bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric COVID-19: Correlations between Clinical and Imaging Perspectives
Authors: Ali Heba A. , Mohammad Shaimaa A.
Published: May 2023

Background. Although SARS-CoV-2 infection primarily affects adults, the increasing emergence of infected pediatric patients has been recently reported. However, there is a paucity of data regarding the value of imaging in relation to the clinical severity of this pandemic emergency. Objectives. To demonstrate the relationships between clinical and radiological COVID-19 findings and to determine the most effective standardized pediatric clinical and imaging strategies predicting the disease severity. Patients and Methods. This observational study enrolled eighty pediatric patients with confirmed COVID-19 infection. The studied patients were categorized according to the disease severity and the presence of comorbidities. Patients’ clinical findings, chest X-ray, and CT imaging results were analyzed. Patients’ evaluations using several clinical and radiological severity scores were recorded. The relations between clinical and radiological severities were examined. Results. Significant associations were found between severe-to-critical illness and abnormal radiological findings (

p
=
0.009

). In addition, chest X-ray score, chest CT severity score, and rapid evaluation of anamnesis, PO2, imaging disease, and dyspnea-COVID (RAPID-COVID) score were significantly higher among patients with severe infection (

p
<
0.001

, <0.001, and 0.001) and those with comorbidities (

p
=
0.005

, 0.002, and <0.001). Conclusions. Chest imaging of pediatric patients with COVID-19 infection may be of value during the evaluation of severe cases of infected pediatric patients and in those with underlying comorbid conditions, especially during the early stage of infection. Moreover, the combined use of specific clinical and radiological COVID-19 scores are likely to be a successful measure of the extent of disease severity.
Multiple Attribute Trigonometric Decision-Making and Its Application to the Selection of Engineers
Authors: Palanikumar M. , Arulmozhi K. , Al-Shanqiti Omaima , Jana Chiranjibe , Pal Madhumangal
Published: May 2023

A novel method is presented for solving MADM under a sine trigonometric Pythagorean neutrosophic normal interval-valued set (ST-PyNSNIVS). An identifying feature of ST-PyNSNIVS is that it is a combination of PyNSIVS, PyNSS, and IVNSS. This article proposes a novel concept of ST-PyNSNIVWA, ST-PyNSNIVWG, ST-GPyNSNIVWA, and ST-GPyNSNIVWG. In addition, we acquired a flowchart and an algorithm that interact with MADM and are called ST-PyNSNIVWA, ST-PyNSNIVWG, ST-GPyNSNIVWA, and ST-GPyNSNIVWG, respectively. In addition to Euclidean and Hamming distances, we addressed new types of two distances in the suggested models, which are future expansions of real-life instances. The sine trigonometric aggregation operations were examined using the PyNSNIV set technique. They are more straightforward and practical, and you can arrive at the best option quickly. Consequently, the conclusions of the defined models are more accurate and closely correlated with

Σ

. Our analysis shows that the investigated models are valid and useful by comparing them to some of the current models. As a final result of the study, some intriguing and enthralling findings are presented.
Matrix Metalloproteinase-7 Associated with Congestive Heart Failure in Peritoneal Dialysis Patients: A Prospective Cohort Study
Authors: Xiao Zhiwen , Tian Jianwei , Zhang Fen , Zhong Xiaohong , Zhang Tingting , Yi Zhixiu , Lin Yanhong , Yang Cong , Tang Dan , Gong Nirong , Ai Jun
Published: May 2023

