bluuebunny/crossref_metadata_2025 huggingface dataset:
First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma
Authors: Strauss Julius , Deville Jean-Laurent , Sznol Mario , Ravaud Alain , Maruzzo Marco , Pachynski Russell K , Gourdin Theodore S , Maio Michele , Dirix Luc , Schlom Jeffrey , Donahue Renee N , Tsai Yo-Ting , Wang XiaoZhe , Vugmeyster Yulia , Beier Frank , Seebeck Joerg , Schroeder Andreas , Chennoufi Sarah , Gulley James L
Published: May 2023

Background

In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.

Methods

In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated.

Results

At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges.

Conclusions

M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.
Effects of weight loss and weight loss maintenance on cardiac autonomic function in obesity: a randomized controlled trial
Authors: McGee Joshua E. , Early Kate S. , Huff Anna C. , Clunan Marie C. , Hursey Nicole R. , Osborne Briceida , Bucher Colleen , Tanner Charles , Brewer Savanna B. , Brophy Patricia M. , Clark Angela , Pories Walter J. , Matarese Laura E. , Houmard Joseph A. , Collier David , May Linda E. , McClung Joseph M. , Earnest Conrad P. , Swift Damon L.
Published: May 2023

To investigate relationships between weight loss and weight loss maintenance with cardiac autonomic function and exercise in obesity, 39 adults (45.7 ± 10.7 years; BMI: 34.2 ± 3.4 kg·m−2) participated in a 10-week, medical weight loss program combined with aerobic exercise. A subset ( n = 18) participated in an aerobic exercise weight loss maintenance program (550 or 970 MET min·week−1) for 18 additional weeks. Primary outcomes included markers of cardiac autonomic function assessed by heart rate variability (HRV) (i.e., SDNN, RMSSD, HFln). Following weight loss, we observed significant improvements for SDNN (48.2 [41.4–55.1] vs. 55.1 [45.7–64.4] ms, p = 0.03), RMSSD (37.7 [29.1–46.4] vs. 47.9 [37.4–58.4] ms, p = 0.002), and HFln (5.88 [5.39–6.36] vs. 6.32 [5.86–6.78] ms, p = 0.001). Regression analyses showed fasting insulin concentration predicted 24% and 27% of the variance in RMSSD ( r2 = 0.236, p = 0.007) and HFln ( r2 = 0.274, p = 0.004), respectively. Following weight loss maintenance, no significant changes in HRV were observed. Changes in LDL ( r=–0.54, p = 0.04) and non-HDL ( r=–0.77, p = 0.001) were inversely associated with RMSSD changes. Clinically significant weight loss via caloric restriction and aerobic exercise improved HRV markers of cardiac vagal modulation. Following weight loss maintenance, we did not observe any further changes in HRV. Thus, our data suggest that commonly prescribed exercise volumes contribute to maintenance of parasympathetic modulation following medical weight loss programming and exercise.

Novelty

Caloric restriction and exercise exert significant improvements in cardiac autonomic function as measured by HRV in overweight and obesity. Aerobic exercise training, within recommended guidelines coupled with weight loss maintenance, retains cardiac autonomic function benefits from weight loss in previously obese individuals.
Consistency of phenolic profiles with taxonomic distribution and adaptation of birch species (Betula L.) to environmental conditions
Authors: Likhanov Artur F. , Vasylyshyn Roman D. , Marchuk Yurii M. , Kurdyuk Oleksandr M. , Honchar Hanna Yu. , Borysov Oleksandr V. , Bilous Svitlana Yu. , Yakubenko Borys Ye. , Naggar Yahya Al
Published: May 2023

The phenolic compounds in the leaves of 12 species of birch trees of the subgenera Neurobetula, Betulenta, and Betula were biochemically profiled using HPTLC. The duration of the vegetation period was found to be significantly related to the content of total phenols ( r = 0.74) and flavonoids in leaves ( r = 0.65). The correlations for Neurobetula plants were 0.86 and 0.91, respectively. The relationship between the duration of the growing season and the concentration of phenolic compounds in Betula plants was inverse ( r = −0.84). A cluster analysis of phytochemical profiles revealed that the studied birch species form groups that coincide with the subgenera proposed by De Jong due to an affinity with the qualitative composition of phenolic compounds. A multiple correlation analysis confirmed the relationship between the qualitative composition of phenolic compounds and the morphological characteristics of the leaves. The results of phytochemical profiling revealed that the qualitative composition of polyphenols in the leaves of 12 birch species is quite specific, allowing the use of individual compounds as additional differential biochemical characters in identifying species and hybrids and studying their potential role in plant adaptation to habitat conditions.
Prediction of asphalt pavement performance based on DEPSO-BP neural network
Authors: Tao Rui , Ding Pengfei , Peng Rui , Qiao Jiangang
Published: May 2023

