bluuebunny/crossref_metadata_2025 huggingface dataset:
The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer
Authors: Kumarasamy Vishnu , Wang Jianxin , Frangou Costakis , Wan Yin , Dynka Andrew , Rosenheck Hanna , Dey Prasenjit , Abel Ethan V. , Knudsen Erik S. , Witkiewicz Agnieszka K.
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed the response to pharmacologic inhibition of KRAS, the central oncogenic driver of PDAC. In a panel of PDAC cell lines, inhibition of KRASG12D with MRTX1133 yielded variable efficacy in suppressing cell growth and downstream gene expression programs in 2D cultures. On the basis of CRISPR-Cas9 loss-of-function screens, ITGB1 was identified as a target to enhance the therapeutic response to MRTX1133 by regulating mechanotransduction signaling and YAP/TAZ expression, which was confirmed by gene-specific knockdown and combinatorial drug synergy. Interestingly, MRTX1133 was considerably more efficacious in 3D cell cultures. Moreover, MRTX1133 elicited a pronounced cytostatic effect in vivo and controlled tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition led to tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicated that MRTX1133-mediated KRAS inhibition enhanced IFNγ signaling and induced antigen presentation that modulated the tumor microenvironment. Further investigation of the immunologic response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and -extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of patients with PDAC.

Significance:

Pharmacologic inhibition of KRAS elicits varied responses in pancreatic cancer 2D cell lines, 3D organoid cultures, and xenografts, underscoring the importance of mechanotransduction and the tumor microenvironment in regulating therapeutic responses.
Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M.
Published: January 2024

Purpose:

We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models.

Experimental Design:

We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis.

Results:

Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest.

Conclusions:

Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.
Model-Informed Clinical Pharmacology Profile of a Novel Fixed-Dose Combination of Nivolumab and Relatlimab in Adult and Adolescent Patients with Solid Tumors
Authors: Zhao Yue , Hu Zheyi , Bathena Sai Praneeth , Keidel Sarah , Miller-Moslin Karen , Statkevich Paul , Bello Akintunde , Roy Amit , Suryawanshi Satyendra
Published: January 2024

Purpose:

Progression-free survival (PFS) was significantly improved with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination (FDC) every 4 weeks (Q4W) versus nivolumab alone in patients with previously untreated advanced melanoma in RELATIVITY-047. In addition, RELATIVITY-020 (Part D) demonstrated a manageable safety profile and potential for durable response with nivolumab plus relatlimab in previously treated patients. Here, we evaluate the clinical pharmacology profile (CPP) of nivolumab plus relatlimab to support the approved regimen for adult and adolescent patients with advanced melanoma and its continued clinical development in solid tumors.

Experimental Design:

The pharmacokinetics (PK) and immunogenicity of relatlimab and nivolumab were assessed using data from RELATIVITY-047 and RELATIVITY-020. Patients with advanced solid tumors received relatlimab alone or nivolumab plus relatlimab as single-agent vials (SAV) or FDC. PK was characterized using a population PK (popPK) model.

Results:

Relatlimab demonstrated nonlinear and time-varying PK. Nonlinearity in relatlimab PK represented approximately 31% of total CL of relatlimab 160 mg Q4W. Relatlimab PK was dose proportional at doses ≥160 mg Q4W. Geometric mean exposures were similar for SAV and FDC cohorts receiving equivalent dosing regimens. No dose adjustment was required for covariates. Incidence of relatlimab antidrug antibodies was <6% for nivolumab plus relatlimab and had no clinically meaningful impact. There was no PK-related drug interaction of nivolumab plus relatlimab.

Conclusions:

The CPP of relatlimab alone or in combination with nivolumab supports the approved dosing in advanced melanoma and the continued evaluation of nivolumab and relatlimab across other solid tumors.

See related commentary by Gopalakrishnan and Amaria, p. 2862
Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A
Authors: Huang Dan , Wu Zhipeng , Wu Zhengyi , Li Nuoya , Hao Liang , Li Kuangfan , Zeng Junquan , Qiu Bingbing , Zhang Shouhua , Yan Jinlong
Published: January 2024

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.
First Co-Occurrence of Griscelli Syndrome Type 2 and Neurofibromatosis Type 1
Authors: Kendir-Demirkol Yasemin , Yeter Burcu , Yararbaş Kanay
Published: January 2024

