bluuebunny/crossref_metadata_2025 huggingface dataset:
Cord blood–derived V
δ
2
+
and V
δ
2
−
T cells acquire differential cell state compositions upon in vitro expansion
Authors: Ng Jeremy Wee Kiat , Tan Kar Wai , Guo Dian Yan , Lai Joey Jia Hui , Fan Xiubo , Poon Zhiyong , Lim Tse Hui , Lim Alvin Soon Tiong , Lim Tony Kiat Hon , Hwang William Ying Khee , Li Shang , Eaves Connie J. , Goh Yeow Tee , Cheung Alice Man Sze
Published: June 2023

Human cord blood–derived γδ T cells (CB
γδ
) display a highly diverse TCR
γδ
repertoire and have a unique subtype composition different from fetal or adult peripheral blood counterparts. We expanded CB
γδ
in vitro using an irradiated Epstein-Barr virus–transformed feeder cell–based modified rapid expansion protocol (REP). Single-cell RNA sequencing tracked progressive differentiation of naïve CB
γδ
into cells expressing neoantigen-reactive tumor-infiltrating lymphocyte as well as tissue-resident memory precursor–like and antigen-presenting cell–like gene signatures. TCR
γδ
clonal tracing revealed a bias toward cytotoxic effector differentiation in a much larger proportion of V
δ
2
−
clones compared to V
δ
2
+
clones, resulting in the former being more cytotoxic at the population level. These clonotype-specific differentiation dynamics were not restricted to REP and were recapitulated upon secondary nonviral antigen stimulations. Thus, our data showed intrinsic cellular differences between major subtypes of human γδ T cells already in operation at early postnatal stage and highlighted key areas of consideration in optimizing cell manufacturing processes.
Enantioselective synthesis of α,α-diarylketones by sequential visible light photoactivation and phosphoric acid catalysis
Authors: Liu Hong-Fu , Long Liang , Zhu Zhi-Qiang , Wu Teng-Fei , Zhang Yi-Rui , Pan Han-Peng , Ma Ai-Jun , Peng Jin-Bao , Wang Yong-Heng , Gao Hao , Zhang Xiang-Zhi
Published: June 2023

Chiral ketones and their derivatives are useful synthetic intermediates for the synthesis of biologically active natural products and medicinally relevant molecules. Nevertheless, general and broadly applicable methods for enantioenriched acyclic α,α-disubstituted ketones, especially α,α-diarylketones, remain largely underdeveloped, owing to the easy racemization. Here, we report a visible light photoactivation and phosphoric acid–catalyzed alkyne-carbonyl metathesis/transfer hydrogenation one-pot reaction using arylalkyne, benzoquinone, and Hantzsch ester for the expeditious synthesis of α,α-diarylketones with excellent yields and enantioselectivities. In the reaction, three chemical bonds, including C═O, C─C, and C─H, are formed, providing a de novo synthesis reaction for chiral α,α-diarylketones. Moreover, this protocol provides a convenient and practical method to synthesize or modify complex bioactive molecules, including efficient routes to florylpicoxamid and BRL-15572 analogs. Computational mechanistic studies revealed that C-H/π interactions, π-π interaction, and the substituents of Hantzsch ester all play crucial roles in the stereocontrol of the reaction.
Magma migration and surface uplift in Pamir–western Tibet driven by deep lithospheric dynamics
Authors: Tang Gong-Jian , Wyman Derek A. , Dan Wei , Wang Qiang , Gadoev Mustafo , Oimahmadov Ilhomjon
Published: June 2023

There are two parallel >1200-km-long semi-continuous (ultra)potassic magmatic belts in the southern (Karakorum-Lhasa) and the northern (Central Pamir–western Kunlun) parts of Pamir–western Tibet. The southern belt is widely attributed to northward subduction of the Indian plate, while it has been suggested that the northern belt relates to the southward subduction of the Asian plate. We report new zircon U-Pb ages and isotopic data for the northern belt that show eastward magma migration between ca. 20 Ma and the present, which are contemporaneous with continental-scale thermochronometric cooling ages. Whereas magma migration in the south was caused by progressive west-to-east Indian lithosphere break-off, magma generation in the north is shown to be related to asthenospheric mantle upflow through a small mantle window (~100 km width) forced by Indian lithosphere underthrusting, Pamir–western Tibet lithosphere mantle dripping, and resistance of the Tarim lithosphere. Northern belt magma migration relates to progressively eastward underthrusting of the Indian lithosphere that took ~15 m.y. to move northward across ~350 km to meet Asian lithosphere. Accordingly, both belts of (ultra)potassic magmatism relate to the northward subduction of the Indian plate that was responsible for plateau uplift in Pamir–western Tibet.
Cross-country and panel data estimates of the price elasticity of demand for cigarettes in Europe
Authors: Kohler Andreas , Vinci Linda , Mattli Renato
Published: June 2023

Objective

Our goal is to provide estimates of the price elasticity of demand for cigarettes in Europe as a basis for public health policy on tobacco taxation.

