bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of HBV Novel Serum Markers across Distinct Phases in Treatment-Naïve Chronic HBV-Infected Patients
Authors: Liao Hao , Li Le , Zheng Wei V. , Zou Jun , Yu Guangxin , Si Lanlan , Ge Feilin , Zhou Tao , Ji Dong , Chen Xiangmei , Xu Dongping , Cheng Guanxun , Liu Yan , Chen Junhui 
Published: July 2022

Background and aims. To investigate the clinical implications of serum HBV RNA, serum hepatitis B core-related antigen (HBcrAg), and quantitative anti-HBc in treatment-naïve patients with chronic HBV infection. Methods. A total of 111 patients in total from different disease phases were recruited, including 21 in immune-tolerant (IT) phase, 49 in immune-clearance (IC) phases, 29 in immune-control or low replicative (LR) phase, and 12 in reactivation phases. Serum HBV RNA, anti-HBc, HBcrAg, and intrahepatic covalently closed circular DNA (cccDNA) were quantified and each of these indicator’s correlation with liver inflammation was analyzed. Results. HBeAg-positive individuals had significant higher serum levels of HBV RNA and HBcrAg than those who were HBeAg negative, similar to that of serum HBV DNA. Comparatively, HBV RNA (

r

=0.79,

P
<
0.01

) and HBcrAg (

r

=0.78,

P
<
0.01

) had almost same higher overall correlation with the cccDNA, as that of HBV DNA (

r

=0.81,

P
<
0.01

). Serum anti-HBc level (

r

= -0.52,

P
<
0.05

) is negatively correlated with cccDNA level at IT phase rather than the other three phases. When set the cutoff value at 4.00 log10 IU/mL, serum anti-HBc showed potential to indicate liver inflammation, with AUC as 0.79 and the specificities as 78.85% for HBeAg positive, and with AUC as 0.72 and the specificities as 62.16% for HBeAg-negative patients, respectively. Conclusions. In treatment-naïve patients, levels of serological markers HBV RNA and HBcrAg could mirror intrahepatic cccDNA level, but were not superior to HBV DNA level. Serum anti-HBc level had certain potential to be used as a predicting marker for liver inflammation.
Neoadjuvant Trastuzumab and Pyrotinib for Locally Advanced HER2-Positive Breast Cancer (NeoATP): Primary Analysis of a Phase II Study
Authors: Yin Wenjin , Wang Yaohui , Wu Ziping , Ye Yumei , Zhou Liheng , Xu Shuguang , Lin Yanping , Du Yueyao , Yan Tingting , Yang Fan , Zhang Jie , Liu Qiang , Lu Jinsong 
Published: July 2022

Abstract

Purpose:
Despite accumulating evidence on dual blockade of HER2 for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy.

Patients and Methods:
The phase II NeoATP trial included female patients with histologically confirmed stage IIA to IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel–cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathologic complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis, and safety.

Results:
Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor–negative and –positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00%, respectively, for those with and without PIK3CA mutation (P = 0.958). The most frequently reported Grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%), and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction &lt;50% or &gt;10 points drop from baseline to before surgery was reported.

Conclusions:
The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.
Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer
Authors: Ruggieri Amanda N. , Yarchoan Mark , Goyal Subir , Liu Yuan , Sharon Elad , Chen Helen X. , Olson Brian M. , Paulos Chrystal M. , El-Rayes Bassel F. , Maithel Shishir K. , Azad Nilofer S. , Lesinski Gregory B. 
Published: July 2022

AbstractPurpose:Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC.Experimental Design:We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC.Results:At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progression-free survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively.Conclusions:This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.
A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma
Authors: Saulnier-Sholler Giselle , Duda Dan G. , Bergendahl Genevieve , Ebb David , Snuderl Matija , Laetsch Theodore W. , Michlitsch Jennifer , Hanson Derek , Isakoff Michael S. , Bielamowicz Kevin , Kraveka Jacqueline M. , Ferguson William , Carmeliet Peter , De Deene A. , Gijsen Lore , Jain Rakesh K. 
Published: July 2022

Abstract

Purpose:
Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma models.