Introduction: Griscelli syndrome type 2 (GS2) and neurofibromatosis type 1 (NF1) are both rare genetic disorders, but their coexistence has not been documented prior to this report. Case Presentation: We present the case of a 4-year-old girl initially diagnosed with GS2 due to albinism and immunodeficiency, and later with NF1, manifested by the development of multiple café-au-lait macules (CALMs) and MRI findings. The patient was the second child of consanguineous parents and exhibited symptoms early, with silver-gray hair at birth and subsequent health complications at 9 months. GS2 was confirmed via the identification of a homozygous frameshift variant in the RAB27A gene, and a de novo heterozygous splice site mutation in the NF1 gene established the NF1 diagnosis. Her treatment included hematopoietic stem cell transplantation and ongoing surveillance for NF1-associated complications. Discussion/Conclusion: This case emphasizes the importance of considering the potential for concurrent rare genetic diseases in clinical evaluations, especially with progressive or evolving symptomatology.
Sleep and 24-H Activity Rhythms and the Risk of Stroke: A Prospective Cohort Study
Authors: Hoepel Sanne J.W. , Berghout Bernhard P. , Luik Annemarie I. , Ikram M.Kamran
Published: January 2024

Introduction: Short and long self-reported sleep durations are associated with a higher risk of stroke, but the association between objective estimates of sleep and 24-h activity rhythms is less clear. We studied the association of actigraphy-estimated sleep and 24-h activity rhythms with the risk of stroke in a population-based cohort of middle-aged and elderly. Methods: We included 1,718 stroke-free participants (mean age 62.2 ± 9.3 years, 55.1% women) from the prospective, population-based Rotterdam Study. Actigraphy-estimated sleep (total sleep time, sleep efficiency, sleep onset latency, and wake after sleep onset) and 24-h activity rhythms (interdaily stability, intradaily variability, and onset of the least active 5 h) were measured during a median of 7 days (Q1–Q3: 6–7 days). The association of sleep and 24-h activity rhythms with risk of stroke was analyzed using Cox proportional hazards models. Results: During a mean follow-up of 12.2 years (SD: 3.2), 105 participants developed a stroke, of whom 81 had an ischemic event. Although there was no clear association between actigraphy-estimated sleep and the risk of stroke, a more fragmented 24-h activity rhythm was associated with a higher risk of stroke (hazard ratio [HR] per SD increase 1.28, 95% confidence interval [CI] 1.07–1.53). A less stable (HR per SD increase in stability 0.78, 95% CI: 0.63–0.97) and more fragmented (HR 1.28, 95% CI: 1.04–1.58) 24-h activity rhythm was also associated with a higher risk of ischemic stroke. Conclusions: Disturbed 24-h activity rhythms, but not sleep, are associated with a higher risk of stroke in middle-aged and elderly persons. This suggests that unstable and fragmented activity rhythms may play a more prominent role in the risk of stroke than sleep per se.
A novel solar PV integrated fuzzy-logic controlled UAPQC device for power quality enhancement
Authors: Rao Lingineni Shanmukha , Sharma Pidatala Prabhakara , Shankar Maddiguntla Bhavani , Sakethnath Sakila Venkata , Kumar Govindu Bharat
Published: January 2024

A novel solar photovoltaics (PV) connected unified active power quality conditioner (UAPQC) device is extensively adopted for enhancing the voltage and current quality of the distribution system. In a three-phase distribution system, the proposed UAPQC mitigates both load-side and source-side allied power quality (PQ) issues. Furthermore, as part of the distributed generation (DG) system, active electricity from solar PV is injected into the grid or source when solar PV is available. In this regard, the proposed UAPQC has been operated by using a workable control method, in both PQ improvement mode and DG incorporation mode. The direct current-link (DC-link) control of the shunt voltage source inverter (VSI) utilizes the proportional-integral controller, which is not suited for the regulation of DC-link voltage at the desired level because of improper selection of gain values. In this work, an intelligent fuzzy-logic DC-link control of UAPQC evidences the intelligent knowledge base for better regulation of power-quality issues. The suggested fuzzy-logic controlled UAPQC device's performance for both PQ improvement and integration of DG is validated using the MATLAB/Simulink computing tool, and simulation findings are given with an appealing comparison analysis.
Quantized consensus of finite-level multi-agent networked systems
Authors: Nuga Olubusola Olufunke , Amusa Kamoli Akinwale , Olanipekun Ayorinde Joseph , Matthew Simeon
Published: January 2024

In this paper, analysis of a quantized consensus finite-level multi-agent networked system is considered. Logarithmic quantizer is utilized for the transmission of the state of the networked agents. Two protocols employed in the investigation are, the consensus protocol which is determined from the outputs and states of a set of encoder-decoder pair, and the convergence rate protocol that is precisely characterized using a dynamic scaling factor. The asymptotic consensus can be reached through information exchange among neighbour agents. Validity of the protocols for the connected network system is established through careful selection of parameters of the quantizer. A four-agent networked system is used to illustrate the implementation of the protocols. Obtained result showed that information exchange in an undirected networked system is achievable through a communication channel equipped with encoder and decoder pairs. More so, the desired asymptotic convergence is achievable through careful choice of the parameters of the quantizer.
Detecting and identifying occluded and camouflaged objects in low-illumination environments
Authors: Bakshi Gaytri , Aggarwal Alok
Published: January 2024