With the application of machine learning rapidly gaining popularity in computer science and other fields, neural network techniques have successfully simulated the performance of in-service pavements as they are efficient in predicting and solving nonlinear relationships and in dealing with uncertain large-area pavement problems. In this paper, we address the problem of the optimal timing of preventive maintenance of asphalt pavements to accurately predict the condition index (pavement condition index, PCI) of highway asphalt pavements and develop a highly accurate, long-period, multifactor prediction model with the suitability of preventive maintenance at its core. The prediction model is called differential evolution particle swarm optimization back propagation (DEPSO-BP) neural network, and the input dimension of the prediction model is determined by gray correlation analysis (GCA), and DEPSO is used to improve the search efficiency of BP neural network and the asphalt pavement usage performance with parameter continuity prediction model. Finally, the Qinglan Highway (G22) PCI of Gansu Province, China, is selected for example validation, and the prediction results are compared with those of the four models. The results show that the multifactor prediction model based on DEPSO-BP neural network has good generalization ability. This model is important for improving the economic efficiency of road maintenance, and can be used in the long-cycle process to provide model reference and scientific basis for the subsequent road maintenance budget application and decision-making scheme.
A Hybrid Method for Enhancement of Both Contrast Distorted and Low-Light Images
Authors: Ozturk Nurullah , Ozturk Serkan
Published: May 2023

Many different histogram equalization (HE)-based image enhancement methods have been developed to overcome the problems of low or high image brightness, contrast sensitivity, and difficulty in revealing details of dark areas under low-light environments. In this paper, a novel image enhancement method based on HE and adaptive gamma correction with weight distribution (AGCWD) is proposed for natural and effective image enhancement. In this method, histogram stretching is performed on Red–Green–Blue (RGB) color components of image, and then the color space of RGB image is converted to Hue–Saturation–Intensity (HSI) color space. The histograms of S and I components are divided into sub-histograms according to the exposure threshold. The underexposure regions are enhanced with a new AGCWD. Then, the color space of HSI image is converted to RGB color space. Finally, the HE is applied to the input image with the obtained image histogram map. Thus, the method has not only effectively prevented the over-enhancement of the contrast but also obtained the quality and natural enhanced image. The proposed method is compared with the most known contrast enhancement methods and low-light enhancement methods. Experimental results have supported that the proposed method outperforms other methods in terms of both visual perception and objective evaluation.
Buckling of Spherical Grid-Shells Made of Smooth Triaxial Weaving with Naturally In-Plane Curved Ribbons
Authors: Song Guang-Kai , Sun Bo-Hua
Published: May 2023

The woven structure made of naturally curved (in-plane) ribbons has smooth geometry and fewer geometric imperfections, but there is no study of its buckling mechanical properties under vertical loads. The aim of this paper is to investigate buckling mechanical properties of spherical woven structures. Three spherical woven structures with different ribbon types and six new spherical woven structures with different ribbon widths and thicknesses were designed and the quasi-static vertical compression tests were carried out. The buckling load of spherical woven structures were studied by nonlinear finite element and ring buckling theory. Results indicate that the failure mode of the spherical weave structure under vertical loading can be divided into two stages, where a flat contact region forms between the spherical weave structure and the rigid plate and inward dimple of ribbons. Spherical weave structures using naturally curved (in-plane) ribbon weaving have better buckling stability than those woven with straight ribbon. Based on theoretical and finite element analysis, we propose a buckling load equation and buckling correction factor equation for the new spherical weave structure under vertical compression load. The formula is validated and has good agreement with the test results, which could help to design the stability of spherical weave structures with in-plane ribbons.
A Novel Method for Seismic Resilience Assessment of Urban Hospital Network Systems Based on a Real-Time Simulation Model
Authors: Gu Quan , Huang Caigui , Qiu Zhijian , Wang Tao , Li Quanwang , Zhai Changhai
Published: May 2023

