus to reduce NK cell-mediated rejection. In murine xenograft models of AML, CB-012 significantly reduced the tumor burden and increased the survival of mice bearing CLL-1+PD-L1+ tumors. Methods: CB-012 is being evaluated in a multicenter, Phase 1 clinical trial in patients with relapsed/refractory (r/r) AML. A 3+3 dose escalation design is being utilized with the primary objectives to determine the safety and tolerability of CB-012 and the recommended Phase 2 dose (RP2D). An expansion phase will follow dose escalation at the recommended dose(s) for expansion. Additional objectives include preliminary antitumor activity and pharmacokinetics. Key inclusion criteria include nonproliferative disease defined as ≤25% blasts in the bone marrow and peripheral blood, ECOG performance status ≤1, and adequate organ function. After receiving lymphodepletion therapy with cyclophosphamide (750 mg/m2/d) and fludarabine (30 mg/m2/d) administered concurrently for 3 days followed by a 2-day break, patients receive a single-dose infusion of CB-012 and are followed for safety and efficacy. The dose escalation portion of the study is actively enrolling patients. The AMpLify trial is registered at clinicaltrials.gov (NCT06128044). Clinical trial information: NCT06128044 .
Time Toxicity Experienced by Early-Phase Cancer Clinical Trial Participants
Authors: Durbin Sienna M. , Lundquist Debra M. , Pelletier Andrea , Jimenez Rachel , Petrillo Laura , Kim Janice , Lynch Kaitlyn , Healy Megan , Johnson Andrew , Ollila Nicholas , Yalala Vaishnavi , Malowitz Benjamin , Kehlmann Allison , Chevalier Nicholas , Turbini Victoria , Bame Viola , Heldreth Hope , Silva Jenipher , McIntyre Casandra , Juric Dejan , Nipp Ryan D.
Published: June 2024

PURPOSE

Early-phase clinical trials (EP-CTs) are designed to determine optimal dosing, tolerability, and preliminary activity of novel cancer therapeutics. Little is known about the time that patients spend interacting with the health care system (eg, time toxicity) while participating in these studies.

METHODS

We retrospectively reviewed the electronic health records of consecutive patients enrolled in EP-CTs from 2017 to 2019 to obtain baseline characteristics and number of health care–associated days, defined as all inpatient and outpatient visits while on trial. We used univariable and multivariable analyses to identify predictors of increased time toxicity, defined as the proportion of health care–associated days among total days on trial. For ease of interpretation, we created a dichotomous variable, with high time toxicity defined as ≥20% health care–associated days during time on trial and used regression models to evaluate relationships between time toxicity and clinical outcomes.

RESULTS

Among 408 EP-CT participants (mean age, 60.5 years [standard deviation, SD, 12.6]; 56.5% female; 88.2% White; 96.0% non-Hispanic), patients had an average of 22.5% health care–associated days while on trial (SD, 13.8%). Those with GI ( B = 0.07; P = .002), head/neck ( B = 0.09; P = .004), and breast ( B = 0.06; P = .015) cancers and those with worse performance status ( B = 0.04; P = .017) and those receiving targeted therapies ( B = 0.04; P = .014) experienced higher time toxicity. High time toxicity was associated with decreased disease response rates (odds ratio, 0.07; P < .001), progression-free survival (hazard ratio [HR], 2.10; P < .001), and overall survival (HR, 2.16; P < .001).

CONCLUSION

In this cohort of EP-CT participants, patients spent more than one-fifth of days on trial with health care contact. We identified characteristics associated with higher time toxicity and found that high toxicity correlated with worse clinical outcomes. These data could help inform patient-clinician discussions about EP-CTs, guide future trial design, and identify at-risk patients.
Respect for the Patient-Oncologist Relationship May Limit Serious Illness Communication by Acute and Postacute Care Clinicians After Discharge to a Skilled Nursing Facility
Authors: Singh Sarguni , Dafoe Ashley , Cagle John , Messersmith Wells A. , Kessler Elizabeth R. , Lum Hillary D. , Holliman Brooke Dorsey , Fischer Stacy
Published: June 2024

PURPOSE

There is a need to increase palliative care access for hospitalized older adults with cancer discharged to a skilled nursing facility (SNF) at risk of poor outcomes. Assessing and Listening to Individual Goals and Needs (ALIGN) is a palliative care intervention developed to address this gap. This study gathered perspectives from clinicians across care settings to describe perceptions on serious illness communication and care coordination for patients with cancer after discharge to a SNF to guide ALIGN refinements.