Patients and Methods:
We conducted a phase I, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved four dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3 + 3 dose-escalation scheme. Subjects received two doses of TB-403 (days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics, and detection of pharmacodynamic biomarkers.

Results:
Fifteen subjects were treated in four dose levels. All subjects received two doses of TB-403 in cycle 1. Five serious treatment-emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed subjects with medulloblastoma experienced stable disease, which persisted for more than 100 days in 4 of 7 subjects.

Conclusions:
TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with medulloblastoma.
Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities
Authors: Fendler Wolfgang P. , Pabst Kim M. , Kessler Lukas , Fragoso Costa Pedro , Ferdinandus Justin , Weber Manuel , Lippert Maria , Lueckerath Katharina , Umutlu Lale , Kostbade Karina , Mavroeidi Ilektra A. , Schuler Martin , Ahrens Marit , Rischpler Christoph , Bauer Sebastian , Herrmann Ken , Siveke Jens T. , Hamacher Rainer 
Published: July 2022

Abstract

Purpose:
We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities.

Experimental Design:
Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT.

Results:
Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and &lt;0.14 Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients with thrombocytopenia (n = 6) and anemia (n = 6) being most prevalent.

Conclusions:
90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.
Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms
Authors: Bertrums Eline J.M. , Rosendahl Huber Axel K.M. , de Kanter Jurrian K. , Brandsma Arianne M. , van Leeuwen Anaïs J.C.N. , Verheul Mark , van den Heuvel-Eibrink Marry M. , Oka Rurika , van Roosmalen Markus J. , de Groot-Kruseman Hester A. , Zwaan C. Michel , Goemans Bianca F. , van Boxtel Ruben 
Published: July 2022

Abstract

Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure.

Significance:
Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging.
ILRUN Promotes Atherosclerosis Through Lipid-Dependent and Lipid-Independent Factors
Authors: Bi Xin , Stankov Sylvia , Lee Paul C. , Wang Ziyi , Wu Xun , Li Li , Ko Yi-An , Cheng Lan , Zhang Hanrui , Hand Nicholas J. , Rader Daniel J. 
Published: July 2022

Background:

Common genetic variation in close proximity to the
ILRUN
gene are significantly associated with coronary artery disease as well as with plasma lipid traits. We recently demonstrated that hepatic inflammation and lipid regulator with ubiquitin-associated domain-like and NBR1-like domains (ILRUN) regulates lipoprotein metabolism in vivo in mice. However, whether ILRUN, which is expressed in vascular cells, directly impacts atherogenesis remains unclear. We sought to determine the role of ILRUN in atherosclerosis development in mice.

Methods:

For our study, we generated global
Ilrun
-deficient (
Ilrun
KO) male and female mice on 2 hyperlipidemic backgrounds: low density lipoprotein receptor knockout (
Ldlr
KO) and apolipoprotein E knockout (
Apoe
KO; double knockout [DKO]).

Results:

Compared with littermate control mice (single
Ldlr
KO or
Apoe
KO), deletion of
Ilrun
in DKO mice resulted in significantly attenuated both early and advanced atherosclerotic lesion development, as well as reduced necrotic area. DKO mice also had significantly decreased plasma cholesterol levels, primarily attributable to non-HDL (high-density lipoprotein) cholesterol. Hepatic-specific reconstitution of
ILRUN
in DKO mice on the
Apoe
KO background normalized plasma lipids, but atherosclerotic lesion area and necrotic area remained reduced in DKO mice. Further analysis showed that loss of
Ilrun
increased efferocytosis receptor MerTK expression in macrophages, enhanced in vitro efferocytosis, and significantly improved in situ efferocytosis in advanced lesions.