Earthquake hazards may cause a significant loss to urban hospital network system (UHNS), including hospitals and medical transportation networks. As such, systematic seismic resilience assessment of such systems is of paramount importance to reduce loss and optimize casualty care during earthquakes. For that purpose, this paper proposes a novel method for assessing the seismic resilience of UHNS that considers the logical dependencies or coupling among the system’s components, such as the casualty sources, the hospitals and the medical transportation networks. A resilience index is defined as the ratio between the average “shortest” time for a casualty to receive medical treatment before and after an earthquake. The time consists of both transportation time to a hospital and queuing time at the hospital. To obtain the shortest time, a real-time simulation model is proposed that considers the casualty sources, the changes in road traffic, the updates of Origin-Destination (OD) matrix for transportation time, the modifications of waiting time in hospital, the path reselection by casualty, and the changes in functionalities of bridges, hospitals and roads. The functionalities are obtained by analyzing fragility models, calculating residual functionality and estimating functionality recovery times. To calculate the fragilities of bridges and hospitals, a refined nonlinear finite element (FE) analysis is performed based on a general FE software, OpenSees, and the damages are obtained for various structural and nonstructural components, e.g. column, stairs and CT scanner of hospitals, as well as piers, bearings and abutments of bridges. The proposed method is demonstrated in a seismic resilience assessment of a realistic UHNS in Xiamen city of China and provides valuable references to assessments of seismic resilience of UHNS.
Exploring Graph-based Transformer Encoder for Low-Resource Neural Machine Translation
Authors: Nguyen Long H. B. , Nguyen Binh , Le Binh , Dinh Dien
Published: May 2023

The Transformer is commonly used in Neural Machine Translation (NMT), but it faces issues with over-parameterization in low-resource settings. This means that simply increasing the model parameters significantly will not lead to improved performance. In this study, we propose a graph-based approach that slightly increases the parameters while significantly outperforming the scaled version of the Transformer. We accomplish this by utilizing Graph Neural Networks to encode Universal Conceptual Cognitive Annotation (UCCA), allowing the linguistic features of UCCA to be incorporated into the word embeddings. This improves the performance of the NMT system since the word embedding is now more capable and informative. Experimental results demonstrate that the proposed method outperforms the scaled Transformer model by +0.4, +0.41, and +0.33 BLEU, respectively, in English-Vietnamese/French/Czech datasets. Furthermore, this method reduces the number of parameters by 47% when compared to the scaled Transformer. A thorough analysis of error patterns reveals that the proposed method provides structural awareness to translation systems. Our code is available at: https://github.com/nqbinh17/UCCA_GNN.
Mitochondrial respiration analysis in permeabilized porcine left ventricular and human right atrial specimens with ischemia-reperfusion
Authors: Eickelmann Chantal , Lieder Helmut Raphael , Shehada Sharaf-Eldin , Thielmann Matthias , Heusch Gerd , Kleinbongard Petra
Published: May 2023

Methods to quantify mitochondrial function in translationally relevant models and in human tissue are needed to improve the translation of cardioprotection to patients. Our present approach, using PMT instead of isolated mitochondria for the quantification of mitochondrial ischemia-reperfusion damage, provides a reference for further studies in translationally relevant large animal models and in human tissue, thus possibly improving the translation of cardioprotection to the benefit of patients with acute myocardial infarction.
Renal histaminergic system and acute effects of histamine receptor 2 blockade on renal damage in the Dahl salt-sensitive rat
Authors: Spires Denisha R. , Schibalski Ryan S. , Domondon Mark , Clarke Callie , Perez Samantha , Anwar Fabiha , Burns Emily , Saeed Muhammad Irfan , Walton Samuel D. , Zamaro Aleksandra S. , Amoah Thelma , Arkhipov Sergey N. , Christopher Courtney J. , Campagna Shawn R. , Mattson David L. , Pavlov Tengis S. , Ilatovskaya Daria V.
Published: May 2023