METHODS

We conducted 37 semistructured interviews with clinicians and leaders in hospital medicine (n = 12), oncology (n = 9), palliative care (n = 12), home health care (n = 6), and hospice (n = 4). Some participants had experience working in more than one specialty. The Practical Robust Implementation and Sustainability Model framework was used to develop the interview guide that explored barriers to care, prognosis discussions, and hospice recommendations. Interviews were coded and analyzed using thematic content analysis.

RESULTS

Analysis identified four themes: (1) discharge to a SNF is recognized as a time of worsening prognosis; (2) care silos create communication and information barriers during a period of increasing palliative care need; (3) family caregiver distress escalates following care transitions; and (4) lack of clarity of roles and respect for the patient-oncologist relationship limits prognostic communication and changes in focus of treatment.

CONCLUSION

These findings suggest that acute and postacute care clinicians defer serious illness conversations to the oncologist when patients are on a steep trajectory of decline, experiencing multiple care transitions, and may have limited contact with their oncologist. There is a need to clarify roles among nononcology and oncology clinicians in discussing prognosis and recommending hospice for older adults discharged to SNF.
Common and Uncommon Mouse Models of Growth Hormone Deficiency
Authors: List Edward O , Basu Reetobrata , Berryman Darlene E , Duran-Ortiz Silvana , Martos-Moreno Gabriel Á , Kopchick John J
Published: June 2024

Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the 5 “common” mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity. Since these common mouse lines outlive their normal-sized littermates—and have protection from age-associated disease—they have become important fixtures in the aging field. On the other hand, the 12 “uncommon” mouse models of GHD described herein have tremendously divergent health outcomes ranging from beneficial aging phenotypes (similar to those described for the common models) to extremely detrimental features (such as improper development of the central nervous system, numerous sensory organ defects, and embryonic lethality). Moreover, advancements in next-generation sequencing technologies have led to the identification of an expanding array of genes that are recognized as causative agents to numerous rare syndromes with concomitant GHD. Accordingly, this review provides researchers with a comprehensive up-to-date collection of the common and uncommon mouse models of GHD that have been used to study various aspects of physiology and metabolism associated with multiple forms of GHD. For each mouse line presented, the closest comparable human syndromes are discussed providing important parallels to the clinic.
Dysregulated Urinary Extracellular Vesicle Small RNAs in Diabetic Nephropathy: Implications for Diagnosis and Therapy
Authors: Ali Hamad , Malik Md Zubbair , Abu-Farha Mohamed , Abubaker Jehad , Cherian Preethi , Al-Khairi Irina , Nizam Rasheeba , Jacob Sindhu , Bahbahani Yousif , Al Attar Abdulnabi , Thanaraj Thangavel Alphonse , Al-Mulla Fahd
Published: June 2024

Background

Diabetic nephropathy (DN) represents a major chronic kidney disorder and a leading cause of end-stage renal disease (ESRD). Small RNAs have been showing great promise as diagnostic markers as well as drug targets. Identifying dysregulated micro RNAs (miRNAs) could help in identifying disease biomarkers and investigation of downstream interactions, shedding light on the molecular pathophysiology of DN. In this study, we analyzed small RNAs within human urinary extracellular vesicles (ECVs) from DN patients using small RNA next-generation sequencing.

Method

In this cross-sectional study, urine samples were collected from 88 participants who were divided into 3 groups: type 2 diabetes (T2D) with DN (T2D + DN, n = 20), T2D without DN (T2D − DN, n = 40), and healthy individuals (n = 28). The study focused on isolating urinary ECVs to extract and sequence small RNAs. Differentially expressed small RNAs were identified, and a functional enrichment analysis was conducted.

Results

The study revealed a distinct subset of 13 miRNAs and 10 Piwi-interacting RNAs that were significantly dysregulated in urinary ECVs of the DN group when compared to other groups. Notably, miR-151a-3p and miR-182-5p exhibited a unique expression pattern, being downregulated in the T2D − DN group, and upregulated in the T2D + DN group, thus demonstrating their effectiveness in distinguishing patients between the 2 groups. Eight driver genes were identified PTEN, SMAD2, SMAD4, VEGFA, CCND2, CDK6, LIN28B, and CHD1.

Conclusion

Our findings contribute valuable insights into the pathogenesis of DN, uncovering novel biomarkers and identifying potential therapeutic targets that may aid in managing and potentially decelerating the progression of the disease.
BirthSeq, a new method to isolate and analyze dated cells in different vertebrates
Authors: Rueda-Alaña Eneritz , Grillo Marco , Vázquez Enrique , Salas Sergio Marco , Senovilla-Ganzo Rodrigo , Escobar Laura , Quintas Ana , Benguría Alberto , Aransay Ana María , Bengoa-Vergniory Nora , Dopazo Ana , Encinas Juan Manuel , Nilsson Mats , García-Moreno Fernando
Published: June 2024