One of the prevailing areas of contemporary research involves the differentiation and identification of diverse objects within a given scene through automated systems. The field of study under consideration presents a multitude of obstacles, including but not limited to issues such as diminished lighting conditions, occlusion, and camouflage. The captured image exhibits variations in illumination, resulting in uneven brightness, reduced contrast, and the presence of noise. The fundamental basis of computer vision algorithms lies in the process of extracting features from datasets and subsequently discerning these features through neural networks. The task of extracting distinct feature key points from images captured under low lighting conditions is exceedingly challenging. To address this issue, the present study seeks to employ deep learning models to implement image enhancement techniques specifically designed for low-light conditions. The primary emphasis lies in obtaining key feature points that are differentiable, thereby enabling the utilization of this annotated data for specific tasks such as object detection. The task of identifying occluded and camouflaged objects has been successfully accomplished, yielding an impressive accuracy rate of 93% in total. The mean average precision has been achieved as 85% which is reasonably high compared to many earlier works.
Green conversion of red snapper fish scale-derived carbon dots and its absorption properties for solar thermal desalination
Authors: Pandara Dolfie Paulus , Tamuntuan Gerald Hendrik , Bobanto Maria Daurina , Ferdy Ferdy
Published: January 2024

Fisheries wastes have been used as precursors for the synthesis of carbon dots (CDs). These wastes are often converted using hydrothermal methods which require high temperature and pressure, leading to high production costs, especially for large-scale production. This study aims to innovate a low-cost synthesis method with the potential for large-scale production. Green conversion of CDs from red snapper fish scale waste was carried out using a combination of immersion method and ultrasonic wave treatment. The results showed that the products had an absorption peak at a wavelength of 404 nm and an energy bandgap of 2.7 eV. Excitation at 404 nm was associated with non-bonding n orbital to antibonding orbital 𝝅* electronic transitions due to the presence of free electron pairs and related with carbon-nitrogen (C-N) bonds. The 2.7 eV energy bandgap was associated with the state of amine groups containing free electron pairs located on the surface of CDs as well as blue light emission at a wavelength of 460 nm when CDs were illuminated with ultraviolet light. Red snapper fish scale-derived CDs showed fluorescence characteristics and the presence of nitrogen elements, making them potential photothermal materials for solar-powered seawater desalination processes.
Reperfusion in Patients With ST-Segment–Elevation Myocardial Infarction With Cardiogenic Shock and Prolonged Interhospital Transport Times
Authors: van Diepen Sean , Zheng Yinggan , Senaratne Janek M. , Tyrrell Benjamin D. , Das Debraj , Thiele Holger , Henry Timothy D. , Bainey Kevin R. , Welsh Robert C.
Published: January 2024

BACKGROUND:

In patients with ST-segment–elevation myocardial infarction complicated by cardiogenic shock, primary percutaneous coronary intervention (pPCI) is the preferred revascularization option. Little is known about the efficacy and safety of a pharmacoinvasive approach for patients with cardiogenic shock presenting to a non-PCI hospital with prolonged interhospital transport times.

METHODS:

In a retrospective analysis of geographically extensive ST-segment–elevation myocardial infarction network (2006–2021), 426 patients with cardiogenic shock and ST-segment–elevation myocardial infarction presented to a non–PCI-capable hospital and underwent reperfusion therapy (53.8% pharmacoinvasive and 46.2% pPCI). The primary clinical outcome was a composite of in-hospital mortality, renal failure requiring dialysis, cardiac arrest, or mechanical circulatory support, and the primary safety outcome was major bleeding defined as an intracranial hemorrhage or bleeding that required transfusion was compared in an inverse probability weighted model. The electrocardiographic reperfusion outcome of interest was the worst residual ST-segment–elevation.

RESULTS:

Patients with pharmacoinvasive treatment had longer median interhospital transport (3 hours versus 1 hour) and shorter median symptom-onset-to-reperfusion (125 minute-to-needle versus 419 minute-to-balloon) times. ST-segment resolution ≥50% on the postfibrinolysis ECG was 56.6%. Postcatheterization, worst lead residual ST-segment–elevation <1 mm (57.3% versus 46.3%;
P
=0.01) was higher in the pharmacoinvasive compared with the pPCI cohort, but no differences were observed in the worst lead ST-segment–elevation resolution ≥50% (77.4% versus 81.8%;
P
=0.57). The primary clinical end point was lower in the pharmacoinvasive cohort (35.2% versus 57.0%; inverse probability weighted odds ratio, 0.44 [95% CI, 0.26–0.72];
P
<0.01) compared with patients who received pPCI. An interaction between interhospital transfer time and reperfusion strategy with all-cause mortality was observed, favoring a pharmacoinvasive approach with transfer times >60 minutes. The incidence of the primary safety outcome was 10.1% in the pharmacoinvasive arm versus 18.7% in pPCI (adjusted odds ratio, 0.41 [95% CI, 0.14–1.09];
P
=0.08).