Background. Matrix metalloproteinase-7 (MMP7) is markedly expressed in patients with chronic kidney disease; its expression in dialysate and role in patients undergoing peritoneal dialysis (PD) have not been well established. Methods. Participants undergoing PD from June 1st, 2015, to June 30th, 2020, were involved and were followed up every 3 months for the first year and every 6 months thereafter until death, PD withdrawal, or the end of the study. Data at each follow-up point were collected and analyzed for the association with congestive heart failure (CHF), PD withdrawal, and combined endpoint. Results. A total of 283 participants were included in this study. During a median follow-up of 21 months, 20 (7%) participants died, 93 (33%) withdrew from PD, and 105 (37%) developed CHF. A significantly increased level of serum and dialysate MMP7 was observed at baseline. Dialysate MMP7 presented a good linearity with serum MMP7. Baseline serum and dialysate MMP7 levels were associated with CHF in multivariable Cox proportional hazards regression models. After categorization, participants with high baseline MMP7 levels had a higher incidence of CHF (42%), and the hazard ratios (95% confidence intervals) were 1.595 (1.023-2.488). Interestingly, participants with higher serum MMP7 levels were trended to use dialysate with higher glucose concentration. However, the ultrafiltration volumes were not significantly increased. Higher MMP7 levels were also positively associated with PD withdrawal and combined endpoint. Conclusions. The expression of MMP7 in serum and dialysate was markedly increased and was tightly associated with the risk of CHF in PD patients. This finding suggests that the measurement of MMP7 may inform strategies for managing CHF at an earlier stage.
Optimization of CLS Content of Asphalt Mixtures Based on Balanced Mix Design Approach
Authors: Ziaee Seyed Ali , Fatemi Seyed Saeed , Shaker Hamid , Ameri Mahmoud , Saadatjoo Seyed Amir
Published: May 2023

Over the years, there have been many studies on the performance improvement of asphalt mixtures using different materials and additives, especially those of the recycled variety, because of the environmental benefits they bring to the design. This study investigated the properties of asphalt mixtures made with different amounts of calcium lignosulfonate (CLS), which is a waste product, and used the Balanced Mix Design (BMD) approach to determine the appropriate mix design for CLS-containing mixtures. In this process, the results of the dynamic creep test were used as a measure of rutting resistance, the results of the indirect tensile test were used as a measure of moisture susceptibility, and the results of the Illinois Flexibility Index Test (IFIT) and Indirect Tensile Cracking Test (IDEAL-CT) were used independently as a measure of cracking resistance. On the other hand, since previous studies have suggested that CLS has antiaging properties, the specimens were made and tested in two groups: those with long-term aging and without long-term aging. So the objective was to determine the amount of CLS that should ideally be used as a bitumen additive in aged and unaged asphalt mixtures. The results showed that using 15% or 20% CLS will always yield acceptable outcomes in terms of BMD criteria for both aged and unaged conditions. However, a CLS content of 10% may also be acceptable for both aged and unaged conditions if IDEAL-CT results are used as the measure of cracking resistance.
Tracheal Resection for Critical Airway Obstruction in Morquio A Syndrome
Authors: Frauenfelder Claire , Maughan Elizabeth , Kenth Johnny , Nandi Reema , Jones Simon , Walker Robert , Walsh Bill , Muthialu Nagarajan , Bruce Iain , Hewitt Richard , Butler Colin
Published: May 2023

Introduction. The primary cause of death in Morquio A syndrome (mucopolysaccharidosis (MPS) IVA) is airway obstruction, brought about by an inexorable and pathognomonic multilevel airway tortuosity, buckling, and obstruction. The relative pathophysiological contributions of an inherent cartilage processing defect versus a mismatch in longitudinal growth between the trachea and the thoracic cage are currently a subject of debate. Enzyme replacement therapy (ERT) and multidisciplinary management continue to improve life expectancy for Morquio A patients by slowing many of the multisystem pathological consequences of the disease but are not as effective at reversing established pathology. An urgent need has developed to consider alternatives to palliation of progressive tracheal obstruction to preserve and maintain these patients’ hard-won good quality of life, as well as to facilitate spinal and other required surgery. Case Report. Following multidisciplinary discussion, transcervical tracheal resection with limited manubriectomy was successfully performed, without the need for cardiopulmonary bypass, in an adolescent male on ERT with the severe airway manifestations of Morquio A syndrome. His trachea was found to be under significant compressive forces at surgery. On histology, chondrocyte lacunae appeared enlarged, but intracellular lysosomal staining and extracellular glycosaminoglycan staining was comparable to control trachea. At 12 months, this has resulted in a significant improvement in respiratory and functional status, with corresponding enhancement to his quality of life. Conclusion. This addressing of tracheal/thoracic cage dimension mismatch represents a novel surgical treatment approach to an existing clinical paradigm and may be useful for other carefully selected individuals with MPS IVA. Further work is needed to better understand the role and optimal timing of tracheal resection within this patient cohort so as to individually balance considerable surgical and anaesthetic risks against the potential symptomatic and life expectancy benefits.
Data from FPR2 shapes an immune-excluded pancreatic tumor microenvironment and drives T-cell exhaustion in a sex-dependent manner
Authors: He Fei , Tay Apple H.M. , Calandigary Ahmed , Malki Enana , Suzuki Sayaka , Liu Tianjie , Wang Qi , Fernández-Moro Carlos , Kaisso Marina , Olofsson‐Sahl Peter , Melssen Marit , Sze Siu Kwan , Björnstedt Mikael , Löhr Matthias J. , Karlsson Mikael C.I. , Heuchel Rainer , Sarhan Dhifaf
Published: May 2023