Conclusions:
Our results support ILRUN as an important novel regulator of atherogenesis that promotes lesion progression and necrosis. It influences atherosclerosis through both plasma lipid-dependent and lipid-independent mechanisms. These findings support ILRUN as the likely causal gene responsible for genetic association of variants with coronary artery disease at this locus and suggest that suppression of ILRUN activity might be expected to reduce atherosclerosis.
Changes in Poleward Atmospheric Energy Transport over a Wide Range of Climates: Energetic and Diffusive Perspectives and A Priori Theories
Authors: Merlis Timothy M. , Feldl Nicole , Caballero Rodrigo 
Published: July 2022

Abstract
The midlatitude poleward atmospheric energy transport increases in radiatively forced simulations of warmed climates across a range of models from comprehensive coupled general circulation models (GCMs) to idealized aquaplanet moist GCMs to diffusive moist energy balance models. These increases have been rationalized from two perspectives. The energetic (or radiative) perspective takes the atmospheric energy budget and decomposes energy flux changes (radiative forcing, feedbacks, or surface fluxes) to determine the energy transport changes required by the budget. The diffusive perspective takes the net effect of atmospheric macroturbulence to be a diffusive energy transport down-gradient, so transport changes can arise from changes in mean energy gradients or turbulent diffusivity. Here, we compare these perspectives in idealized moist, gray-radiation GCM simulations over a wide range of climates. The energetic perspective has a dominant role for radiative forcing in this GCM, with cancellation between the temperature feedback components that account for the GCM’s nonmonotonic energy transport changes in response to warming. Comprehensive CMIP5 simulations have similarities in the Northern Hemisphere to the idealized GCM, although a comprehensive GCM over several CO2 doublings has a distinctly different feedback evolution structure. The diffusive perspective requires a non-constant diffusivity to account for the idealized GCM-simulated changes, with important roles for the eddy velocity, dry static stability, and horizontal energy gradients. Beyond diagnostic analysis, GCM-independent a priori theories for components of the temperature feedback are presented that account for changes without knowledge of a perturbed climate state, suggesting that the energetic perspective is the more parsimonious one.
Downregulation of Calreticulin and Annexin A2 Expression in Acquired Middle Ear Cholesteatoma by 2-DE Analysis
Authors: Chang Ning-Chia , Wu Yu-Jen , Wang Ling-Feng , Chan Leong-Perng , Chai Chee-Yin , Chen, MS Wan-Tzu , Tsai Shih-Meng , Chien Chen-Yu , Ho Kuen-Yao 
Published: July 2022

Background: Many factors are thought to be associated with the development of cholesteatoma, while the mechanisms of its formation remain unclear. This study aimed to identify the potential mechanisms of the proliferation and growth of cholesteatoma by analysis of the differential expressions of proteins in cholesteatoma and retroauricular skin tissue collected from the same patients. Methods: The present study is a retrospective study performed in an academic medical center. Comparative proteomics analyses using two-dimensional gel electrophoresis (2-DE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), in addition to immunohistochemical analysis, were conducted to identify differentially-expressed proteins in cholesteatoma tissue as compared with retroauricular skin tissue. Western blotting was also employed to verify the expression patterns of the specific proteins identified by 2-DE and to measure the changes in potential modulators related to cholesteatoma proliferation and growth. Results: Calreticulin (CRT) and annexin A2 (AnxA2) were identified as being differentially-expressed in cholesteatoma by 2-DE and LC-MS/MS, the results of which were in agreement with the results of immunohistochemical analysis and western blotting. Downregulation of CRT and AnxA2 were observed in cholesteatoma. Conclusion: Our data suggests that CRT and AnxA2 downregulation are seen in cholesteatoma compared to retroauricular skin. We speculate that the reduced expression of CRT and the persistent inflammatory response play important roles in the epithelial proliferation of cholesteatoma.
Assessing Postoperative Recovery With Volatile Gas Versus Total Intravenous Anesthesia in Patients With and Without Obstructive Sleep Apnea
Authors: Sagalow Emily S. , Stewart Matthew , Estephan Leonard , Rodin Julianna , Ananth Ashwin , Curcio Brian , Krein Howard , Heffelfinger Ryan , Thaler Adam , Hunt Patrick , Boon Maurits , Huntley Colin 
Published: July 2022