CONCLUSIONS:

In patients with ST-segment–elevation myocardial infarction presenting with cardiogenic shock and prolonged interhospital transport times, a pharmacoinvasive approach was associated with improved electrocardiographic reperfusion and a lower rate of death, dialysis, or mechanical circulatory support without an increase in major bleeding.
Cardiac Arrest Following Drug Overdose in the United States: An Analysis of the Cardiac Arrest Registry to Enhance Survival
Authors: Shekhar Aditya C. , Nathanson Brian H. , Mader Timothy J. , Coute Ryan A.
Published: January 2024

Background

Given increases in drug overdose‐associated mortality, there is interest in better understanding of drug overdose out‐of‐hospital cardiac arrest (OHCA). A comparison between overdose‐attributable OHCA and nonoverdose‐attributable OHCA will inform public health measures.

Methods and Results

We analyzed data from 2017 to 2021 in the Cardiac Arrest Registry to Enhance Survival (CARES), comparing overdose‐attributable OHCA (OD‐OHCA) with OHCA from other nontraumatic causes (non‐OD‐OHCA). Arrests involving patients <18 years, health care facility residents, patients with cancer diagnoses, and patients with select missing data were excluded. Our main outcome of interest was survival with good neurological outcome, defined as Cerebral Performance Category score 1 or 2. From a data set with 537 100 entries, 29 500 OD‐OHCA cases and 338 073 non‐OD‐OHCA cases met inclusion criteria. OD‐OHCA cases involved younger patients with fewer comorbidities, were less likely to be witnessed, and less likely to present with a shockable rhythm. Unadjusted survival to hospital discharge with Cerebral Performance Category score =1 or 2 was significantly higher in the OD‐OHCA cohort (OD: 15.2% versus non‐OD: 6.9%). Adjusted results showed comparable survival with Cerebral Performance Category score =1 or 2 when the first monitored arrest rhythm was shockable (OD: 28.9% versus non‐OD: 23.5%,
P
=0.087) but significantly higher survival rates with Cerebral Performance Category score =1 or 2 for OD‐OHCA when the first monitored arrest rhythm was nonshockable (OD: 9.6% versus non‐OD: 3.1%,
P
<0.001).

Conclusions

Among patients presenting with nonshockable rhythms, OD‐OHCA is associated with significantly better outcomes. Further research should explore cardiac arrest causes, and public health efforts should attempt to reduce the burden from drug overdoses.
Use of Direct‐Acting Oral Anticoagulants in Patients With Atrial Fibrillation and Significant Tricuspid Regurgitation
Authors: Yang Yujin , Kim Mijin , Kim Jun , Cho Min Soo , Lee Sahmin , Song Jong‐Min , Kim Dae‐Hee
Published: January 2024

Background

There are limited data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation with significant tricuspid regurgitation (TR), which can lead to hepatic dysfunction and intestinal malabsorption. We aimed to compare the efficacy and safety of DOACs and warfarin for patients with atrial fibrillation with significant (moderate to severe) TR.

Methods and Results

A total of 1215 patients with significant TR and atrial fibrillation who were treated with warfarin (N=491) or DOACs (N=724) were retrospectively analyzed. The primary outcomes were ischemic stroke, systemic embolic events, and hospitalization for major bleeding. The secondary outcomes were intracranial hemorrhage, hospitalization for gastrointestinal bleeding, all‐cause mortality, and a composite outcome. The median follow‐up duration was 2.4 years. In the inverse probability treatment weighting–adjusted cohort, DOACs and warfarin had a similar risk for ischemic stroke and systemic embolic events (adjusted hazard ratio [aHR], 0.95 [95% CI, 0.67–1.36];
P
=0.79) and major bleeding (aHR, 0.78 [95% CI, 0.57–1.06];
P
=0.11). For the secondary outcomes, relative to warfarin, DOACs had a lower risk of intracranial hemorrhage and the composite outcome, and a comparable risk for gastrointestinal bleeding and all‐cause mortality. In the subgroup analysis, the effects of DOACs on ischemic stroke and systemic embolic events were comparable to the effects of warfarin, even in patients with inferior vena cava plethora (increased right atrial pressure) or severe TR.

Conclusions

In this study, relative to warfarin, DOACs demonstrated comparable efficacy for ischemic stroke and systemic embolic events and major bleeding, with a lower intracranial hemorrhage risk in patients with significant TR and atrial fibrillation, indicating their effectiveness and safety.
Prospective Observational Study for the Comparison of Screening Methods Including Tongue Pressure and Repetitive Saliva Swallowing With Detailed Videofluoroscopic Swallowing Study Findings in Patients With Acute Stroke
Authors: Nakamori Masahiro , Imamura Eiji , Maetani Yuta , Yoshida Mitsuyoshi , Yoshikawa Mineka , Nagasaki Toshikazu , Masuda Shin , Kayashita Jun , Mizoue Tatsuya , Wakabayashi Shinichi , Maruyama Hirofumi , Hosomi Naohisa
Published: January 2024

Background

Simple, noninvasive, and repeatable screening methods are essential for assessing swallowing disorders. We focused on patients with acute stroke and aimed to assess the characteristics of swallowing screening tests, including the modified Mann Assessment of Swallowing Ability score, tongue pressure, and repetitive saliva swallowing test (RSST), compared with detailed videofluoroscopic swallowing study (VFSS) findings to contribute as a helpful resource for their comprehensive and complementary use.