Methods

We use secondary data on cigarette retail sales including illicit trade, prices, tobacco control measures and income from 2010 to 2020 of 27 European countries from Euromonitor, the WHO, the Tobacco Control Scale and the World Bank. We estimate the price elasticity of demand using instrumental variable regressions as well as panel data regressions taking into account that prices and quantities are determined simultaneously in the market.

Results

Based on cross-section data at the country level, we find that during the decade from 2010 to 2020, the demand for cigarettes in Europe has become neither more nor less elastic. Our estimates of the price elasticity based on panel data are around −0.4 (95% CI −0.67 to –0.24), in line with previous estimates for high-income countries. Furthermore, our analysis shows that estimates of the price elasticity of demand that are based on data including illicit trade tend to be lower. This has also been found in the previous literature.

Conclusions

By providing state-of-the-art, up-to-date estimates of the price elasticity of demand that are in line with the previous literature, we show that taxation can still be a cost-effective tobacco policy to reduce cigarette consumption and thus, the burden of smoking.
Systems science methods in public health: what can they contribute to our understanding of and response to the cost-of-living crisis?
Authors: Höhn Andreas , Stokes Jonathan , Pollack Roxana , Boyd Jennifer , Chueca Del Cerro Cristina , Elsenbroich Corinna , Heppenstall Alison , Hjelmskog Annika , Inyang Elizabeth , Kopasker Daniel , Sonthalia Shreya , Thomson Rachel M , Zia Kashif , Katikireddi Srinivasa Vittal , Meier Petra
Published: June 2023

Background

Many complex public health evidence gaps cannot be fully resolved using only conventional public health methods. We aim to familiarise public health researchers with selected systems science methods that may contribute to a better understanding of complex phenomena and lead to more impactful interventions. As a case study, we choose the current cost-of-living crisis, which affects disposable income as a key structural determinant of health.

Methods

We first outline the potential role of systems science methods for public health research more generally, then provide an overview of the complexity of the cost-of-living crisis as a specific case study. We propose how four systems science methods (soft systems, microsimulation, agent-based and system dynamics models) could be applied to provide more in-depth understanding. For each method, we illustrate its unique knowledge contributions, and set out one or more options for studies that could help inform policy and practice responses.

Results

Due to its fundamental impact on the determinants of health, while limiting resources for population-level interventions, the cost-of-living crisis presents a complex public health challenge. When confronted with complexity, non-linearity, feedback loops and adaptation processes, systems methods allow a deeper understanding and forecasting of the interactions and spill-over effects common with real-world interventions and policies.

Conclusions

Systems science methods provide a rich methodological toolbox that complements our traditional public health methods. This toolbox may be particularly useful in early stages of the current cost-of-living crisis: for understanding the situation, developing solutions and sandboxing potential responses to improve population health.
Penumbra-targeted CircOGDH siRNA-loaded nanoparticles alleviate neuronal apoptosis in focal brain ischaemia
Authors: Liu Yanfang , Zhang Tianyuan , Zou Xing , Yuan Zhongwen , Li Yufeng , Zang Jiankun , He Niu , He Lizhen , Xu Anding , Lu Dan
Published: June 2023

Background

Nanoparticles (NPs) are a class of substances that can be loaded with therapeutic agents delivered to specific areas. In our earlier research, we identified a neuron-derived circular RNA (circRNA), circular oxoglutarate dehydrogenase (CircOGDH), as a promising therapeutic target for acute ischaemic stroke. This study dedicated to explore a prospective preliminary strategy of CircOGDH-based NP delivered to the ischaemic penumbra region in middle cerebral artery occlusion/reperfusion (MCAO/R) mice.

Methods

Immunofluorescence in primary cortex neurons and in vivo fluorescence imaging revealed endocytosis of Poly(lactide-co-glycolide) (PLGA) poly amidoamine(PAMAM)@CircOGDH small interfering RNA (siRNA) NPs. Western blotting analysis and CCK8 assay were performed to evaluate the apoptotic level in ischaemic neurons treated with PLGA–PAMAM@CircOGDH siRNA NPs. Quantitative reverse transcription PCR experiments, mice behaviour test, T2 MRI analysis, Nissl and TdT-mediated dUTP nick end labeling (TUNEL) co-staining were performed to evaluate the apoptosis level of ischaemic penumbra neurons in MCAO/R mice. Biosafety evaluation of NPs in MCAO/R mice was detected by blood routine examination, liver and kidney function examination and HE staining.

Results

PLGA–PAMAM@CircOGDH siRNA NPs were successfully assembled. Endocytosis of PLGA–PAMAM@CircOGDH siRNA NPs in ischaemic neurons alleviated neuronal apoptotic level in vitro and in vivo. Furthermore, mice behaviour test showed that the neurological defects of MCAO/R mice were significantly alleviated after the tail injection of PLGA–PAMAM@CircOGDH siRNA NPs, and no toxic effects were observed.

