bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS, MYC, and ARF6: inseparable relationships cooperatively promote cancer malignancy and immune evasion
Authors: Sabe Hisataka 
Published: May 2023

AbstractMutations in the KRAS gene and overexpression of protein products of the MYC and ARF6 genes occur frequently in cancer. Here, the inseparable relationships and cooperation of the protein products of these three genes in cancer malignancy and immune evasion are discussed. mRNAs encoded by these genes share the common feature of a G-quadruplex structure, which directs them to be robustly expressed when cellular energy production is increased. These three proteins are also functionally inseparable from each other, as follows.　1) KRAS induces MYC gene expression, and may also promote eIF4A-dependent MYC and ARF6 mRNA translation, 2) MYC induces the expression of genes involved in mitochondrial biogenesis and oxidative phosphorylation, and 3) ARF6 protects mitochondria from oxidative injury. ARF6 may moreover promote cancer invasion and metastasis, and also acidosis and immune checkpoint. Therefore, the inseparable relationships and cooperation of KRAS, MYC, and ARF6 appear to result in the activation of mitochondria and the driving of ARF6-based malignancy and immune evasion. Such adverse associations are frequent in pancreatic cancer, and appear to be further enhanced by TP53 mutations.
A comparison between knotted and knotless medial row of suture bridge technique in arthroscopic rotator cuff repair surgery: a meta-analysis
Authors: Xiao Qiuping , Quan Xiaolin , Hu Shidong , Xiao Yujia , Wu Jiangping , Nie Mao 
Published: May 2023

Abstract
Background
The shoulder arthroscopic suture bridge technique is currently very popular, but scientific evidence relating to the clinical outcomes of the medial row with or without knots has not been systematic reviewed.

Purpose
The purpose of this study was to compare the clinical outcomes of knotted versus knotless double-row suture bridges for rotator cuff repairs.

Study design
Meta-analysis.

Method
Five databases that contain literature in English were searched (Medline, PubMed, Embase, Web of Science, and the Cochrane Library), with a focus on works published between 2011 and 2022. Clinical data relating to arthroscopic rotator cuff repair with the suture bridge approach was examined and the outcomes of medial row knotting contrasted with that of the knotless technique. The search phrase used was: (double row) AND (rotator cuff) AND (repair), and the search method is subject term plus free word search. Literature quality evaluation was performed using the Cochrane “risk of bias” tool 1.0 and the Newcastle–Ottawa scale quality assessment instrument.

Results
One randomized controlled trial, four prospective cohort studies, and five retrospective cohort studies were included in this meta-analysis. Data pertaining to 1146 patients was drawn from these ten original papers and analyzed. Meta-analyses that were performed on 11 postoperative outcomes revealed that none of the differences were statistically significant (P > 0.05) and that the publications were unbiased (P > 0.05). Postoperative retear rate and postoperative retear categorization were the outcomes assessed. Scores on postoperative pain, forward flexion, abduction, and external rotation mobility were collated and evaluated. The University of California, Los Angeles scoring systems in the first year following surgery, the American Shoulder and Elbow Surgeons score and Constant scales in the first and second years after surgery were the secondary outcomes spotlighted in this study.

Conclusion
The clinical outcomes of shoulder arthroscopic rotator cuff repair with the suture bridge technique with or without a knotted medial row was proven to be equivalent. These outcomes are about postoperative retear, postoperative retear classification, postoperative shoulder function score, postoperative shoulder mobility, and postoperative pain, respectively. It should be noted that the conclusions are based on short-term clinical follow-up data.
First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors
Authors: Zhao Yuanyuan , Ma Yuxiang , Zang Aimin , Cheng Ying , Zhang Yiping , Wang Xiangcai , Chen Zhendong , Qu Song , He Jianbo , Chen Chuanben , Jin Chuan , Zhu Dongyuan , Li Qingshan , Liu Xianling , Su Wuyun , Ba Yi , Hao Yanrong , Chen Junmin , Zhang Guoping , Qu Shenhong , Li Yong , Feng Weineng , Yang Mengxiang , Liu Baorui , Ouyang Weiwei , Liang Jin , Yu Zhuang , Kang Xiaoyan , Xue Shilin , Yang Guihong , Yan Wei , Yang Yingying , Liu Zhi , Peng Yufeng , Fanslow Bill , Huang Xian , Zhang Li , Zhao Hongyun 
Published: May 2023

Abstract
Background
QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies.