Embryonic development is a complex and dynamic process that unfolds over time and involves the production and diversification of increasing numbers of cells. The impact of developmental time on the formation of the central nervous system is well documented, with evidence showing that time plays a crucial role in establishing the identity of neuronal subtypes. However, the study of how time translates into genetic instructions driving cell fate is limited by the scarcity of suitable experimental tools. We introduce BirthSeq, a new method for isolating and analyzing cells based on their birth date. This innovative technique allows for in vivo labeling of cells, isolation via fluorescence-activated cell sorting, and analysis using high-throughput techniques. We calibrated the BirthSeq method for developmental organs across three vertebrate species (mouse, chick and gecko), and utilized it for single-cell RNA sequencing and novel spatially resolved transcriptomic approaches in mouse and chick, respectively. Overall, BirthSeq provides a versatile tool for studying virtually any tissue in different vertebrate organisms, aiding developmental biology research by targeting cells and their temporal cues.
Quantitative proteomics reveals insights into the assembly of IFT trains and ciliary assembly
Authors: Shao Shangjin , Chen Yuling , Deng Haiteng , Pan Junmin
Published: June 2024

Intraflagellar transport (IFT) is required for ciliary assembly. The IFT machinery comprises the IFT motors kinesin-2 and IFT dynein plus IFT-A and IFT-B complexes, which assemble into IFT trains in cilia. To gain mechanistic understanding of IFT and ciliary assembly, here, we performed an absolute quantification of IFT machinery in Chlamydomonas reinhardtii cilium. There are ∼756, ∼532, ∼276 and ∼350 molecules of IFT-B, IFT-A, IFT dynein and kinesin-2, respectively, per cilium. The amount of IFT-B is sufficient to sustain rapid ciliary growth in terms of tubulin delivery. The stoichiometric ratio of IFT-B:IFT-A:dynein is ∼3:2:1 whereas the IFT-B:IFT-A ratio in an IFT dynein mutant is 2:1, suggesting that there is a plastic interaction between IFT-A and IFT-B that can be influenced by IFT dynein. Considering diffusion of kinesin-2 during retrograde IFT, it is estimated that one kinesin-2 molecule drives eight molecules of IFT-B during anterograde IFT. These data provide new insights into the assembly of IFT trains and ciliary assembly.
Frailty Increases Morbidity and Mortality in Patients Undergoing Oncological Liver Resections: A Systematic Review and Meta-analysis
Authors: Lunca Sorinel , Morarasu Stefan , Rouet Kevin , Ivanov Andreea Antonina , Morarasu Bianca Codrina , Roata Cristian Ene , Clancy Cillian , Dimofte Gabriel-Mihail
Published: June 2024

Background

Considered to reflect a patients’ biological age, frailty is a new syndrome shown to predict surgical outcomes in elderly patients. In view of the increasing age at which patients are proposed oncological liver surgery and the morbidity associated with it, we attempted to perform a systematic review and meta-analysis to compare morbidity and mortality between frail and nonfrail patients after liver resections.

Methods

The study was registered with PROSPERO. A systematic search of PubMed and EMBASE databases was performed for all comparative studies examining surgical outcomes after liver resections between frail and nonfrail patients.

Results

Ten studies were included based on the selection criteria with a total of 71,102 patients, split into two groups: frail (n = 17,167) and the control group (n = 53,928). There were more elderly patients with a lower preoperative albumin level in the frail group (p = 0.02, p = 0.001). Frail patients showed higher rates of morbidity with more major complications and a higher incidence of postoperative liver failure (p < 0.001). Mortality (p < 0.001) and readmission rate (p = 0.021) also was higher in frail patients.

Conclusions

Frailty seems to be a solid predictive risk factor of morbidity and mortality after liver surgery and should be considered a selection criterion for liver surgery in at-risk patients.
Hamstrings Hypertrophy Is Specific to the Training Exercise: Nordic Hamstring versus Lengthened State Eccentric Training
Authors: MAEO SUMIAKI , BALSHAW THOMAS G. , NIN DARREN Z. , MC DERMOTT EMMET J. , OSBORNE THOMAS , COOPER NAOMI B. , MASSEY GARRY J. , KONG PUI W. , PAIN MATTHEW T. G. , FOLLAND JONATHAN P.
Published: June 2024

Introduction

The hamstring muscles play a crucial role in sprint running but are also highly susceptible to strain injuries, particularly within the biceps femoris long head (BFlh). This study compared the adaptations in muscle size and strength of the knee flexors, as well as BFlh muscle and aponeurosis size, after two eccentrically focused knee flexion training regimes: Nordic hamstring training (NHT) vs lengthened state eccentric training (LSET, isoinertial weight stack resistance in an accentuated hip-flexed position) vs habitual activity (no training controls: CON).