Conclusion

In conclusion, our results suggest that PLGA–PAMAM@CircOGDH siRNA NPs can be delivered to the ischaemic penumbra region and alleviate neuron apoptosis in MCAO/R mice and in ischaemic neurons; therefore, our study provides a desirable approach for using circRNA-based NPs for the treatment of ischaemic stroke.
Cause-specific mortality in COPD subpopulations: a cohort study of 339 647 people in England
Authors: Whittaker Hannah , Rothnie Kieran J , Quint Jennifer K
Published: June 2023

Background

Identifying correlates of cause-specific mortality in patients with chronic obstructive pulmonary disease (COPD) may aid the targeting of therapies to reduce mortality. We determined factors associated with causes of death in a primary care COPD population.

Methods

Clinical Practice Research Datalink Aurum was linked to Hospital Episode Statistics and death certificate data. People with COPD alive between 1 January 2010 and 1 January 2020 were included. Patient characteristics were defined before the start of follow-up: (a) frequency and severity of exacerbations; (b) emphysema or chronic bronchitis; (c) Global Obstructive Lung Disease (GOLD) groups A–D; and (d) airflow limitation. We used Cox Proportional Hazards regression and competing risks to investigate the association between patient characteristics and risk of all-cause, COPD and cardiovascular (CV) mortality.

Results

339 647 people with COPD were included of which 97 882 died during follow-up (25.7% COPD related and 23.3% CV related). Airflow limitation, GOLD group, exacerbation frequency and severity, and COPD phenotype were associated with all-cause mortality. Exacerbations, both increased frequency and severity, were associated with COPD-related mortality (≥2 exacerbations vs none adjusted HR: 1.64, 1.57–1.71; 1 severe vs none adjusted HR: 2.17, 2.04–2.31, respectively). Patients in GOLD groups B–D had a higher risk of COPD and CV mortality compared with GOLD group A (GOLD group D vs group A, adjusted HR for COPD mortality: 4.57, 4.23–4.93 and adjusted HR for CV mortality: 1.53, 1.41–1.65). Increasing airflow limitation was also associated with both COPD and CV mortality (GOLD 4 vs 1, adjusted HR: 12.63, 11.82–13.51 and adjusted HR: 1.75, 1.60–1.91, respectively).

Conclusion

Poorer airflow limitation, worse functional status and exacerbations had substantial associations with risk of all-cause mortality. Differing results for CV and COPD-related mortality suggests interventions to prevent mortality may need to target particular characteristics or time points in the disease course.
Perspectives on laser-plasma physics in the relativistic transparency regime
Authors: King Martin , Wilson Robbie , Bacon Ewan F. J. , Dolier Ewan J. , Frazer Timothy P. , Goodman Jack , Gray Ross J. , McKenna Paul
Published: June 2023

With the advent of multi-petawatt lasers, the relativistic transparency regime of laser-plasma interactions becomes readily accessible for near-solid density targets. Initially opaque targets that undergo relativistic self-induced transparency (RSIT) have already shown to result in promising particle acceleration and radiation generation mechanisms, as well as relativistic optical and photonics phenomena that modify the spatial, temporal, spectral and polarization properties of the laser pulse itself. At the maximum laser intensities currently available, this opaque-to-RSIT transition regime can be achieved through ultrafast ionization, heating and expansion of initially ultrathin foil targets. Here, we review findings from our programme of work exploring this regime experimentally and numerically, including changes to the laser energy absorption, mechanisms for laser-driven particle acceleration and the generation of a relativistic plasma aperture. New physics induced by this aperture, such as the production of intense light with higher order spatial modes and higher harmonics, and spatially-structured and temporally-varying polarization states, is summarized. Prospects for exploring the physics of the RSIT regime with higher intensity and high repetition rate lasers, including expected new phenomena such as high-field effects and the application of new techniques such as machine learning, are also discussed; outlining directions for the future development of this promising laser-plasma interaction regime.
Stability and Hopf Bifurcation Analysis for an Age-Structured Tumor Immune Model with Time Delay
Authors: Luo Zhonghu , Liu Zijian , Tan Yuanshun
Published: June 2023

In this paper, we propose and analyze an age-structured tumor immune model with time delay. We divide immune cells into two kinds. One is those whose growth is independent of tumor and the other is those whose growth depends on the simulation of the tumor. For these cells, their physiological ages are considered. A mature time delay [Formula: see text] is introduced to the tumor-simulation-dependent immune cells to restrict those cells who participate in the immune response to grow to a minimum physiological age. The existence and stability threshold [Formula: see text] is established for the tumor-free equilibrium state. If [Formula: see text], the tumor-free equilibrium state is both locally and globally asymptotically stable. Whereas, when [Formula: see text], the tumor equilibrium state is locally asymptotically stable if [Formula: see text] and a Hopf bifurcation occurs when [Formula: see text] passes through the threshold [Formula: see text]. This may partly explain the periodic recurrence of some tumors. Finally, theoretical results are verified by some numerical simulations.
Existence, Number and Stability of Periodic Orbits Induced by Homoclinic Loops in Three-Dimensional Piecewise Linear Systems with an Admissible Saddle-Focus
Authors: Wang Lei , Yang Xiao-Song
Published: June 2023

