bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of a predictive model for pulmonary infection risk in patients with traumatic brain injury in the ICU: a retrospective cohort study based on MIMIC-IV
Authors: Shi Yulin , Hu Yong , Xu Guo Meng , Ke Yaoqi 
Published: August 2024

ObjectiveTo develop a nomogram for predicting occurrence of secondary pulmonary infection in patients with critically traumatic brain injury (TBI) during their stay in the intensive care unit, to further optimise personalised treatment for patients and support the development of effective, evidence-based prevention and intervention strategies.Data sourceThis study used patient data from the publicly available MIMIC-IV (Medical Information Mart for Intensive Care IV) database.DesignA population-based retrospective cohort study.MethodsIn this retrospective cohort study, 1780 patients with TBI were included and randomly divided into a training set (n=1246) and a development set (n=534). The impact of pulmonary infection on survival was analysed using Kaplan-Meier curves. A univariate logistic regression model was built in training set to identify potential factors for pulmonary infection, and independent risk factors were determined in a multivariate logistic regression model to build nomogram model. Nomogram performance was assessed with receiver operating characteristic (ROC) curves, calibration curves and Hosmer-Lemeshow test, and predictive value was assessed by decision curve analysis (DCA).ResultThis study included a total of 1780 patients with TBI, of which 186 patients (approximately 10%) developed secondary lung infections, and 21 patients died during hospitalisation. Among the 1594 patients who did not develop lung infections, only 85 patients died (accounting for 5.3%). The survival curves indicated a significant survival disadvantage for patients with TBI with pulmonary infection at 7 and 14 days after intensive care unit admission (p<0.001). Both univariate and multivariate logistic regression analyses showed that factors such as race other than white or black, respiratory rate, temperature, mechanical ventilation, antibiotics and congestive heart failure were independent risk factors for pulmonary infection in patients with TBI (OR>1, p<0.05). Based on these factors, along with Glasgow Coma Scale and international normalised ratio variables, a training set model was constructed to predict the risk of pulmonary infection in patients with TBI, with an area under the ROC curve of 0.800 in the training set and 0.768 in the validation set. The calibration curve demonstrated the model’s good calibration and consistency with actual observations, while DCA indicated the practical utility of the predictive model in clinical practice.ConclusionThis study established a predictive model for pulmonary infections in patients with TBI, which may help clinical doctors identify high-risk patients early and prevent occurrence of pulmonary infections.
Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy
Authors: Nakamura Motoki , Magara Tetsuya , Yoshimitsu Maki , Kano Shinji , Kato Hiroshi , Yokota Keisuke , Okuda Katsuhiro , Morita Akimichi 
Published: August 2024

BackgroundEnhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear.MethodsWe conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs.ResultsInhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer).ConclusionG6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.
Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study
Authors: Overman Michael J , Gelsomino Fabio , Aglietta Massimo , Wong Mark , Limon Miron Maria Luisa , Leonard Gregory , García-Alfonso Pilar , Hill Andrew G , Cubillo Gracian Antonio , Van Cutsem Eric , El-Rayes Bassel , McCraith Stephen M , He Beilei , Lei Ming , Lonardi Sara 
Published: August 2024

BackgroundProgrammed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study.MethodsIn this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR).ResultsA total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9–49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3–33.1) months, and median duration of response was 42.7 (range 2.8–47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported.ConclusionsNivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC.Trial registration numberNCT02060188.
Intensive care unit interventions to improve quality of dying and death: scoping review
Authors: Naya Kazuaki , Sakuramoto Hideaki , Aikawa Gen , Ouchi Akira , Oyama Yusuke , Tanaka Yuta , Kaneko Kentaro , Fukushima Ayako , Ota Yuma 
Published: August 2024