Methods
In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated.

Results
Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively.

Conclusions
QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials.
Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.
Impact of early relapse within 24 months after first-line systemic therapy (POD24) on outcomes in patients with marginal zone lymphoma: A US multisite study
Authors: Epperla Narendranath , Welkie Rina Li , Torka Pallawi , Shouse Geoffrey , Karmali Reem , Shea Lauren , Anampa-Guzmán Andrea , Oh Timothy S. , Reaves Heather , Tavakkoli Montreh , Lindsey Kathryn , Greenwell Irl Brian , Hansinger Emily , Thomas Colin , Chowdhury Sayan Mullick , Annunzio Kaitlin , Christian Beth , Barta Stefan K. , Geethakumari Praveen Ramakrishnan , Bartlett Nancy L. , Herrera Alex F. , Grover Natalie S. , Olszewski Adam J. 
Published: May 2023

AbstractProgression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53–4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.
Convergence of YAP/TAZ, TEAD and TP63 activity is associated with bronchial premalignant severity and progression
Authors: Ning Boting , Tilston-Lunel Andrew M. , Simonetti Justice , Hicks-Berthet Julia , Matschulat Adeline , Pfefferkorn Roxana , Spira Avrum , Edwards Matthew , Mazzilli Sarah , Lenburg Marc E. , Beane Jennifer E. , Varelas Xaralabos 
Published: May 2023

Abstract
Background
Bronchial premalignant lesions (PMLs) are composed primarily of cells resembling basal epithelial cells of the airways, which through poorly understood mechanisms have the potential to progress to lung squamous cell carcinoma (LUSC). Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we examine the functional association of YAP/TAZ, TEADs and TP63 in bronchial epithelial cells and PMLs.

Methods
We performed RNA-seq in primary human bronchial epithelial cells following small interfering RNA (siRNA)-mediated depletion of YAP/TAZ, TEADs or TP63, and combined these data with ChIP-seq analysis of these factors. Directly activated or repressed genes were identified and overlapping genes were profiled across gene expression data obtained from progressive or regressive human PMLs and across lung single cell RNA-seq data sets.

Results
Analysis of genes regulated by YAP/TAZ, TEADs, and TP63 in human bronchial epithelial cells revealed a converged transcriptional network that is strongly associated with the pathological progression of bronchial PMLs. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal epithelial cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets we identified include the MHC Class II transactivator CIITA, which is repressed in progressive PMLs and associates with adaptive immune responses in the lung. Our findings provide molecular insight into the control of gene expression events driving PML progression, including those contributing to immune evasion, offering potential new avenues for lung cancer interception.

Conclusions
Our study identifies important gene regulatory functions for YAP/TAZ-TEAD-TP63 in the early stages of lung cancer development, which notably includes immune-suppressive roles, and suggest that an assessment of the activity of this transcriptional complex may offer a means to identify immune evasive bronchial PMLs and serve as a potential therapeutic target.
Impact of cardiac output and alveolar ventilation in estimating ventilation/perfusion mismatch in ARDS using electrical impedance tomography
Authors: Tuffet Samuel , Maraffi Tommaso , Lacheny Matthieu , Perier François , Haudebourg Anne-Fleur , Boujelben Mohamed Ahmed , Alcala Glasiele , Mekontso-Dessap Armand , Carteaux Guillaume 
Published: May 2023

Abstract
Introduction
Electrical impedance tomography (EIT) can be used to assess ventilation/perfusion (V/Q) mismatch within the lungs. Several methods have been proposed, some of them neglecting the absolute value of alveolar ventilation (VA) and cardiac output (QC). Whether this omission results in acceptable bias is unknown.

Methods
Pixel-level V/Q maps of 25 ARDS patients were computed once considering (absolute V/Q map) and once neglecting (relative V/Q map) the value of QC and VA. Previously published indices of V/Q mismatch were computed using absolute V/Q maps and relative V/Q maps. Indices computed with relative V/Q maps were compared to their counterparts computed using absolute V/Q maps.