For a class of three-dimensional piecewise linear systems with an admissible saddle-focus, the existence of three kinds of homoclinic loops is shown. Moreover, the birth and number of the periodic orbits induced by homoclinic bifurcation are investigated, and various sufficient conditions are obtained to guarantee the appearance of only one periodic orbit, finitely many periodic orbits or countably infinitely many periodic orbits. Furthermore, the stability of these newborn periodic orbits is analyzed in detail and some conclusions are made about them to be periodic saddle orbits or periodic sinks. Finally, some examples are given.
PHENOTYPIC, PHYLOGENETIC ANALYSIS AND PATHOGENIC DETECTION OF VIBRIO PARAHAEMOLYTICUS IN FARMED PENAEUS VANNAMEI IN TAIWAN
Authors: Nguyen Dieu-An Le , Cheng Li-Wu , Wang Pei-Chi , Chen Shih-Chu
Published: June 2023

Acute hepatopancreatic necrosis disease (AHPND) was first reported in China in 2009. Recently, it has been identified as an emerging threat to shrimp aquaculture industries due to the significant economic losses. The causative agent of AHPND is Vibrio parahaemolyticus (VPAHPND). This study aimed to screen AHPND toxins in bacterial isolates from farmed Penaeus vannamei in Taiwan. In Southern Taiwan, sixty shrimp cases were collected. The prevalence of AHPND positive cases was 65% (39/60), with 4 severely infected cases and 35 moderately infected ones. Eighty-nine bacterial strains were also isolated from white-leg shrimp farms. All of the bacterial isolates were gram-negative, short-rod shaped, and motility-positive, with catalase, oxidase, indole, and glucose fermentation. Eighty-nine strains were identified as V. parahaemolyticus using polymerase chain reaction (PCR). Fifty-nine V. parahaemolyticus isolates tested positive for toxin genes (PirA and PirB) using nested PCR, among them four isolates showed positive in the first step nest PCR. Phylogenetic analysis of these four AHPND isolates revealed complete similarity with AHPND isolates from China, Malaysia, and Thailand. The challenge test showed that these strains produced mass death of up to 90–100% within 24 h after receiving 107 CFU/shrimp intramuscular injection. Histopathological examination of the hepatopancreas revealed haemocyte infiltration and the presence of bacteria within hepatopancreatic lumen. Our findings show that V. parahaemolyticus is the causal agent of AHPND in Taiwanese shrimp farms.
Physical-Digital Programming
Authors: Tran O'Leary Jasper , Benabdallah Gabrielle , Peek Nadya
Published: June 2023

Scientists, artists, and engineers are innovating with digital fabrication machines, yet they lack effective tools to program machines for unconventional tasks. We argue for programming language foundations to empower these practitioners to build bespoke fabrication workflows for themselves.
A Comprehensive Examination of the Protocols, Technologies, and Safety Requirements for Electric Vehicle Charging Infrastructure
Authors: Bommana Babji , Kumar J. S. V. Siva , Nuvvula Ramakrishna S. S. , Kumar Polamarasetty P. , Khan Baseem , Muthusamy Suresh , Inapakurthi Ravikiran
Published: June 2023

Electric vehicles (EVs) have various advantages over traditional internal combustion engines (ICEs), including reduced carbon emissions, greater energy efficiency, and a lessened reliance on petroleum supplies. The use of EV charging infrastructure and power levels are reviewed in this article. Battery performance is affected by the design of the battery as well as the charger parameters and infrastructure. In this paper, the off-board and on-board charging methods with bidirectional and unidirectional power flow are compared. Hardware restrictions and connectivity concerns are eased with a unidirectional charger. The bidirectional charger enables both battery energy injection back into the grid and the vehicle. Power is constrained by the onboard charger due to its size, weight, and price. Both conductive and inductive onboard chargers are viable. For high current rates, which are not supported by EVs, it is feasible to develop an off-board charger. The time required for charging, amount of power, cost, equipment, location, infrastructure configurations, and other parameters are provided, compared, and reviewed for different power level chargers, such as level-1 (slow), level-2 (semi-fast), and level-3 (fast).
L-Carnitine Prevents Behavioural Alterations in Ketamine-Induced Schizophrenia in Mice: Possible Involvement of Oxidative Stress and Inflammation Pathways
Authors: Ebrahimi Mehrasa , Ahangar Nematollah , Zamani Ehsan , Shaki Fatemeh
Published: June 2023