Introduction: To determine if there is a recovery time difference between patients with and without obstructive sleep apnea (OSA) when using total intravenous anesthesia (TIVA) compared to volatile gas inhalational anesthesia. Patients and Methods: OSA and Non-OSA patients were identified at a tertiary institution between January 2019 and November 2020. Non-OSA patients were defined as those who have not been formerly diagnosed with OSA. A modified STOP-BANG score (MSBS) was performed to screen Non-OSA patients for OSA. Recovery was measured by Phase I recovery time, or time it took a patient to reach ≥9/10 on the Aldrete scoring system. Results: A total of 334 patients were included with 142 in the OSA cohort (59 TIVA, 83 inhalational anesthesia) and 192 in the Non-OSA cohort (119 TIVA, 73 inhalational anesthesia). In OSA patients, there was a 41.29-minute recovery time reduction when using TIVA versus sevoflurane ( P < .0001). Non-OSA patients recovered faster than OSA patients when undergoing inhalational anesthesia by 46.76 minutes and TIVA by 18.58 minutes ( P < .0001 and P = .0907, respectively). Non-OSA patients with a MSBS < 3 and ≥3 had a shorter recovery time compared to OSA patients when both underwent sevoflurane anesthesia (57.27 minutes, P < .0001 and 56.23 minutes, P = .040, respectively). Non-OSA patients with a MSBS of <3 had a decrease in recovery time of 26.68 minutes when compared to OSA patients who underwent TIVA ( P = .0004). Conclusions: When utilizing TIVA over inhalational anesthesia, patients with OSA have significantly increased benefit in terms of reduced Phase I recovery times as compared to Non-OSA patients.
Treatment-Monitoring Capabilities of Serum and Urine Biomarkers for Meniscal Allograft Transplantation in a Preclinical Canine Model
Authors: Ewing Michael A. , Stoker Aaron M. , Leary Emily V. , Bozynski Chantelle C. , Luk Josephine , Stannard James P. , Cook James L. 
Published: July 2022

Background: Meniscal allograft transplantation (MAT) has been developed as a treatment for meniscal deficiency. Despite promising outcomes, there are no real-time methods to evaluate graft survivorship and predict functional outcomes. Hypothesis: Assessment of serum and urine biomarkers could be used to develop biomarker panels—prognostic (1- and 3-month postsurgical time points) and diagnostic (6-month time point)—based on strong associations with clinically relevant outcome metrics obtained 6 months after surgery. Study Design: Descriptive laboratory study. Methods: Twelve adult purpose-bred research hounds were included and underwent medial meniscal release to induce meniscal deficiency. Three months after meniscal release surgery, medial menisci were replaced with fresh-frozen meniscus (n = 4), fresh meniscus (n = 4), or fresh meniscotibial osteochondral allograft (n = 4) such that a spectrum of pain and functional outcomes could be anticipated. Serum and urine from all dogs were collected preoperatively and at 1, 3, and 6 months after MAT surgery. Dogs were assessed for pain-related and functional outcomes at the same time points. To develop a prognostic panel of biomarkers, biomarker data from the 1- and 3-month post-MAT surgery time points were used to model 6-month clinical outcomes. A diagnostic panel of biomarkers was developed using data from the 6-month post-MAT surgery to model 6-month clinical outcomes. Primary outcomes for pain and function were visual analog scale (VAS) and operated limb percentage total pressure index (%TPI), respectively. Using random subject effects, linear mixed models were used to develop prognostic biomarker panels, and linear fixed-effect models were used to develop diagnostic biomarker panels, with variance explained for each panel reported ( R2) along with individual biomarker relationships. Results: Across prognostic biomarker panels, a panel including serum IL-6, IL-8, IL-10, and IL-18 was fit for the primary functional outcome, operated limb %TPI ( R2 = 0.450), whereas a panel including serum CTX-II and OPG was fit for the primary pain-related outcome, VAS ( R2 = 0.516). Across diagnostic biomarker panels, a panel including serum MMP-1 and MMP-3 and urine PINP and TIMP-1 was fit for %TPI ( R2 = 0.863). Separately, a panel including urine CTX-I, CTX-II, IL-8, MMP-2, and TIMP-1 was fit as diagnostic biomarkers for the VAS for pain ( R2 = 0.438). Conclusion: Biomarker panels of selected serum and/or urine proteins can model clinically relevant metrics for function and pain in a preclinical model of MAT. Clinical Relevance: Biomarker panels could be used to provide real-time diagnostic and prognostic data regarding outcomes after MAT.