Methods and Results

We enrolled first‐ever patients with acute stroke conducting simultaneous assessments, including VFSS, modified Mann Assessment of Swallowing Ability score, tongue pressure measurement, and RSST. VFSS assessed aspiration, laryngeal penetration, oral cavity residue, vallecular residue, pharyngeal residue, and swallowing reflex delay. Screening tests were compared with VFSS findings, and multiple logistic analysis determined variable importance. Cutoff values for each abnormal VFSS finding were assessed using receiver operating characteristic analyses. We evaluated 346 patients (70.5±12.6 years of age, 143 women). The modified Mann Assessment of Swallowing Ability score was significantly associated with all findings except aspiration. Tongue pressure was significantly associated with oral cavity and pharyngeal residue. The RSST was significantly associated with all findings except oral cavity residue. Receiver operating characteristic analyses revealed that the minimum cutoff value for all VFSS abnormal findings was RSST ≤2.

Conclusions

The modified Mann Assessment of Swallowing Ability is useful for broadly detecting swallowing disorders but may miss mild issues and aspiration. The RSST, with a score of ≤2, is valuable for indicating abnormal VFSS findings. Tongue pressure, especially in oral and pharyngeal residues, is useful. Combining these tests might enhance accuracy of the swallowing evaluation.
Hypoxia Attenuates Pressure Overload‐Induced Heart Failure
Authors: Froese Natali , Szaroszyk Malgorzata , Galuppo Paolo , Visker Joseph R. , Werlein Christopher , Korf‐Klingebiel Mortimer , Berliner Dominik , Reboll Marc R. , Hamouche Rana , Gegel Simona , Wang Yong , Hofmann Winfried , Tang Ming , Geffers Robert , Wende Adam R. , Kühnel Mark P. , Jonigk Danny D. , Hansmann Georg , Wollert Kai C. , Abel E. Dale , Drakos Stavros G. , Bauersachs Johann , Riehle Christian
Published: January 2024

Background

Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support.

Methods and Results

We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased
Tbx5
and increased
Hsd11b1
mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for
TBX5
and
HSD11B1
as observed in HxTAC hearts.

Conclusions

Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.
The Story of Adoram the Taskmaster over the Forced Labor and the Traditions Regarding the Kingdom’s Division
Authors: Darshan Guy
Published: January 2024

This study compares the three major versions of the concluding verses of the story of the assembly at Shechem (1 Kgs 12:13–20): the Masoretic Text (MT), its Septuagint counterpart (G*), and the version found in 3 Kgdms 12:24s–u LXX called the “Alternative Story” (AS). While the MT version includes an account concerning Adoram the taskmaster over the forced labor (12:18a, 19), the shorter AS lacks this detail. This fact, together with additional historical and philological considerations, serves as the basis for the article’s proposal that the brief report on Adoram originated from an independent account that provides a unique and distinct explanation for the Kingdom’s division. This tradition diverges from, yet exhibits certain similarities to other explanations for the schism, as described in the Shechem assembly story, the account of Jeroboam’s rise, and the Deuteronomistic editorial strata.
‘A Jurisprudence for the Future’: Anticolonial Lawyering during the Vietnam War Years
Authors: Kiechel Charlotte
Published: January 2024

This article explores the dilemmas of progressive legalism during the Vietnam War years (1965–1975) by investigating the history of the Russell Tribunal. Scholars have argued that the 1960s witnessed a flourishing of anticolonial legalism, as activists sought to purge international law of its imperial origins. However, as the history of the Russell Tribunal shows, the transformation of law from a handmaiden of empire into a tool of anti-imperial resistance was not straightforward. This article examines the strategies employed by activists to overcome international law’s imperial biases. It argues that activists focused on developing a ‘jurisprudence for the future’, a mode of activism aimed at constructing international rules and norms that challenged, rather than sustained, European domination. By advocating for a future-oriented activism, tribunal members sought a temporary solution to the predicament of law’s imperial leanings. They defended their use of international law by asserting that their protests would contribute to the emergence of a future and more emancipatory international law. Nevertheless, an examination of the World Tribunal on Iraq (2003–2005) reveals that this envisioned future international law has yet to materialize. This article highlights the significance of futurism in the history of anticolonial lawyering and suggests that scholars should evaluate the limitations of a future-oriented legal activism.
Taking Stock of the Scholarship on the Relationship between International Investment Law and the Need for Raised Climate Ambition
Authors: Hall Jenny , Koen Louis
Published: January 2024