Schizophrenia is a chronic mental complaint known as cognitive impairment. There has been evidence that inflammation and oxidative stress play a main role in schizophrenia pathophysiology. This study aimed to investigate the effects of l-carnitine, as a potent antioxidant, on the treatment of behavioural and biochemical disturbances in mice with ketamine-induced schizophrenia. In this study, schizophrenia was induced in mice by ketamine (25 mg/kg/day, i.p). Before induction of schizophrenia, mice were treated with l-carnitine (100, 200, and 400 mg/kg/day, i.p). Then, behavioural impairments were evaluated by open field (OF) assessment and social interaction test (SIT). After brain tissue isolation, reactive oxygen species (ROS), glutathione concentration (GSH), lipid peroxidation (LPO), protein carbonyl oxidation, superoxide dismutase activity (SOD), and glutathione peroxidase activity (GPx) were assessed as oxidative stress markers. Furthermore, inflammatory biomarkers such as tumour necrosis factor alpha (TNF-α) and nitric oxide (NO) were evaluated in brain tissue. Our results showed ketamine increased inflammation and oxidative damage in brain tissue that was similar to behaviour disorders in mice. Interestingly, l-carnitine significantly decreased oxidative stress and inflammatory markers compared with ketamine-treated mice. In addition, l-carnitine prevented and reversed ketamine-induced alterations in the activities of SOD and GPx enzymes in mice’s brains. Also, improved performance in OFT (locomotor activity test) and SIT was observed in l-carnitine-treated mice. These data provided evidence that, due to the antioxidant and anti-inflammatory effects of l-carnitine, it has a neuroprotective effect on mice model of schizophrenia.
Figure S1, Figure S2, Figure S3, Figure S4, Figure S5 from Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers
Authors: DiPeri Timothy P. , Evans Kurt W. , Raso Maria Gabriela , Zhao Ming , Rizvi Yasmeen Q. , Zheng Xiaofeng , Wang Bailiang , Kirby Bryce P. , Kong Kathleen , Kahle Michael , Yap Timothy A. , Dumbrava Ecaterina E. , Ajani Jaffer A. , Fu Siqing , Keyomarsi Khandan , Meric-Bernstam Funda
Published: June 2023

Supplemental Figures 1 - 5
Supplementary Figure S1 from Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non–Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042)
Authors: Gadgeel Shirish M. , Miao Jieling , Riess Jonathan W. , Moon James , Mack Philip C. , Gerstner Gregory J. , Burns Timothy F. , Taj Asma , Akerley Wallace L. , Dragnev Konstantin H. , Laudi Noel , Redman Mary W. , Gray Jhanelle E. , Gandara David R. , Kelly Karen
Published: June 2023

Supplementary Figure 1. Progression-Free Survival and Overall Survival in patients with cancers with TP53 co-mutations, and STK11 co-mutations.
Supplementary Figure S1 from HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette
Published: June 2023

HLA-II expression in longitudinal melanoma samples
Data from Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers
Authors: DiPeri Timothy P. , Evans Kurt W. , Raso Maria Gabriela , Zhao Ming , Rizvi Yasmeen Q. , Zheng Xiaofeng , Wang Bailiang , Kirby Bryce P. , Kong Kathleen , Kahle Michael , Yap Timothy A. , Ileana Dumbrava Ecaterina E. , Ajani Jaffer A. , Fu Siqing , Keyomarsi Khandan , Meric-Bernstam Funda
Published: June 2023

Abstract
Purpose: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. Experimental Design: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and immunohistochemistry. In vitro CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by immunohistochemistry and reverse phase protein array. Results: Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43% and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2 overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2 expressing tumor types, including a T-DXd-treated colon cancer model. Conclusions: We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications.
Data from Phase II study of docetaxel and trametinib in patients with KRAS mutation positive recurrent non-small cell lung cancer (NSCLC) (SWOG S1507, NCT-02642042)
Authors: Gadgeel Shirish M. , Miao Jieling , Riess Jonathan W. , Moon James , Mack Philip C. , Gerstner Gregory J. , Burns Timothy F. , Taj Asma , Akerley Wallace L. , Dragnev Konstantin H. , Laudi Noel , Redman Mary W. , Gray Jhanelle E. , Gandara David R. , Kelly Karen
Published: June 2023

Abstract
Purpose: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and co-mutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC. Patients and Methods: S1507 is a single arm phase II assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients with at least 25 with G12C mutation. The design was 2-stage design to rule out a 17% RR, within the overall population at the 1-sided 3% level and within the G12C subset at the 5% level. Results: Between July 18, 2016 and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% (95%CI- 22-48) overall and 28% (95%CI- 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR:2.85, 95%CI 1.16-7.01) and RR (0% vs. 56%, p = 0.004) were worse in patients with TP53 mutated versus wild type cancers. Conclusions: RRs were significantly improved in the overall population. Contrary to pre-clinical studies, the combination showed no improvement in efficacy in G12C patients. Co-mutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation.
Table S6 from An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression
Authors: Indeglia Alexandra , Leung Jessica C. , Miller Sven A. , Leu Julia I-Ju , Dougherty James F. , Clarke Nicole L. , Kirven Nicole A. , Shao Chunlei , Ke Lei , Lovell Scott , Barnoud Thibaut , Lu David Y. , Lin Cindy , Kannan Toshitha , Battaile Kevin P. , Yang Tyler Hong Loong , Batista Oliva Isabela , Claiborne Daniel T. , Vogel Peter , Liu Lijun , Liu Qin , Nefedova Yulia , Cassel Joel , Auslander Noam , Kossenkov Andrew V. , Karanicolas John , Murphy Maureen E.
Published: June 2023