Histamine is a nitrogenous compound crucial for the inflammatory response. The knowledge regarding the renal effects of histamine is very limited. We showed that renal epithelia exhibit expression of the components of the histaminergic system. Furthermore, we revealed that there was a shift in the histaminergic tone in salt-sensitive rats when they were challenged with a high-salt diet. These data support the notion that histamine plays a role in renal epithelial physiological and pathophysiological functions.
Different ramp-incremental slopes elicit similar V̇o2max and fatigability profiles in females and males despite differences in peak power output
Authors: Azevedo Rafael de Almeida , Fleitas-Paniagua Pablo R. , Trpcic Mackenzie , Iannetta Danilo , Millet Guillaume Y. , Murias Juan M.
Published: May 2023

It was unknown whether performance fatigability and its recovery are affected by different slopes in a ramp incremental (RI) test. It was also uncertain if females and males would respond differently. Performance fatigability was the same regardless of the RI slope adopted and the sex of the population, which was accompanied by similar maximal oxygen uptake but different power output achieved. The recovery of contractile function was similar between sexes but delayed after slower RI slopes.
Multiplicative Generalized Reverse

∗

CE-Derivations Acting on Rings with Involution
Authors: Khaled A. M. , Ghareeb A. , El-Sayiad M. S. Tammam
Published: May 2023

Let

S

be a ring with involution having a nontrivial symmetric idempotent element

e

. If

Ω

is any appropriate multiplicative generalized reverse

 
∗

CE-derivation of

S

with involution

∗

, then under some suitable restrictions on

S

,

Ω

is centrally-extended additive.
Exosomal miR-141-3p from PDLSCs Alleviates High Glucose-Induced Senescence of PDLSCs by Activating the KEAP1-NRF2 Signaling Pathway
Authors: Liu Min , Chen Rui , Xu Yunxuan , Zheng Jiawen , Wang Min , Wang Ping
Published: May 2023

Human periodontal ligament stem cells (PDLSCs) are the most promising stem cells for periodontal tissue engineering. Senescent PDLSCs have diminished abilities to proliferate and differentiate, affecting the efficiency of periodontal tissue repair and regeneration. Stem cell-derived exosomes are important participants in intercellular information exchange and can help ameliorate senescence. In this study, we investigated PDLSC senescence in a high glucose microenvironment as well as the ability of human periodontal ligament stem cell-derived exosomes (PDLSC-Exos) to alleviate cellular senescence and the underlying mechanisms. Herein, PDLSCs and PDLSC-Exos were isolated and extracted. Then, cellular senescence indicators were evaluated after high glucose (25 mM) treatment of cultured PDLSCs. PDLSC-Exos were cocultured with senescent PDLSCs to further explore the role of PDLSC-Exos in cellular senescence and determine the differences in cellular oxidative stress levels after PDLSC-Exo treatment. Next, we investigated whether PDLSC-Exos alleviated cellular senescence by restoring the balance of oxidative stress signals and explored the underlying molecular pathways. We discovered that PDLSCs underwent premature senescence due to high glucose culture, but they were rejuvenated by PDLSC-Exos. The rejuvenating effects of PDLSC-Exos were notably reversed by cotreatment with ML385, an inhibitor of nuclear factor erythroid 2-related factor 2 (NRF2), indicating that this recovery depended on NRF2 activation. Further analyses revealed that microRNA-141-3p (miR-141-3p) was expressed at relatively high levels in PDLSC-Exos and was instrumental in PDLSC-Exo-mediated restoration by downregulating Kelch-like ECH-associated protein 1 (KEAP1), which is a negative regulator of NRF2 expression. Our findings suggest that PDLSC-Exos alleviate high glucose-induced senescence of PDLSCs by transferring miR-141-3p to activate the KEAP1-NRF2 signaling pathway. Based on this research, PDLSC-Exos may behave similarly to their parental PDLSCs and have significant effects on cellular senescence by delivering their encapsulated bioactive chemicals to target cells.
Supplementary Data from RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a Real-world Lenalidomide Monotherapy Cohort in Relapsed or Refractory Diffuse Large B-cell Lymphoma
Authors: Zinzani Pier Luigi , Rodgers Thomas , Marino Dario , Frezzato Maurizio , Barbui Anna Maria , Castellino Claudia , Meli Erika , Fowler Nathan H. , Salles Gilles , Feinberg Bruce , Kurukulasuriya Nuwan C. , Tillmanns Sascha , Parche Stephan , Dey Debarshi , Fingerle-Rowson Günter , Ambarkhane Sumeet , Winderlich Mark , Nowakowski Grzegorz S.
Published: May 2023