Increasingly dire warnings about the climate crisis mean that it is more urgent than ever that different legal regimes, including international investment law, are aligned with climate objectives and not implemented in discord with climate solutions. Many works have been produced over the last twenty years which examine whether the norms underlying climate law and international investment law necessarily conflict or can be reconciled. These works reflect deeply contested views amongst scholars as to whether regulation aimed at ensuring climate ambition can, or is likely to, be adequately safeguarded by the international investment law regime that is designed to provide conditions of stability for investors – including those that are large greenhouse gas emitters. This article provides an overview of the different perspectives that have been offered on the relationship between climate change law and international investment law in respect of three role-players – namely, arbitrators, civil society, and states. It concludes by offering tentative thoughts on the course that the interaction between the two regimes may take in the future.
A Determination Method for the Biomass Lower-Calorific-Value-Based Blending Ratio in Co-Firing Power Plants
Authors: He Ailing , Sun Tanglei , Wang Ruisi , Zhang Lu , Yang Yantao , Wu Qigang , Liu Peng , Lei Tingzhou
Published: January 2024

The accurate measurement of the biomass lower-calorific-value-based blending ratio (BLBR) is the premise and key to scale development of the power generation technology from co-firing of biomass and coal. However, existing determination methods of BLBR are less accurate, which has impeded
the scale utilization of the co-firing technology of biomass and coal. To accurately determine the BLBR, this research proposed a flue gas sampling system suitable for determining BLBR through 14C quantitative analysis and established a medium-scale experimental platform for BLBR
determination. In addition, predictive models for the lower calorific values of coal and biomass fuels were built and the BLBR calculation model for co-firing power plants was deduced. Furthermore, experimental verification of the BLBR determination was also conducted. The results show that
the lower calorific values of coal and biomass fuels are highly linearly positively correlated with the carbon content. The relative errors of the established prediction models for lower calorific values of biomass and coal are separately lower than 5% and 8%. The results indicate that the
proposed BLBR determination method is accurate.
Optimal Extraction Technique and Antibacterial Properties of Essential Oil Through Magnolia sieboldii K. Koch Leaves
Authors: Fu Cong , Lan Xuehan , Yu Zhongliang , Liu Yongshuai , Li Liming , Yuan Mengqi , Tan Tingting , Du Fengguo
Published: January 2024

To provide scientific support for the exploration and application of the essential oil derived through leaves of Magnolia sieboldii K. Koch, this paper explores extraction technology optimization, composition analysis, and antibacterial properties for the essential oil derived
through Magnolia sieboldii K. Koch leaves. Essential oil derived through Magnolia sieboldii K. Koch leaves was extracted by adopting hydrodistillation. With single-factor test and reaction surface improvement methods, the extraction technology of essential oil derived through
Magnolia sieboldii K. Koch leaves was optimized. The structure of chemicals has been explored through the use of gas chromatographmass spectrometer (GC-MS) technology. By conducting Kirby-Bauer test and applying spread plate method, the antibacterial properties for essential oil has
been measured. The liquid-solid ratio was 7.15 mL/g, the dilution period was 4.00 h, and the NaCl mass percentage was 2.26% as a consequence of the response surface optimization. The rate about gathered essential oil under such circumstances was 0.31537%. By performing chemical composition
analysis, 43 compounds were measured from essential oil. Thel oil was sensitive to Staphylococcus aureus, Bacillus subtilis, and Escherichia coli with inhibitory area diameters of 17.27, 10.85, and 9.56 mm, respectively. The minimum inhibitory concentration (MIC) values for the
three bacteria strains were 2.5 × 10–6, 5 × 10–6, and 10 × 10–6 g/mL, respectively. The optimum extraction rate of essential oil derived through leaves of Magnolia sieboldii K. Koch
by hydro distillation is 0.35%, with the cancer-fighting substance β-elemene reaching up to a maximum of 42.53%. Simultaneously, the essential oil derived through leaves of Magnolia sieboldii K. Koch exhibits notable antibacterial effect and large development potential,
suggesting the comprehensive development and utilization.
Preventive Effect of Astaxanthin on Diabetic Cataracts and Its Protective Effect on Lens Epithelial Cells
Authors: Chen Yao , Su Fanfan , Guo Ming , Su Bo
Published: January 2024

To better combat the development of diabetic cataracts (DC), we conducted a study on the use of astaxanthin (ATX) as an innovative antioxidant. Our research found that ATX exhibited good biocompatibility with lens epithelial cells (LECs) and increasing its concentration did not reduce
cell activity. In the presence of high glucose, LECs experienced elevated oxidative stress levels, leading to a significant inhibition of their activity. However, the addition of ATX increased the antioxidant levels in LECs, resulting in a concentration-dependent increase in cell activity.
Furthermore, when tested on diabetic rat models, higher concentrations of ATX application effectively prevented the development of DC and suppressed the level of oxidative stress in the lens. Our findings highlight the strong antioxidant effect of ATX, which can safeguard LEC activity in the
presence of high glucose and inhibit the development of DC.
Exploring the Dual Components and Mechanism of Panax notoginseng-Eucommia ulmoides for Managing Osteoporosis-Associated Lumbar Disc Herniation Using Network Pharmacology
Authors: Lin Zehong , Wei Jihu , Lv He , Lu Yan , Feng Zhe , Zhou Honghai
Published: January 2024