Key Reagents List for this study.
Automated Whole Cochlear T2 Signal Demonstrates Weak Correlation with Hearing Loss in Observed Vestibular Schwannoma
Authors: Cass Nathan D , Fan Yubo , Lindquist Nathan R , Dawant Benoit M. , Tawfik Kareem O
Published: June 2023

Introduction: We sought to evaluate the correlation between whole cochlear T2 signal changes obtained with a novel automated segmentation method and hearing levels, both at diagnosis and over time, in patients with observed vestibular schwannoma. Methods: This retrospective correlation study within an academic medical center neurotology practice evaluated 127 patients with vestibular schwannoma observed over time, each with ≥2 MRI scans (367 total) and ≥2 audiograms (472 total). 86 patients had T2-weighted sequences with sufficient resolution for cochlear signal analysis, yielding 348 unique timepoint intervals. The main outcome measure was correlation of the ipsilateral-to-contralateral ratio of whole cochlear T2 signal with hearing outcomes as measured by pure tone average (PTA) and word recognition score (WRS). Results: Whole cochlear T2 signal ratios did not show a correlation with hearing levels at diagnosis. Change in signal ratio over time showed weak correlation with changes in PTA, but not WRS, over time. Cochlear signal ratio did not precede changes in hearing but did follow changes in both PTA and WRS. Conclusion: Whole cochlear T2 signal ratios were weakly correlated with changes in hearing in patients with observed vestibular schwannoma. The technology of automated segmentation and signal processing holds promise for future evaluation of clinical entities causing cochlear signal changes.
Delabeling of Penicillin Allergy: Room for Improvement
Authors: Fransson Sara , Damving Christina Monnerup , Boel Jonas Bredtoft , Arpi Magnus , Skinhøj Ida Gjørup , Jarløv Jens Otto , Mosbech Holger F. , Poulsen Lars K. , Garvey Lene H.
Published: June 2023

Background: Penicillin allergy labels have been shown to be associated with suboptimal treatment, negative health outcomes, and increased antibiotic resistance. Many inpatients claim to have penicillin allergy, but studies show that allergy can be disproved and the label removed in up to 90% of cases. Objectives: The purpose of the study was to investigate the proportion of patients with a penicillin allergy label in a Danish hospital and to classify patients according to the risk of having penicillin allergy in “no risk,” low, and high risk. Methods: For 22 days, inpatients with penicillin allergy labels were interviewed, had their dispensed penicillin prescriptions examined, and were subsequently categorized into risk groups based on the risk evaluation criteria in national guidelines. Results: In total, 260 patients had a penicillin allergy label (10% of the inpatients). Out of 151 included patients, 25 were “no risk” patients (17%), who could potentially have their penicillin allergy label removed without testing. 42 were low-risk patients (28%). 10 “no risk” patients and 20 low-risk patients had been prescribed and dispensed one or more penicillins despite an allergy label. Conclusion: Ten percent of inpatients have a penicillin allergy label in a Danish hospital. 17% of these could potentially have their penicillin allergy label removed without allergy testing.
Adverse Effects of COVID-19 Vaccination in Patients with Transfusion-Dependent Thalassemia: An Observational Study from a Tertiary Care Center in Punjab, India
Authors: Kakkar Shruti , Jain Evani , Jain Anirudh , Dewan Priyanka
Published: June 2023

Vaccination against SARS-CoV-2 is the most important weapon in the arsenal in the battle against COVID-19. There is concern about an increased risk of adverse effects in patients with transfusion-dependent thalassemia (TDT), which affects vaccine acceptance. A predesigned questionnaire was used to evaluate adverse effects (local/systemic within 90 days after vaccination) in participants >18 years of age with TDT. A total of 100 patients received 129 vaccine doses. The mean age of the patients was 24.3 ± 5.7 years, and M:F ratio of 1.6:1. Covishield (Serum Institute of India) was administered to 89% of the participants, and Covaxin (Bharat Biotech Limited) to 11% of the participants. Adverse effects were documented in 62% of the respondents and were more pronounced after the first dose (52%) compared to the second dose (9%). The most frequent adverse effects were pain at the injection site (43%) and fever (37%). All adverse effects were mild and none of the participants required hospitalization. There were no differences in adverse effects among different vaccines, in the presence or absence of comorbidities, blood groups, or ferritin levels. The SARS-CoV-2 vaccine appears to be safe for patients with TDT.
Efficacy of PD-1 Inhibitors in First-Line Treatment for Advanced Gastroesophageal Junction and Gastric Cancer by Subgroups: A Systematic Review and Meta-Analysis
Authors: Fei Shengqi , Lu Yu , Chen Jing , Qi Jia , Wu Wenxuan , Wang Beidi , Han Yaxuan , Wang Kefan , Han Xiaying , Zhou Haiyan , Wang Jun , Chen Jian
Published: June 2023