Abstract
Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA-sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune‐excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced pro-inflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared to wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared to WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex‐specific precision immunotherapy strategy.
Data from NAT10 drives cisplatin chemoresistance by enhancing ac4C-associated DNA repair in bladder cancer
Authors: Xie Ruihui , Cheng Liang , Huang Ming , Huang Lin , Chen Ziyue , Zhang Qiang , Li Hong , Lu Junlin , Wang Hongjin , Zhou Qianghua , Huang Jian , Chen Xu , Lin Tianxin
Published: May 2023

Abstract
Epitranscriptomic RNA modifications constitute a critical gene regulatory component that can affect cancer progression. Among these, the RNA N4-acetylcytidine (ac4C) modification, which is mediated by the ac4C writer N-acetyltransferase 10 (NAT10), regulates the stabilization of mRNA. Here, we identified that the ac4C modification is induced upon cisplatin treatment and correlates with chemoresistance in bladder cancer (BCa). Both in vitro and in vivo, NAT10 promoted cisplatin chemoresistance in BCa cells by enhancing DNA damage repair. Mechanistically, NAT10 bound and stabilized AHNAK mRNA by protecting it from exonucleases, and AHNAK-mediated DNA damage repair was required for NAT10-induced cisplatin resistance. Clinically, NAT10 overexpression was associated with chemoresistance, recurrence, and worse clinical outcome in BCa patients. Cisplatin-induced NFκB signaling activation was required for the upregulation of NAT10 expression, and NFκB p65 directly bound to the NAT10 promoter to activate transcription. Moreover, pharmacological inhibition of NAT10 with Remodelin sensitized BCa organoids and mouse xenografts to cisplatin. Overall, the present study uncovered a mechanism of NAT10-mediated mRNA stabilization in BCa, laying the foundation for NAT10 as a therapeutic target to overcome cisplatin resistance in BCa.
Data from LSD1 inhibition disrupts super-enhancer driven oncogenic transcriptional programs in castration-resistant prostate cancer
Authors: Li Muqing , Liu Mingyu , Han Wanting , Wang Zifeng , Han Dong , Patalano Susan , Macoska Jill A. , Balk Steven P. , He Housheng Hansen. , Corey Eva , Gao Shuai , Cai Changmeng
Published: May 2023

Abstract
The lysine demethylase LSD1 (also called KDM1A) plays important roles in promoting multiple malignancies including both hematologic cancers and solid tumors. LSD1 targets histone and non-histone proteins and can function as a transcriptional corepressor and coactivator. LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer (PCa) and to regulate the AR cistrome via demethylation of its pioneer factor FOXA1. A deeper understanding of the key oncogenic programs targeted by LSD1 could help stratify PCa patients for treatment with LSD1 inhibitors, which are currently under clinical investigation. In this study, we performed transcriptomic profiling in an array of castration-resistant PCa (CRPC) xenograft models that are sensitive to LSD1 inhibitor treatment. Impaired tumor growth by LSD1 inhibition was attributed to significantly decreased MYC signaling, and MYC was found to be a consistent target of LSD1. Moreover, LSD1 formed a network with BRD4 and FOXA1 and was enriched at super-enhancer (SE) regions exhibiting liquid-liquid phase separation. Combining LSD1 inhibitors with BET inhibitors exhibited strong synergy in disrupting the activities of multiple drivers in CRPC, thereby inducing significant growth repression of tumors. Importantly, the combination treatment showed superior effects than either inhibitor alone in disrupting a subset of newly identified CRPC-specific SEs. These results provide mechanistic and therapeutic insights for co-targeting two key epigenetic factors and could be rapidly translated in the clinic for CRPC patients.
Data from Nucleophosmin Plays a Role in Repairing DNA Damage and Is a Target for Cancer Treatment
Authors: Sekhar Konjeti R. , Freeman Michael L.
Published: May 2023