Osteoporosis (OP) combined with lumbar intervertebral disc herniation (LDH) is a complex disease that exhibits limited efficacy in drug treatment, physical therapy, and surgical intervention, while also carrying potential side effects and risks. Traditional Chinese medicine treatment
of OP combined with LDH primarily aims to address deficiencies and regulate the body. Several active ingredients found in Panax notoginseng and Eucommia ulmoides, such as quercetin and beta-sitosterol, have demonstrated the ability to enhance osteoblast proliferation and bone
matrix synthesis. While historical literature contains mechanistic studies on individual herbs, there is a conspicuous dearth of comprehensive and systematic research on their mechanisms of action. By utilizing network pharmacology method, we identified 35 active ingredients present in Panax
notoginseng and Eucommia ulmoides, along with 98 potential targets associated with the treatment of OP combined with LDH using Panax notoginseng-Eucommia ulmoides. Through protein-protein interaction network analysis, we identified 5 essential active ingredients (Quercetin,
Beta-carotene, Kaempferol, Beta-sitosterol, and Notoginsenoside Fe) and 5 core targets (Nuclear factor kappa-B 3 [RELA], hypoxia-induciblefactor-1A [HIF-1A], Myelocytomatosis Viral Oncogene homolog [MYC], Transcription Factor AP-1 [JUN], and Estrogen Receptor 1 [ESR1]). The potential targets
primarily involve IL-17, AGEs-RAGE, the TNF signaling pathway, and other pathways through which they exert therapeutic effects. The key active ingredient was docked with the core target molecule, resulting in all molecules exhibiting binding energies ≤-5 kcal/mol. This study provides preliminary
evidence that treatment with Panax notoginseng-Eucommia ulmoides for OP combined with LDH may lead to improvements in inflammation, oxidative stress, cell proliferation, differentiation, and apoptosis, and cytokine regulation.
Synergistic Effect and Long-Term Efficacy of Shilong Jiedu Formula as An Adjuvant Chemotherapy in the Treatment of Diffuse Large B-Cell Lymphoma Patients
Authors: Ran Changli , Liu Qian
Published: January 2024

Chemotherapy is the main treatment for diffuse large B-cell lymphoma (DLBCL), but the recurrence rate in patients after standard chemotherapy is high. Moreover, there is a significant issue of drug resistance, resulting in low remission rates when retreatment is required. Thus, there
is a need to improve the overall efficacy of DLBCL treatment. In order to identify an effective approach to enhance DLBCL treatment outcomes without increasing adverse reactions, this study focused on DLBCL patients who visited our hospital from January to December 2020. The study included
53 patients who received the CHOP treatment plan in the CHOP group, and another 53 patients who received adjuvant chemotherapy with Shilong Jiedu Formula in the combination group. The treatment efficacy, quality of life, changes in molecular markers, and two-year progression-free survival
were recorded for all patients, and differences between the two groups were compared. The research results reveal that patients who combined Shilong Jiedu Formula with chemotherapy achieved better remission rates compared to those who only received chemotherapy. Meanwhile, patients who combined
Shilong Jiedu Formula with chemotherapy experienced higher quality of life and stronger immune function after treatment, indicating significant improvements (P < 0.05) in these aspects compared to patients who solely received chemotherapy. Importantly, adjuvant chemotherapy with
Shilong Jiedu Formula also demonstrated a certain extent of improvement in the progression-free survival rate of DLBCL patients. Therefore, this study suggests that the Shilong Jiedu Formula, primarily consisting of Rehmanniae Radix Praeparata and Cuscutae Semen, holds high value
as an adjuvant chemotherapy for the treatment of DLBCL.
Phytochemical Composition, In Vitro Antioxidant, and Anticancer Activities of Cold Pressed Oil from Sesame (Sesamum indicum L.) from the Kingdom of Saudi Arabia
Authors: Albaqami Jawaher J.
Published: January 2024