Supplementary Methods, Tables, and Figures
Supplementary Table S9 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Table S9. Gene Signatures
Supplementary Table S8 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Table S8. DEGs for 6 months Comparison of CD49d+ and CD49d-
Supplementary Table S2 from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: May 2023

Study Representativeness
Supplementary Figure S4 from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: May 2023

Comparison of treatment-related adverse events with the combination of berzosertib and topotecan
Supplementary Table S4 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Table S4. Mutations status of patients with disease progression on BTKis
Supplementary Table S2 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Table 2. Baseline characteristics of ibrutinib treated patients
Supplementary Table S10 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Table S10. Outcome Data
Supplementary Methods S1 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Methods
Supplementary Figure S5 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Figure S5. Time to disease progression, prevalence of resistance mutations, and risk category by CLL-4 model
Supplementary Fig. 5 from Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial
Authors: Orgel Etan , Knight Kristin R. , Chi Yueh-Yun , Malvar Jemily , Rushing Teresa , Mena Victoria , Eisenberg Laurie S. , Rassekh Shahrad R. , Ross Colin J.D. , Scott Erika N. , Neely Michael , Neuwelt Edward A. , Muldoon Leslie L. , Freyer David R.
Published: May 2023

Supplementary Fig. 5 Progression-free survival in NAC treated and observation patients
Supplementary Figure S3 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Figure S3. In vivo effect of acalabrutinib on the VLA-4 activation upon BCR and chemokine signaling
Supplementary Figure S2 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Figure S2. In vivo effect of acalabrutinib on the expression of CD49d
Supplementary Fig. 2 from Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial
Authors: Orgel Etan , Knight Kristin R. , Chi Yueh-Yun , Malvar Jemily , Rushing Teresa , Mena Victoria , Eisenberg Laurie S. , Rassekh Shahrad R. , Ross Colin J.D. , Scott Erika N. , Neely Michael , Neuwelt Edward A. , Muldoon Leslie L. , Freyer David R.
Published: May 2023

Supplementary Fig. 2 Cumulative incidence of SIOP Grade ≥2 hearing loss
Supplemental Table S5 from Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Authors: Gibson Christopher J. , Fell Geoffrey , Sella Tal , Sperling Adam S. , Snow Craig , Rosenberg Shoshana M. , Kirkner Greg , Patel Ashka , Dillon Deborah , Bick Alexander G. , Neuberg Donna , Partridge Ann H. , Miller Peter G.
Published: May 2023

Cohort Characteristics Broken Down by CH (Any VAF)
Supplementary Figure S5 from Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies
Authors: Luke Jason J. , Piha-Paul Sarina A. , Medina Theresa , Verschraegen Claire F. , Varterasian Mary , Brennan Aoife M. , Riese Richard J. , Sokolovska Anna , Strauss James , Hava David L. , Janku Filip
Published: May 2023

Supplemental Figure 5. Tumor biopsy gene expression changes in chemokine, cytokine and TLR related signaling pathways after SYNB1891 treatment.
Supplemental Table S2 from Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Authors: Gibson Christopher J. , Fell Geoffrey , Sella Tal , Sperling Adam S. , Snow Craig , Rosenberg Shoshana M. , Kirkner Greg , Patel Ashka , Dillon Deborah , Bick Alexander G. , Neuberg Donna , Partridge Ann H. , Miller Peter G.
Published: May 2023

Genes Sequenced from Paired Baseline and Four-Year Blood Samples
Supplemental Fig. S3 from Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Authors: Gibson Christopher J. , Fell Geoffrey , Sella Tal , Sperling Adam S. , Snow Craig , Rosenberg Shoshana M. , Kirkner Greg , Patel Ashka , Dillon Deborah , Bick Alexander G. , Neuberg Donna , Partridge Ann H. , Miller Peter G.
Published: May 2023

Longitudinal Mutation Analysis in the YWS
Supplementary Figure S1 from Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies
Authors: Luke Jason J. , Piha-Paul Sarina A. , Medina Theresa , Verschraegen Claire F. , Varterasian Mary , Brennan Aoife M. , Riese Richard J. , Sokolovska Anna , Strauss James , Hava David L. , Janku Filip
Published: May 2023

Supplemental Figure 1. Schematic depiction of SYNB1891.
Data from Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies
Authors: Luke Jason J. , Piha-Paul Sarina A. , Medina Theresa , Verschraegen Claire F. , Varterasian Mary , Brennan Aoife M. , Riese Richard J. , Sokolovska Anna , Strauss James , Hava David L. , Janku Filip
Published: May 2023