Abstract
Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia, and NPM1 expression is elevated in several cancer types. NPM1 is a multifunctional oligomeric protein involved in numerous cellular functions that include participating in liquid–liquid phase separation, ribosome biogenesis, chaperoning of histones, and modulation of transcription. In this review, we discuss the underappreciated role of NPM1 in DNA damage repair, specifically Polη-mediated translesion synthesis, base excision, and homologous recombination and highlight the therapeutic potential of NPM1 targeting in cancer treatment.
Supplementary Table S3 from The Association of Neighborhood Characteristics and Frailty in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study
Authors: Schwartz Lindsay F. , Dhaduk Rikeenkumar , Howell Carrie R. , Brinkman Tara M. , Ehrhardt Matthew J. , Delaney Angela , Srivastava Deo Kumar , Lanctot Jennifer Q. , Armstrong Gregory T. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K. , Henderson Tara O.
Published: May 2023

Supplementary Table S3 shows comparisons of pre-frailty/frailty odds between weighted and unweighted models, completed to evaluate for potential participation bias
Data from The Association of Neighborhood Characteristics and Frailty in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study
Authors: Schwartz Lindsay F. , Dhaduk Rikeenkumar , Howell Carrie R. , Brinkman Tara M. , Ehrhardt Matthew J. , Delaney Angela , Srivastava Deo Kumar , Lanctot Jennifer Q. , Armstrong Gregory T. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K. , Henderson Tara O.
Published: May 2023

AbstractBackground:
Childhood cancer survivors experience reduced physiologic reserve, or frailty, earlier and more frequently than peers. In other populations, frailty is impacted by one's neighborhood. This study's purpose was to evaluate associations between neighborhood characteristics and frailty in childhood cancer survivors.
Methods:
Participants in the St. Jude Lifetime Cohort Study with geocoded residential addresses were analyzed. Pre-frailty/Frailty was defined as having 1–2/≥3 of sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion from direct assessments. Neighborhood characteristics [e.g., access to exercise opportunities and healthy food, neighborhood socioeconomic status (nSES), and rurality/urbanicity] were determined using publicly available geospatial data. Nested multivariable logistic regression models identified associations between neighborhood characteristics and pre-frailty/frailty, adjusting for chronic health conditions, individual health behaviors and socio-demographics, and high-risk cancer treatment exposures.
Results:
For our cohort (N = 3,806, 46.79% female, 81.40% white, mean age 33.63±9.91 years), compared with non-frail survivors (n = 2,573; 67.6%), pre-frail (n = 900; 23.6%) and frail survivors (n = 333; 8.7%) were more likely to live in neighborhoods with decreased exercise opportunities (frail OR: 1.62, 1.26–2.09), reduced healthy food access (pre-frail OR: 1.28, 1.08–1.51; frail OR: 1.36, 1.06–1.75), and lower nSES (pre-frail OR: 1.31, 1.12–1.52; frail OR: 1.64, 1.30–2.07). Participants had 8% increased odds (95% confidence interval, 2%–14%) of being pre-frail/frail if they lived in “resource poor” neighborhoods as opposed to “resource rich” neighborhoods after adjusting for other pre-frailty/frailty risk factors.
Conclusions:
The neighborhood a childhood cancer survivor resides in as an adult is associated with pre-frailty/frailty.
Impact:
This study provides valuable information for creating interventions using neighborhood-level factors to mitigate frailty and improve health outcomes in survivors.
Data from The Impact of Improved Treatments on Survival of Adult US Leukemia Patients: 1990 - 2018
Authors: Howlader Nadia , Sharon Elad , Bhattacharya Manami , Ehrlich Lori A. , Richardson Nicholas C. , Gormley Nicole J. , de Claro R. Angelo , Wood Amy E. , Mariotto Angela B. , Cronin Kathleen A.
Published: May 2023