Results
Among 21 patients with ratio of alveolar ventilation to cardiac output (VA/QC) > 1, relative shunt fraction was significantly higher than absolute shunt fraction [37% (24–66) vs 19% (11–46), respectively, p < 0.001], while relative dead space fraction was significantly lower than absolute dead space fraction [40% (22–49) vs 58% (46–84), respectively, p < 0.001]. Relative wasted ventilation was significantly lower than the absolute wasted ventilation [16% (11–27) vs 29% (19–35), respectively, p < 0.001], while relative wasted perfusion was significantly higher than absolute wasted perfusion [18% (11–23) vs 11% (7–19), respectively, p < 0.001]. The opposite findings were retrieved in the four patients with VA/QC < 1.

Conclusion
Neglecting cardiac output and alveolar ventilation when assessing V/Q mismatch indices using EIT in ARDS patients results in significant bias, whose direction depends on the VA/QC ratio value.
Molecular imaging of fibroblast activation in multiple non-ischemic cardiomyopathies
Authors: Wang Jingnan , Huo Li , Lin Xue , Fang Ligang , Hacker Marcus , Niu Na , Li Xiang 
Published: May 2023

Abstract
Background
This pilot study is aimed to perform a pilot visualization study to investigate in vivo fibroblast activation in non-ischemic cardiomyopathies by 68Ga-FAPI-04 PET/CT.

Methods
Twenty-nine consecutive patients with symptomatic non-ischemic cardiomyopathies who underwent 68Ga-FAPI-04 PET/CT were prospectively recruited. Clinical characteristics and echocardiographic parameters were recorded. Cardiac uptake was quantified by standardized uptake values (SUVmax, SUVmean, SUVR) and left ventricular metabolism volume. The relationship between 68Ga-FAPI-04 uptake with clinical and echocardiography parameters was investigated.

Results
Heterogeneous 68Ga-FAPI-04 uptake was observed in different subtypes of non-ischemic cardiomyopathies. Twenty-two (75.9%) patients showed elevated 68Ga-FAPI-04 uptake in the left ventricle, and 10 (34.5%) patients also showed slightly diffuse elevated uptake in the right ventricle. Cardiac uptake values were significantly correlated with enlarged ventricular volume evaluated by echocardiography.

Conclusion
FAPI PET/CT presents a potential value for in vivo visualization and quantification of fibroblast activation on the molecular level. Further study is warranted for investigating the theranostic and prognostic value of elevated FAP signal.
Effects of dietary supplementation of bacteriophage cocktail on health status of weanling pigs in a non-sanitary environment
Authors: Choi YoHan , Hosseindoust Abdolreza , Ha Sang Hun , Kim Joeun , Min YeJin , Jeong YongDae , Mun JunYoung , Sa SooJin , Kim JinSoo 
Published: May 2023

Abstract
Background
The study evaluated the effects of bacteriophage cocktail (BP) and ZnO administered during weaning time for piglets exposed to a non-sanitary environment. The bacteriophages were designed to eliminate Escherichia coli (K88, K99 and F41), Salmonella (typhimurium and enteritidis), and Clostridium perfreingens (types A and C). Forty 21-day-old crossbreed piglets were assigned to four treatments, including the PC (sanitary environment), NC (non-sanitary environment), BP (NC plus 108 pfu/kg BP), and ZO (NC plus 2,500 mg/kg ZnO). Piglets in the NC, BP and ZO were kept in a non-sanitary environment for 14 d, which was contaminated with the feces of infected pigs.

Results
Pigs in the BP and ZO treatments had a higher final body weight compared with the NC. The NC treatment showed the highest concentration of inflammatory cytokines including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α in the plasma. The administration of BP and ZO showed lower myeloperoxidase concentrations compared with the NC. The NC treatment showed a lower concentration of superoxide dismutase in serum compared with the PC. Among the treatments in non-sanitary environment, the NC treatment showed a higher concentration of malondialdehyde compared with the ZO. The PC treatment showed a lower concentration of butyric acid in the feces compared with the BP treatment. Among non-sanitary treatments, the villus height in the duodenum was greater in the BP and ZO compared with the NC. The lower abundance of Proteobacteria phylum was observed in the BP and PC treatments compared with the NC. The highest relative abundance of Eubacterium was recorded in the BP treatment. The abundance of Megasphaera and Schwartzia was higher in the NC pigs compared with the BP piglets. The abundance of Desulfovibrio was lower in the supplemented treatments (BP and ZO) compared with non-supplemented (NC and PC). The abundance of Cellulosilyticum genera was higher in the BP and ZO treatments rather than in the NC. The piglets in the NC treatment had the highest abundance of Escherichia-Shigella, followed by the PC and ZO treatments.