AbstractPurpose:
SYNB1891 is a live, modified strain of the probiotic Escherichia coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia, leading to STimulator of INterferon Genes (STING) activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways.
Patients and Methods:
This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral injections of SYNB1891 either alone or in combination with atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens.
Results:
Twenty-four participants received monotherapy across six cohorts, and 8 participants received combination therapy in two cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24 hours after the first intratumoral dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of IFN-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained predose and 7 days following the third weekly dose. In addition, a dose-related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies.
Conclusions:
Repeat intratumoral injection of SYNB1891 as monotherapy and in combination with atezolizumab was safe and well tolerated, and evidence of STING pathway target engagement was observed.
Data from Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Authors: Gibson Christopher J. , Fell Geoffrey , Sella Tal , Sperling Adam S. , Snow Craig , Rosenberg Shoshana M. , Kirkner Greg , Patel Ashka , Dillon Deborah , Bick Alexander G. , Neuberg Donna , Partridge Ann H. , Miller Peter G.
Published: May 2023

AbstractBackground:
Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping.
Materials and Methods:
We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study.
Results:
We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non–breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM.
Conclusions:
Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.
Facts and Hopes: Immunocytokines for Cancer Immunotherapy
Authors: Pabani Aliyah , Gainor Justin F.
Published: May 2023

The clinical development of cytokines as cancer therapeutics has been limited due to significant toxicities generally observed with systemic administration. This narrow therapeutic window, together with relatively modest efficacy, has made natural cytokines unattractive drug candidates. Immunocytokines represent a class of next-generation cytokines designed to overcome the challenges associated with traditional cytokines. These agents seek to improve the therapeutic index of cytokines by using antibodies as vehicles for the targeted delivery of immunomodulatory agents within the local tumor microenvironment (TME). Various molecular formats and cytokine payloads have been studied. In this review, we provide an overview of the rationale, preclinical support, and current clinical development strategies for immunocytokines.
Transglutaminase 2 Binds to the CD44v6 Cytoplasmic Domain to Stimulate CD44v6/ERK1/2 Signaling and Maintain an Aggressive Cancer Phenotype
Authors: Chen Xi , Adhikary Gautam , Newland John J. , Xu Wen , Keillor Jeffrey W. , Weber David J. , Eckert Richard L.
Published: May 2023

Transglutaminase 2 (TG2) is a key cancer cell survival protein in many cancer types. As such, efforts are underway to characterize the mechanism of TG2 action. In this study, we report that TG2 stimulates CD44v6 activity to enhance cancer cell survival via a mechanism that involves formation of a TG2/CD44v6/ERK1/2 complex that activates ERK1/2 signaling to drive an aggressive cancer phenotype. TG2 and ERK1/2 bind to the CD44v6 C-terminal intracellular cytoplasmic domain to activate ERK1/2 and stimulate cell proliferation and invasion. This is the same region that binds to ERM proteins and ankyrin to activate CD44v6-dependent cell proliferation, invasion, and migration. We further show that treatment with hyaluronan (HA), the physiologic CD44v6 ligand, stimulates CD44v6 activity, as measured by ERK1/2 activation, but that this response is severely attenuated in TG2 or CD44v6 knockdown or knockout cells. Moreover, treatment with TG2 inhibitor reduces tumor growth and that is associated with reduced CD44v6 level and ERK1/2 activity, and reduced stemness and epithelial–mesenchymal transition (EMT). These changes are replicated in CD44v6 knockout cells. These findings suggest that a unique TG2/CD44v6/ERK1/2 complex leads to increased ERK1/2 activity to stimulate an aggressive cancer phenotype and stimulate tumor growth. These findings have important implications for cancer stem cell maintenance and suggest that cotargeting of TG2 and CD44v6 with specific inhibitors may be an effective anticancer treatment strategy.