Abstract
Introduction: Molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) are effective treatments for BCR-ABL-bearing leukemias. We evaluated the impact of TKIs on historical chronic myeloid leukemia (CML) mortality trends compared to acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
Methods: Since mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 US SEER registries (1992-2017) among US adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992-2017) and mortality (1992-2018) trends by subtype and diagnosis year.
Results: For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for CML patients. Five-year CML survival increased dramatically over time, especially between 1996-2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992-2017. ALL mortality decreased 0.6% annually during 1992-2012 and then stopped declining. CLL incidence fluctuated during 1992–2017 while mortality decreased 1.1% annually during 1992-2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992-2016.
Conclusions: Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials.
Impact: Our study highlights the impact of molecularly targeted therapies at the population level.
Table S8 from Clinical Importance of the lncRNA NEAT1 in Cancer Patients Treated with Immune Checkpoint Inhibitors
Authors: Toker Joseph , Iorgulescu J. Bryan , Ling Alexander L. , Villa Genaro R. , Gadet Josephina A.M.A. , Parida Laxmi , Getz Gad , Wu Catherine J. , Reardon David A. , Chiocca E. Antonio , Mineo Marco
Published: May 2023

Genes enriched in NEAT1-high macrophages
Supplementary Fig. 2 from Clinical Importance of the lncRNA NEAT1 in Cancer Patients Treated with Immune Checkpoint Inhibitors
Authors: Toker Joseph , Iorgulescu J. Bryan , Ling Alexander L. , Villa Genaro R. , Gadet Josephina A.M.A. , Parida Laxmi , Getz Gad , Wu Catherine J. , Reardon David A. , Chiocca E. Antonio , Mineo Marco
Published: May 2023

Supplementary Fig. 2 NEAT1 expression is associated with the interferon-gamma response in melanoma.
Data from Clinical importance of the lncRNA NEAT1 in cancer patients treated with immune checkpoint inhibitors.
Authors: Toker Joseph , Iorgulescu J. Bryan. , Ling Alexander L. , Villa Genaro R. , Gadet Josephina A.M.A. , Parida Laxmi , Getz Gad , Wu Catherine J. , Reardon David A. , Chiocca E. Antonio , Mineo Marco
Published: May 2023

Abstract
Purpose: Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint are powerful tools to improve the survival of cancer patients. Understanding the molecular basis of clinical response to these treatments is critical to identify patients who can benefit from this immunotherapy. In this study, we investigated long non-coding RNA (lncRNA) expression in cancer patients treated with anti-PD-1/PD-L1 immunotherapy. Experimental design: LncRNA expression profile was analyzed in one cohort of melanoma patients and two independent cohorts of patients with glioblastoma (GBM) undergoing anti-PD-1/PD-L1 immunotherapy. Single-cell RNA-sequencing analyses were performed to evaluate lncRNA expression in tumor cells and tumor-infiltrating immune cells. Results:We identified the lncRNA NEAT1 as commonly upregulated between melanoma patients with complete therapeutic response and GBM patients with longer survival following anti-PD-1/PD-L1 treatment. Gene set enrichment analyses revealed that NEAT1 expression was strongly associated with the interferon-gamma pathways, along with downregulation of cell-cycle-related genes. Single-cell RNA-sequencing analyses revealed NEAT1 expression across multiple cell types within the GBM microenvironment, including tumor cells, macrophages, and T cells. High NEAT1 expression levels in tumor cells correlated with increased infiltrating macrophages and microglia. In these tumor-infiltrating myeloid cells, we found that NEAT1 expression was linked to enrichment in TNF alpha/NFKB signaling pathway genes. Silencing NEAT1 suppressed M1 macrophage polarization and reduced the expression of TNF alpha and other inflammatory cytokines. Conclusions: These findings suggest an association between NEAT1 expression and patient response to anti-PD-1/PD-L1 therapy in melanoma and GBM and have important implications for the role of lncRNAs in the tumor microenvironment.
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

Purpose:

Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL.

Patients and Methods:

In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations.

Results:

Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021–0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011–0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection.