Methods

Forty-two healthy young males completed 34 sessions of NHT or LSET over 12 wk or served as CON (n = 14/group). Magnetic resonance imaging-measured muscle volume of seven individual knee flexors and BFlh aponeurosis area, and maximum knee flexion torque during eccentric, concentric, and isometric contractions were assessed pre- and post-training.

Results

LSET induced greater increases in hamstrings (+18% vs +11%) and BFlh (+19% vs +5%) muscle volumes and BFlh aponeurosis area (+9% vs +3%) than NHT (all P ≤ 0.001), with no changes after CON. There were distinctly different patterns of hypertrophy between the two training regimes, largely due to the functional role of the muscles; LSET was more effective for increasing the size of knee flexors that also extend the hip (2.2-fold vs NHT), whereas NHT increased the size of knee flexors that do not extend the hip (1.9-fold vs LSET; both P ≤ 0.001). Changes in maximum eccentric torque differed only between LSET and CON (+17% vs +4%; P = 0.009), with NHT (+11%) inbetween.

Conclusions

These results suggest that LSET is superior to NHT in inducing overall hamstrings and BFlh hypertrophy, potentially contributing to better sprint performance improvements and protection against hamstring strain injuries than NHT.
Impact of coenzyme Q10 as an adjuvant therapy to letrozole on spermiogram results and sex hormone levels in Iraqi men with infertility; randomized open label comparative study
Authors: Fadhil Essa Bahauldeen , Mohammed ‎ Mohammed Mahmood , Alkawaz Ula M.
Published: June 2024

Background: Worldwide, infertility affects about 15% of reproductive-age couples. In many cases, infertility can't be treated, however new treatment options with promising value have been involved in recent clinical trials. The aim of this clinical trial was to evaluate the impacts of adding coenzyme Q10 (CoQ10) to letrozole on the results of spermiogram and sex hormone tests in men diagnosed with idiopathic oligoasthenoteratozoospermia (iOAT) syndrome, which is a type of male defective spermatogenesis of unknown etiology. Methods: This randomized, open-label, parallel two-arm interventional study included 67 adult male patients aged 18-60 years with a confirmed diagnosis of iOAT syndrome recruited from The High Institute for Infertility Diagnosis & Assisted Reproduction Technologies/Nahrain University. Patients were randomly separated into two groups, Group A included 29 patients treated with letrozole 2.5 mg tablet orally twice a week, Group B included 38 patients treated with a combination of letrozole 2.5 mg tablet orally twice a week plus CoQ10 400 mg per day. Both groups completed treatment for three months. Semen samples, serum follicle-stimulating hormone (FSH), estradiol (E2), and testosterone (T) were analyzed at day one, and at the end of month one, two and three. Results: Both groups showed that sperm concentration, normal morphology, total sperm count and motility, serum testosterone and FSH levels, and T/E2 ratio were significantly increased, while estradiol levels significantly decreased after three months of treatment. Seminal fluid volume changed significantly in group A only. In comparing between the two groups, all measured parameters, apart from sperm motility and FSH level, demonstrated a significant difference after three months of treatment, while sperm volume reached significant value after only two months of therapy. Conclusions: CoQ10 as adjuvant treatment to letrozole effectively improved most of the tested sperm parameters in Iraqi men with iOAT. Registration: ClinicalTrials.gov (NCT05847257, May 6, 2023).
The Aquatic Symbiosis Genomics Project: probing the evolution of symbiosis across the Tree of Life
Authors: McKenna Victoria , Archibald John M. , Beinart Roxanne , Dawson Michael N. , Hentschel Ute , Keeling Patrick J. , Lopez Jose V. , Martín-Durán José M. , Petersen Jillian M. , Sigwart Julia D. , Simakov Oleg , Sutherland Kelly R. , Sweet Michael , Talbot Nick , Thompson Anne W. , Bender Sara , Harrison Peter W. , Rajan Jeena , Cochrane Guy , Berriman Matthew , Lawniczak Mara K.N. , Blaxter Mark
Published: June 2024

We present the Aquatic Symbiosis Genomics Project, a global collaboration to generate high quality genome sequences for a wide range of eukaryotes and their microbial symbionts. Launched under the Symbiosis in Aquatic Systems Initiative of the Gordon and Betty Moore Foundation, the ASG Project brings together researchers from across the globe who hope to use these reference genomes to augment and extend their analyses of the dynamics, mechanisms and environmental importance of symbioses. Applying large-scale, high-throughput sequencing and assembly technologies, the ASG collaboration will assemble and annotate the genomes of 500 symbiotic organisms – both the “hosts” and the microbial symbionts with which they associate. These data will be released openly to benefit all who work on symbioses, from conservation geneticists to those interested in the origin of the eukaryotic cell.