Implications:

TG2 and CD44v6 are important procancer proteins. TG2 and ERK1/2 bind to the CD44v6 C-terminal domain to form a TG2/CD44v6/ERK1/2 complex that activates ERK1/2 to stimulate the cancer phenotype.
Figure S4 from Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells
Authors: Islam S.M. Rafiqul , Maeda Takuya , Tamaoki Naritaka , Good Meghan L. , Kishton Rigel J. , Paria Biman C. , Yu Zhiya , Bosch-Marce Marta , Bedanova Nicole M. , Liu Chengyu , Kruhlak Michael J. , Restifo Nicholas P. , Vizcardo Raul
Published: May 2023

Figure S4: Characterization of tumor antigen specific TIL-iPSC clone derived from patient 3784
FIGURE 6 from Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells
Authors: Islam S.M. Rafiqul , Maeda Takuya , Tamaoki Naritaka , Good Meghan L. , Kishton Rigel J. , Paria Biman C. , Yu Zhiya , Bosch-Marce Marta , Bedanova Nicole M. , Liu Chengyu , Kruhlak Michael J. , Restifo Nicholas P. , Vizcardo Raul
Published: May 2023

T cells with tumor-reactive TCRs of extremely low frequency were reprogrammed to TIL-iPSCs. A, Summary of five candidate TCR pairs including four newly found TCRs (NF TCR 1–4) and one PIR-TCR (IV) identified in TIL-iPSCs which were sequenced individually. The table includes CDR3 amino acid sequences of α and β chains, Vα family, Vβ family, and immunosequencing analysis of TCRβ which contains frequency in bulk (before coculture) and in sorted DP population after coculture, and enrichment (DP/Bulk). B and C, CD137 (4-1BB) upregulation assay of T cells transduced with candidate TCRα and TCRβ pairs identified from TIL-iPSCs (Fig. 6A). T cells were cocultured with autologous or allogeneic tumor cell lines. B shows the representative FACS plots and C shows the percentage of 4-1BB+ cells in each condition. Representative data of four independent experiments. Control PBL; no transgene, Mock indicates empty vector transduced T cells used as a negative control, TIL; expanded TIL containing tumor-reactive T cells. D, A bar graph showing the results of ELISA IFNγ production assay of T cells transduced with candidate TCRα and TCRβ pairs identified from TIL-iPSCs (A). T cells were cocultured with autologous or allogeneic tumor cell lines for 16 hours and culture soup were analyzed for IFNγ by ELISA (N = 3). Representative data of four independent experiments. E, A graph showing the real-time cell growth monitoring (cell count/image) of RFP-overexpressed tumor cells from pt-3784 cocultured with different TCRs (listed in A), analyzed by the Incucyte live imaging and analysis system in an effector-to-target ratio of 2:1. Mock indicates empty vector transduced T cells used as a negative control; TC only indicates tumor cells alone, and four newly found candidate TCRs (NF TCR 1–4) and a PIR-TCR IV were used for coculture and their antitumor properties were measured over 72 hours time period. The results are shown as mean ± SD of N = 4 each condition. A representative data of four independent experiments.
FIGURE 5 from Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells
Authors: Islam S.M. Rafiqul , Maeda Takuya , Tamaoki Naritaka , Good Meghan L. , Kishton Rigel J. , Paria Biman C. , Yu Zhiya , Bosch-Marce Marta , Bedanova Nicole M. , Liu Chengyu , Kruhlak Michael J. , Restifo Nicholas P. , Vizcardo Raul
Published: May 2023

TIL-tumor cell coculture activated tumor-reactive T cells and generated tumor-reactive TIL-iPSCs from TIL of patient 3784. A, FACS panels showing the gating strategy to sort PD1+ 4-1BB+ CD8+ T cells after TIL-tumor cell coculture. Top panel shows the phenotype of TIL without coculture. Dump gate is a mixture of different T lineage markers (CD25, CD56, and TCRγδ) to exclude regulatory T cells (CD25+), natural killer cells (CD56+), and gamma-delta T cells (TCRγδ+). B, A summary table of the TCRβ sequence of eight preidentified tumor-reactive TCRs indicating their CDR3β amino acid sequence, Vβ family, frequency in bulk (before coculture) and in sorted PD1+ 4-1BB+ (DP) population, enrichment (DP/bulk) and presence in established iPSC clones. C, A bar graph showing the relative frequency of TCR clones, which were present in bulk population (starting cells) and reprogrammed to iPSCs, in four sorted populations [PD1− 4-1BB− (DN), PD1+ 4-1BB− (PD1+ SP), PD1− 4-1BB+ (4-1BB+ SP), PD1+ 4-1BB+ (DP)] after TIL-tumor cell coculture relative to bulk frequency of each TCR clone before coculture. Please see Supplementary Table S1 for the details of the TCR clones (TCR 2, 3, 6, 9, 11, 12, 15, and 17).
Video 1 from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring
Authors: Nakhle Jean , Khattar Khattar , Özkan Tülin , Boughlita Adel , Abba Moussa Daouda , Darlix Amelie , Lorcy Frédérique , RIGAU Valérie , BAUCHET Luc , Gerbal-Chaloin Sabine , Daujat-Chavanieu Martine , Bellvert Floriant , Turchi Laurent , Virolle Thierry , Hugnot Jean-Philippe , Buisine Nicolas , Galloni Mireille , Dardalhon Valerie , Rodriguez Anne-Marie , Vignais Marie-Luce
Published: May 2023