BackgroundIntensive care units (ICUs) have mortality rates of 10%–29% owing to illness severity. Postintensive care syndrome-family affects bereaved relatives, with a prevalence of 26% at 3 months after bereavement, increasing the risk for anxiety and depression. Complicated grief highlights issues such as family presence at death, inadequate physician communication and urgent improvement needs in end-of-life care. However, no study has comprehensively reviewed strategies and components of interventions to improve end-of-life care in ICUs.AimThis scoping review aimed to analyse studies on improvement of the quality of dying and death in ICUs and identify interventions and their evaluation measures and effects on patients.MethodsMEDLINE, CINAHL, PsycINFO and Central Journal of Medicine databases were searched for relevant studies published until December 2023, and their characteristics and details were extracted and categorised based on the Joanna Briggs model.ResultsA total of 24 articles were analysed and 10 intervention strategies were identified: communication skills, brochure/leaflet/pamphlet, symptom management, intervention by an expert team, surrogate decision-making, family meeting/conference, family participation in bedside rounds, psychosocial assessment and support for family members, bereavement care and feedback on end-on-life care for healthcare workers. Some studies included alternative assessment by family members and none used patient assessment of the intervention effects.ConclusionThis review identified 10 intervention strategies to improve the quality of dying and death in ICUs. Many studies aimed to enhance the quality by evaluating the outcomes through proxy assessments. Future studies should directly assess the quality of dying process, including symptom evaluation of the patients.
Absolute lymphocyte count as a biomarker for best supportive care transition in metastatic breast cancer
Authors: Horimoto Yoshiya , Jimbo Hikari , Ishizuka Yumiko , Nogami Noriko , Kutomi Goro , Watanabe Junichiro 
Published: August 2024

ObjectivesTime is crucial for patients with metastatic breast cancer (MBC), and clinicians are expected to determine the optimal timing for best supportive care (BSC) transition but no evident marker has been established. We recently revealed that absolute lymphocyte count (ALC) was a prognostic marker for patients with MBC. Thus, we investigated whether ALC could be an indicator of the best timing for the BSC transition.Methods101 patients with MBC were retrospectively investigated, and the relationship between clinicopathological factors, including ALC, and the duration of the last treatment was analysed.ResultsMean ALC significantly gradually decreased during the last three systemic treatments towards BSC transition. Patients of younger age, with special histology type, hormone receptor-positive tumours and low ALC at the start of the last treatment had significantly shorter time-to-treatment-termination (TTT) for the last treatment. When ALC was classified into low and high, the mean TTT of the last treatment in the ALC-low group was significantly shorter (16.4 weeks) compared with that in the ALC-high group (30.2 weeks; p=0.004).ConclusionsOur data suggest that ALC values, which decrease as MBC progresses, could serve as a potential indicator for determining the optimal timing of BSC transition.
Transcoding V-PCC Point Cloud Streams in Real-time
Authors: Rudolph Michael , Schneegass Stefan , Rizk Amr 
Published: August 2024

Dynamic Point Clouds are a representation for 3D immersive media that allows users to freely navigate a scene while consuming the content. However, this comes at the cost of substantial data size, requiring efficient compression techniques to make point cloud videos accessible. Addressing this, Video-based Point Cloud Compression (V-PCC) projects points into 2D patches to compress video frames, leveraging the high compression efficiency of legacy video codecs and exploiting temporal correlations in the 2D images. However, clustering and projecting points into meaningful 2D patches is computationally intensive, leading to high encoding latency in V-PCC. Applying adaptive streaming techniques, originating from traditional video streaming, multiplies the computational effort as multiple encodings of the same content are required. In this light, transcoding a compressed representation into lower qualities for dynamic adaptation to user requirements is gaining popularity.
To address the high latency when employing the full decoder-encoder stack of V-PCC during transcoding, we propose RABBIT, a novel technique that only re-encodes the underlying video sub-streams. This is in contrast to slow V-PCC transcoding that reconstructs and re-encodes the raw point cloud at a new quality setting. By eliminating expensive overhead resulting from calculations based on the 3D space representation, the latency of RABBIT is bounded by the latency of transcoding the underlying video streams, allowing optimized video codec implementations to be used to meet the real time requirements of adaptive streaming systems. Our evaluations of RABBIT, using various optimized video codec implementations, shows on-par quality with the baseline V-PCC transcoding given a high-quality representation. Given unicast or multicast distribution of a point cloud stream and in-network or edge transcoders, our evaluations show the tradeoff between rate-distortion performance and the required network bandwidth.
Modernizing the NCI60 Cell Line Screen for Phenotypic Drug Discovery in the 21st Century
Authors: Colombo Gianna M. , Corsello Steven M. 
Published: August 2024