Background: PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined. Objective: This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials. Method: The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability. Results: This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55–0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76–0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69–0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002). Conclusions: For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.
Effects of Intravitreal Ranibizumab Injection to Treat Macular Edema due to Central Retinal Vein Occlusion on Choroidal Findings and Functional-Morphological Parameters
Authors: Yasuda Kanako , Noma Hidetaka , Oyama Eri , Yanagida Kosei , Asakage Masaki , Shimura Masahiko
Published: June 2023

Introduction: Little research has examined the effects of anti-vascular endothelial growth factor therapy on subfoveal choroidal thickness (SCT), choroidal blood flow, aqueous flare, and humor levels of growth and inflammatory factors in patients with macular edema due to central retinal vein occlusion (CRVO). Methods: In 58 patients with macular edema due to CRVO treated by intravitreal ranibizumab injection (IRI), we retrospectively assessed best-corrected visual acuity (BCVA, assessed as the logarithm of the minimum angle of resolution [logMAR]), 8 aqueous factors (by suspension array), mean blur rate (MBR; estimated by laser speckle flowgraphy as a measure of choroidal blood flow), aqueous flare (with a laser flare meter), and SCT and central macular thickness (CMT; by optical coherence tomography). Results: After 4 weeks, IRI resulted in a significant improvement in BCVA and CMT and a significant reduction in SCT, choroidal MBR, and aqueous flare. SCT was significantly positively correlated with placental growth factor and significantly negatively correlated with platelet-derived growth factor-AA, and change in SCT was significantly negatively correlated with change in BCVA (logMAR). Aqueous flare was significantly negatively correlated with SCT. Conclusion: Growth and inflammatory factors may be associated with SCT, and changes in SCT may be associated with changes in BCVA after IRI to treat macular edema due to CRVO.
Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2023
Authors: Park-Simon Tjoung-Won , Müller Volkmar , Jackisch Christian , Albert Ute-Susann , Banys-Paluchowski Maggie , Bauerfeind Ingo , Blohmer Jens-Uwe , Budach Wilfried , Dall Peter , Ditsch Nina , Fallenberg Eva Maria , Fasching Peter A. , Fehm Tanja , Friedrich Michael , Gerber Bernd , Gluz Oleg , Harbeck Nadia , Hartkopf Andreas D. , Heil Joerg , Huober Jens , Kolberg-Liedtke Cornelia , Kreipe Hans H. , Krug David , Kühn Thorsten , Kümmel Sherko , Loibl Sibylle , Lüftner Diana , Lux Michael Patrick , Maass Nicolai , Mundhenke Christoph , Reimer Toralf , Rhiem Kerstin , Rody Achim , Schmidt Marcus , Schneeweiss Andreas , Schütz Florian , Sinn Hans Peter , Solbach Christine , Solomayer Erich-Franz , Stickeler Elmar , Thomssen Christoph , Untch Michael , Witzel Isabell , Wöckel Achim , Wuerstlein Rachel , Janni Wolfgang , Thill Marc
Published: June 2023

Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023. Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.
AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023
Authors: Thill Marc , Kolberg-Liedtke Cornelia , Albert Ute-Susann , Banys-Paluchowski Maggie , Bauerfeind Ingo , Blohmer Jens-Uwe , Budach Wilfried , Dall Peter , Ditsch Nina , Fallenberg Eva Maria , Fasching Peter A. , Fehm Tanja , Friedrich Michael , Gerber Bernd , Gluz Oleg , Harbeck Nadia , Hartkopf Andreas D. , Heil Joerg , Huober Jens , Jackisch Christian , Kreipe Hans H. , Krug David , Kühn Thorsten , Kümmel Sherko , Loibl Sibylle , Lüftner Diana , Lux Michael Patrick , Maass Nicolai , Mundhenke Christoph , Reimer Toralf , Rhiem Kerstin , Rody Achim , Schmidt Marcus , Schneeweiss Andreas , Schütz Florian , Sinn Hans Peter , Solbach Christine , Solomayer Erich-Franz , Stickeler Elmar , Thomssen Christoph , Untch Michael , Witzel Isabell , Wöckel Achim , Wuerstlein Rachel , Müller Volkmar , Janni Wolfgang , Park-Simon Tjoung-Won
Published: June 2023

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2023 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer (mBC).
Perivascular Macrophages Mediate Microvasospasms After Experimental Subarachnoid Hemorrhage
Authors: Lin Xiangjiang , Khalin Igor , Harapan Biyan Nathanael , Terpolilli Nicole Angela , Schwarting Julian , Plesnila Nikolaus
Published: June 2023

BACKGROUND:

Subarachnoid hemorrhage (SAH) is characterized by acute and delayed reductions of cerebral blood flow (CBF) caused, among others, by spasms of cerebral arteries and arterioles. Recently, the inactivation of perivascular macrophages (PVM) has been demonstrated to improve neurological outcomes after experimental SAH, but the underlying mechanisms of protection remain unclear. The aim of our exploratory study was, therefore, to investigate the role of PVM in the formation of acute microvasospasms after experimental SAH.