Cocultures of red MitoTracker-labeled MSCs and green CellTracker-labeled GSCs
Supplementary Materials and Methods from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring
Authors: Nakhle Jean , Khattar Khattar , Özkan Tülin , Boughlita Adel , Abba Moussa Daouda , Darlix Amelie , Lorcy Frédérique , RIGAU Valérie , BAUCHET Luc , Gerbal-Chaloin Sabine , Daujat-Chavanieu Martine , Bellvert Floriant , Turchi Laurent , Virolle Thierry , Hugnot Jean-Philippe , Buisine Nicolas , Galloni Mireille , Dardalhon Valerie , Rodriguez Anne-Marie , Vignais Marie-Luce
Published: May 2023

TMZ dose-response assay
Caspase-GloⓇ 3/7 assay
Cytotox assay
Extracellular Flux Assays
Cell Proliferation
Western Blot
Flow Cytometry
Metabolite usage Mitoplates
Mass Spectrometry Quantification
13C stable isotope tracing experiments
Preparation and quantification of MSC mtDNA in GSCs
Imaging
Figure S2 from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring
Authors: Nakhle Jean , Khattar Khattar , Özkan Tülin , Boughlita Adel , Abba Moussa Daouda , Darlix Amelie , Lorcy Frédérique , RIGAU Valérie , BAUCHET Luc , Gerbal-Chaloin Sabine , Daujat-Chavanieu Martine , Bellvert Floriant , Turchi Laurent , Virolle Thierry , Hugnot Jean-Philippe , Buisine Nicolas , Galloni Mireille , Dardalhon Valerie , Rodriguez Anne-Marie , Vignais Marie-Luce
Published: May 2023

Quantification of mitochondrial DNA (mtDNA) following transfer of MSC mitochondria to GSCs (A) Detection of MSC mtDNA in GSCs. MSC mtDNA concentrations are expressed relative to GSC mtDNA. Mean with SEM, t test with Welch correction, *p < 0.05. (B) Total mtDNA concentrations in GSCs at different time points after MSC mitochondria transfer, expressed relative to GSC genomic DNA. Mean + SEM and multiple t tests, *p < 0.05.
Data from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring
Authors: Nakhle Jean , Khattar Khattar , Özkan Tülin , Boughlita Adel , Abba Moussa Daouda , Darlix Amelie , Lorcy Frédérique , RIGAU Valérie , BAUCHET Luc , Gerbal-Chaloin Sabine , Daujat-Chavanieu Martine , Bellvert Floriant , Turchi Laurent , Virolle Thierry , Hugnot Jean-Philippe , Buisine Nicolas , Galloni Mireille , Dardalhon Valerie , Rodriguez Anne-Marie , Vignais Marie-Luce
Published: May 2023

Abstract
Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSCs), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSCs) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the TCA cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.
Hispanic toponymy of Chile: linguocultural and linguopragmatic approach
Authors: Martynenko Irina A.
Published: May 2023

The article provides a linguo-cultural and linguo-pragmatic analysis of the Hispanic toponymy of Chile. Geographical names are considered from historical, geographical, and linguistic perspectives. A semantic classification of the Chilean Hispanic geonames is presented. Examples of hagiotoponyms, anthropotoponyms, military toponyms, descriptive, expressive toponyms, etc. are provided, and their etymology and morphological structure are analyzed. The author concludes that, in general, the toponymic system of Chile is characterized by both universal features of Latin American toponymy and unique linguo-culturological, morphological, and semantic features.