Over the past three decades, high-throughput phenotypic cancer cell line screens have revealed unanticipated small-molecule activities and illuminated connections between tumor genotypes and anticancer efficacy. Founded in 1984, the National Cancer Institute’s “NCI60” screen laid the conceptual groundwork for the contemporary landscape of phenotypic drug discovery. NCI60 first operated as a primary bioactivity screen, but molecular characterization of the NCI60 cell line panel and development of a small-molecule sensitivity pattern recognition algorithm (called “COMPARE”) have enabled subsequent studies into drug mechanisms of action and biomarker identification. In this issue of Cancer Research, Kunkel and colleagues report an updated version of the NCI60 screen, dubbed “HTS384” NCI60, that better aligns with current cell proliferation assay standards and has higher throughput. Changes include the use of a 384-well plate format, automated laboratory equipment, 3 days of compound exposure, and a CellTiter-Glo luminescent endpoint. To confirm that data from the HTS384 and classic NCI60 screen are comparable, the authors tested a library of 1,003 anticancer agents using both protocols and applied COMPARE to analyze patterns of cell line sensitivities. More than three dozen groups of targeted therapies showed high comparability between screens. Modernization of NCI60, and closer integration with other large-scale pharmacogenomic screens and molecular feature sets, will help this public screening service remain pertinent for cancer drug discovery efforts for years to come.See related article by Kunkel et al., p. 2403
Discovery of RGT-018: A Potent, Selective, and Orally Bioavailable SOS1 Inhibitor for KRAS-Driven Cancers
Authors: Xiao Fei , Wang Kailiang , Wang Xinjuan , Li Huijuan , Hu Zhilong , Ren Xiaoming , Huang Wei , Feng Teng , Yao Lili , Lin Jing , Li Chunlai , Zhang Zhuanzhuan , Mei Liufeng , Zhu Xiaotian , Zhong Wenge , Xie Zhi 
Published: August 2024

Abstract
KRAS is the most frequently dysregulated oncogene with a high prevalence in non–small cell lung cancer, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for patients with cancer with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein of Son of Sevenless 1 (SOS1). SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small-molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single-digit nanomoles per liter potency and was highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced antiproliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR, or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combinations with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.
Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma
Authors: Behrmann Catherine A. , Ennis Kelli N. , Sarma Pranjal , Wetzel Collin , Clark Nicholas A. , Von Handorf Kate M. , Vallabhapurapu Subrahmanya , Andreani Cristina , Reigle James , Scaglioni Pier Paolo , Meller Jarek , Czyzyk-Krzeska Maria F. , Kendler Ady , Qi Xiaoyang , Sarkaria Jann N. , Medvedovic Mario , Sengupta Soma , Dasgupta Biplab , Plas David R. 
Published: August 2024

Abstract

Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis. Genetic inactivation studies to map the signaling network indicated that both S6K1 and S6K2 transmit growth signals in PTEN-deficient GBM. Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM.

Significance:
Therapy for glioblastoma would be advanced by incorporating molecularly targeted kinase-directed agents, similar to standard of care strategies in other tumor types. Here, we identify a kinase targeting approach to inhibit the metabolism and growth of glioblastoma.
Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling
Authors: Banerjee Richa , Knauer Luz A. , Iyer Drishya , Barlow Sara E. , Shalaby Hanan , Dehghan Razieh , Scallan Joshua P. , Yang Ying 
Published: August 2024

BACKGROUND:
Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation.

METHODS:

In vivo and in vitro techniques were used to investigate the role of
Rictor
, a critical component of mTORC2, in lymphatic endothelium.

RESULTS:

Here, we showed that embryonic and postnatal lymphatic deletion of
Rictor
, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels.
RICTOR
knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in
Rictor
knockout mesenteric lymphatic endothelial cells in vivo. Deletion of
Foxo1
in
Rictor
knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery.

CONCLUSIONS:
Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.
Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD
Authors: Shulman Rachel S. , Yang Wei , Cohen Debbie L. , Reese Peter P. , Cohen Jordana B. ,   the CRIC Study Investigators
Published: August 2024

BACKGROUND:
In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications.

METHODS:
Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up.

RESULTS:
A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80–1.11]) or mortality (aHR, 1.06 [95% CI, 0.88–1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63–0.97]) and mortality (aHR, 0.64 [95% CI, 0.48–0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14–0.86]).

CONCLUSIONS:
Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.