Conclusion
In conclusion, these results suggest that the supplementation of bacteriophage cocktail could effectively control Proteobacteria phylum, Clostridium spp. and coliforms population and mitigated the adverse influences of weaning stress in piglets.
ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics
Authors: Panahi Mahmod , Hase Yoshiki , Gallart-Palau Xavier , Mitra Sumonto , Watanabe Atsushi , Low Roger C , Yamamoto Yumi , Sepulveda-Falla Diego , Hainsworth Atticus H , Ihara Masafumi , Sze Siu Kwan , Viitanen Matti , Behbahani Homira , Kalaria Raj N 
Published: May 2023

AbstractCerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but the potential mechanisms involved in their degeneration are still unclear. Focusing on cerebral microvessels in the frontal and anterior temporal lobes and the basal ganglia, we used advanced proteomic and immunohistochemical methods to explore the extent of inflammatory and immune responses in CADASIL subjects compared to similar age normal and other disease controls. There was variable loss of VSMC in medial layers of arteries in white matter as well as the cortex, that could not be distinguished whether NOTCH3 mutations were in the epidermal growth factor (EGFr) domains 1–6 or EGFr7-34. Proteomics of isolated cerebral microvessels showed alterations in several proteins, many associated with endoplasmic reticulum (ER) stress including heat shock proteins. Cerebral vessels with sparsely populated VSMCs also attracted robust accrual of perivascular microglia/macrophages in order CD45+ > CD163+ > CD68+cells, with > 60% of vessel walls exhibiting intercellular adhesion molecule-1 (ICAM-1) immunoreactivity. Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively. We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels. Increased complement expression was corroborated in > 70% of cultured VSMCs bearing the Arg133Cys mutation independent of N3ECD immunoreactivity. Our observations suggest that ER stress and other cellular features associated with arteriolar VSMC damage instigate robust localized inflammatory and immune responses in CADASIL. Our study has important implications for immunomodulation approaches to counter the characteristic arteriopathy of CADASIL.
Conformational characterization of the mammalian-expressed SARS-CoV-2 recombinant receptor binding domain, a COVID-19 vaccine
Authors: Moro-Pérez Leina , Boggiano-Ayo Tammy , Lozada-Chang Sum Lai , Fernández-Saiz Olga Lidia , de la Luz Kathya Rashida , Gómez-Pérez Jose Alberto 
Published: May 2023

AbstractThe COVID-19 pandemic has caused a large number of diseases worldwide. There are few vaccines to constrain this disease and the value of them is high. In this sense, the antigens of the vaccine platform Soberana, the receptor binding domain from SARS-CoV-2 Spike protein, both the monomeric (mRBD) and dimeric (dRBD) forms, have been developed. This study encompassed several analyses by different techniques like circular dichroism (CD), fluorescence spectroscopy (FS) and Gel Filtration- High Performance Liquid ChLC of mRBD and dRBD. Monomer and dimer exhibited similar far-UV CD spectral characteristics with 54% of β-sheet content. Similar conformational features according to near-UV CD and FS studies were observed in both RBD. Stress stability studies by far-UV CD, FS, biological activity and GF-HPLC at 37 °C showed that mRBD is very stable. On the other hand, dRBD fluorescent emission showed a shift towards higher wavelengths as the incubation time increases, suggesting exposition of tryptophan residues, unlike what happens with mRBD. Biological activity outcome confirms these results. GF-HPLC profiles showed that in mRBD, the product of molecular stress are dimers and does not increase over time. However, dRBD showed dimer fragmentation as the main degradation species. This study reveals the usefulness of CD techniques for the analysis of degradation of RBD molecules as well as showed the difference in stability of both RBD molecules. Besides, our work provides useful insights into the production of a key protein used in diagnosis and therapeutics to fight COVID-19 pandemia.