Sesame seed oil (SSO) has long been used in many complementary and alternative medicine systems to treat a variety of maladies and ailments. SSO was obtained by cold pressing Sesamum indicum L. (sesame) seeds. Sesamum indicum L. (sesame) oil’s chemical constituents
identified with GC-MS. Using the DDPH and MTT assays, respectively, the antioxidant and anticancer activities were investigated. phytosterols, (β-sitosterol, Campesterol, and Stigmasterol), lignans such as sesamin, fatty acids such as Oleic Acid, Esters of fatty acid, such as Hexadecanoic
acid, methyl ester, Linoleic acid ethyl ester, flavonoids such as 3′,4′,7Trimethylquercetin, 6,8-di-c-a-glucosylluteolin, the carboxylic ester glycidyl oleate, alcoholic compounds, 1-heptatriacotanol, were the active chemical compounds detected in Sesamum indicum L. (sesame)
oil. SSO has a high tocopherol profile. SSO showed antioxidant properties with DDPH radical scavenging of 63.1% relative to standard beta hydroxyl butyrate (BHT). The anticancer effects of SSO against Ovarian carcinoma (A-2780) cell line with IC50 = 1.68 ± 0.3 μg/mL.
Sesamum indicum L. (sesame) oil’s chemical constituents identified with GC-MS showed antioxidant and anticancer properties.
The Regulation of the Function of Fibroblasts in Patients with Chronic Obstructive Pulmonary Disease by Regulating Tenascin-C Protein Under Feedback Lung Training with Curcumin in Combination with Suzi Jiangqi Decoction
Authors: Ma Cui , Ma Yuning , Gu Zhenjie , Zhang Wei
Published: January 2024

Chronic obstructive pulmonary disease (COPD) is characterized by reduction of elastic fibers in alveolar wall. This study explores the mechanism of curcumin combined with Suzi Jiangqi Decoction in lung fibroblasts. 50 COPD patients suspected of lung cancer were collected. Ten patients
were assigned into control group, and the remaining 40 patients underwent feedback lung training and were divided into model group, curcumin group, Suzi Jiangqi decoction group, and curcumin combined with Suzi Jiangqi decoction group. 5 mL peripheral venous blood was collected and a percutaneous
lung biopsy was performed to collect lung tissue and culture fibroblasts. Tenascin (TNC) level was detected by ELISA and pathological changes of lung tissue were detected by HE staining. CCK-8 assay detected cell proliferation and Transwell chamber detected cell migration. Cell apoptosis was
assessed by flow cytometry and TGF-β1, MMP-9, and TNC expression were evaluated by Real Time Quantitative Polymerase Chain Reaction (RT-qPCR) and Western blot. TNC level in COPD patients decreased significantly and levels of various pulmonary function indexes showed an upward trend.
The epithelial cells in lung tissue of control group were less and alveolar wall was obviously thinner. Epithelial cells gradually increased and alveolar walls gradually fused. TNC protein can improve the development of fibroblasts in COPD patients. Curcumin combined with Suzi Jiangqi Decoction
inhibited TNC expression, and down-regulated TGF-β1 and MMP-9. Curcumin combined with Suzi Jiangqi decoction increased the proliferation ability and reduced apoptosis of lung fibroblasts by down-regulating the expression of Tenascin-C. This study provides a solid theoretical basis
for curcumin combined with Suzi Jiangqi Decoction as a treatment for COPD.
Effects of Payment for Ecosystem Services and Tourism on Conservation and Development: Trade-Off or Synergistic?
Authors: Wang Yujun , Yang Hongbo , Hull Vanessa , Zhang Jindong , Chen Xiaodong , Li Xiang , Zhang Zejun , Li Cheng , Wang Fang , Zhao Zhiqiang , Tang Ying , Liu Jianguo
Published: January 2024

The effects of various strategies aimed at simultaneously promoting environmental conservation and human development are closely related to sustainable development regionally and globally. However, although the effects of many such strategies have been evaluated by ecologists and sociologists separately, their ability to simultaneously meet these two anticipated goals (i.e., environmental conservation and human development) at the fine spatial scale remains unclear. To answer this fundamental but crucial question, incorporating household and forest change data, we concurrently estimated the ecological and socioeconomic effects of two world-renowned Payment for Ecosystem Services (PES) programs (i.e., the Nature Forest Conservation Program, the Grain to Green Program) and nature-based tourism in 30 protected areas across 8 provinces in China. Here we showed a trade-off between the ecological and economic effects of two PES programs, while synergistic effects exist in the ecological and economic benefits of tourism. Attributes of household and protected areas significantly influenced economic and environmental benefits as well. Our research provides new insights into the complex effects of PES programs and tourism, and crucial information to support their adequate and sustainable implementation in China and the rest of the world.

Significance Statement

This work answers a fundamental but crucial question, that is, whether the policies commonly advocated to incorporate environmental conservation and human development can yield positive effects both for conservation and economic development. Our evaluation is also timely to inform some shortness (i.e., negligible economic effects, or the lack of expected positive economic benefits) and provides new insights (e.g., the implication of households and protected-areas attributes in conservation and economic outcomes) of Payment for Ecosystem Services (PES) programs and the complex effects of instruments in the context of multiple policies, particularly given the upcoming 2030 deadline for achieving the Sustainable Development goals (SDGs). We expected that implications in this study can provide important lessons for these two instruments, other PES programs, and other conservation and development instruments to support their adequate and sustainable implementation in China and beyond and to contribute to the achievement of relevant SDGs in the remaining years.