METHODS:

PVMs were depleted in 8- to 10-week-old male C57BL/6 mice (n=8/group) by intracerebroventricular application of clodronate-loaded liposomes and compared with mice with vehicle liposome injections. Seven days later, SAH was induced by filament perforation under continuous monitoring of CBF and intracranial pressure. Results were compared with sham-operated animals and animals who underwent SAH induction but no liposome injection (n=4/group each). Six hours after SAH induction or sham surgery, numbers of microvasospasms per volume of interest and % of affected pial and penetrating arterioles were examined in 9 standardized regions of interest per animal by in vivo 2-photon microscopy. Depletion of PVMs was proven by quantification of PVMs/mm
3
identified by immunohistochemical staining for CD206 and Collagen IV. Statistical significance was tested with
t
tests for parametric data and Mann-Whitney
U
test for nonparametric data.

RESULTS:

PVMs were located around pial and intraparenchymal arterioles and were effectively depleted by clodronate from 671±28 to 46±14 PVMs/mm
3
(
P
<0.001). After SAH, microvasospasms was observed in pial arteries and penetrating and precapillary arterioles and were accompanied by an increase to 1405±142 PVMs/mm
3
. PVM depletion significantly reduced the number of microvasospasms from 9 IQR 5 to 3 IQR 3 (
P
<0.001).

CONCLUSIONS:

Our results suggest that PVMs contribute to the formation of microvasospasms after experimental SAH.
Qohelet as Divine Hedonist
Authors: Sneed Mark
Published: June 2023

This paper will demonstrate that the best descriptor of Qohelet is divine hedonist, not absurdist, skeptic, pessimist, realist, nihilist or “Preacher of Joy.” This will be done by examining the relationship between Qohelet’s hebel-judgments and his carpe diem ethic and comparing Qohelet’s strategy with that of philosopher David Hume. Qohelet’s hebel-judgments serve to deconstruct the traditional formulation of the Tun-Ergehen-Zusammenhang, opening space for legitimating his preferred ethic: the carpe diem. In other words, Qohelet rhetorically paints a dark and dreary world in order to buttress his main ethic, the carpe diem, an ethic that is both hedonistic (using philosophical classification) in seeking pleasure and avoiding pain (reflected in his God-fearing motif), and divine in that this ethic must align with God’s mysterious decrees.
A New Look at Abigail’s Wisdom
Authors: Schwartz Sarah
Published: June 2023

This paper offers a new look at the design of Abigail’s character as a wise woman in 1 Sam 25, based on an analysis of the argumentative component of Abigail’s speech and the connections between her speech and the book of Proverbs. According to this analysis, Abigail is not only portrayed as a rescuer, but is also designed in the image of the wise educator in the book of Proverbs, who teaches David a fundamental theological principle about relying on God instead of on his own strength—despite the essential legitimacy to harm Nabal. This message is relevant to David’s status as an anointed king de jure, but as a refugee de facto. David’s adherence to Abigail’s message designs his character as a wise person who is willing to learn, indicating that the narrative justifies David’s monarchy through his encounter with Abigail.
Seasonal variation in the land hermit crab, Coenobita rugosus H. Milne Edwards, 1837 (Decapoda, Anomura) and a preliminary study of land hermit crabs as a bioindicator of turtle nesting at Penghu County Wang-An Island green turtle nesting refuge, Taiwan
Authors: Hsu Chia-Hsuan , Fang Wei-Ta , Jiang Bing-Rong , Chai Lei , Kao Wei-Cheng , Huang Tsung-Shun
Published: June 2023

The present study surveyed the land hermit crab species, body size, shell type, and shell suitability, at five sites over four seasons in the Penghu County Wang-an Island Green Turtle Nesting Refuge. Coenobita rugosus H. Milne Edwards, 1837 was the only species recorded and found at three sites (Tiantai Hill, Xi’an Reservoir, and Tudigong). The density index of hermit crabs exhibited notable variations across the sites, showing no significant variation with the changing seasons. The bush habitat displayed a higher density index compared to the sand habitat. Additionally, the sites differed significantly in terms of the shell type and body size of the hermit crabs. Further, no significant relationship was established between abundance and weather factors or between crab abundance and sea turtle nesting. This investigation is a preliminary examination of the possibility of land hermit crabs being used as bioindicators for breeding of sea turtles.
The Humours and the Dyes
Authors: Raggetti Lucia
Published: June 2023

This contribution presents the edition and translation of a new manuscript witness to the Arabic tradition of Galenic summaries On urine (MS Collegesville, Minnesota HMML olm 00041). Uroscopy appears to be a complementary diagnostic element in ancient medicine, which gained increasing popularity in later centuries, as attested by the rich traditions in Greek and Arabic. The summary, as attested in this manuscript witness, compares the four bodily humours to dyes, creating a concrete and tangible frame for the study and memorization of this diagnostic branch. This text, moreover, stresses the performative dimension of uroscopy, particularly in the form of instructions for physicians on how to recognize devious fake samples offered by obnoxious people seeking to test the physician in order to undermine his authority and credibility.