Conclusions:

NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.
Data from Triple-Negative Breast Cancer-Derived Extracellular Vesicles Promote a Hepatic Pre-metastatic Niche via a Cascade of Microenvironment Remodeling
Authors: Heo Woohang , Lee Woochan , Cheun Jong Ho , Lee Eun-Shin , Li Songbin , Kim Hoe suk , Son Hye-Youn , Kim Ju Hee , Woo Yeon Duk , Chung Doo Hyun , Yun Jihui , Jung Ji Gwang , Lee Han-Byoel , Han Wonshik , Kim Hong-Kyu , Kim Jong-Il , Moon Hyeong-Gon
Published: May 2023

Abstract
Patients with triple-negative breast cancer (TNBC) often develop metastases in visceral organs including the liver, but the detailed molecular mechanisms of TNBC liver metastasis is not clearly understood. In this study, we tried to dissect the process of pre-metastatic niche formation in the liver by using patient-derived xenograft (PDX) models of TNBC with different metastatic propensity. RNA sequencing of TNBC PDX models that successfully metastasized to liver showed upregulation of the Cx3cr1 gene in the liver microenvironment. In syngeneic breast cancer models, the Cx3cr1 upregulation in liver preceded the development of cancer cell metastasis and was the result of recruitment of CX3CR1-expressing macrophages. The recruitment was induced by the CX3CL1 production from the liver endothelial cells and this CX3CL1–CX3CR1 signaling in the pre-metastatic niche resulted in upregulation of MMP9 that promoted macrophage migration and cancer cell invasion. In addition, our data suggest that the extracellular vesicles derived from the breast cancer cells induced the TNFα expression in liver, which leads to the CX3CL1 upregulation. Lastly, the plasma CX3CL1 levels in 155 patients with breast cancer were significantly associated with development of liver metastasis.
Implications:
Our data provides previously unknown cascades regarding the molecular education of pre-metastatic niche in liver for TNBC.
Data from Critical role of 6-phosphogluconate dehydrogenase in TAp73-mediated cancer cell proliferation
Authors: Qiao Rui , Wei Mengmeng , Chen Hui , Zhang Xianhong , Zhang Jie , Gao Liyang , Ma Haijun , Wang Yujiong , Li Le
Published: May 2023

Abstract
Cancer cells frequently alter their metabolism to support biogenesis and proliferation and survive specific metabolic stressors. The glucose-associated pentose phosphate pathway (PPP) is crucial for cancer cell proliferation. In particular, 6-phosphogluconate dehydrogenase (6PGD), the second dehydrogenase in the PPP, catalyzes the decarboxylation of 6-phosphogluconate into ribulose 5-phosphate (Ru5P). However, the mechanisms controlling 6PGD expression in cancer cells remain unclear. Herein, we show that TAp73 increases Ru5P and NADPH production through 6PGD activation to counteract reactive oxygen species and protects cells from apoptosis. Moreover, 6PGD overexpression rescues the proliferation and tumorigenic ability of TAp73-deficient cells. These findings further establish the critical role of TAp73 on glucose metabolism regulation, demonstrating that TAp73 can activate 6PGD expression to support oncogenic cell growth.

Implications: By transcriptional upregulation of 6PGD, TAp73 promotes the generation of Ru5P and NADPH, and enhances tumor cell proliferation.
Data from Critical Role of 6-Phosphogluconate Dehydrogenase in TAp73-Mediated Cancer Cell Proliferation
Authors: Qiao Rui , Wei Mengmeng , Chen Hui , Zhang Xianhong , Zhang Jie , Gao Liyang , Ma Haijun , Wang Yujiong , Li Le
Published: May 2023

Abstract
Cancer cells frequently alter their metabolism to support biogenesis and proliferation and survive specific metabolic stressors. The glucose-associated pentose phosphate pathway (PPP) is crucial for cancer cell proliferation. In particular, 6-phosphogluconate dehydrogenase (6PGD), the second dehydrogenase in the PPP, catalyzes the decarboxylation of 6-phosphogluconate into ribulose 5-phosphate (Ru5P). However, the mechanisms controlling 6PGD expression in cancer cells remain unclear. Herein, we show that TAp73 increases Ru5P and NADPH production through 6PGD activation to counteract reactive oxygen species and protects cells from apoptosis. Moreover, 6PGD overexpression rescues the proliferation and tumorigenic ability of TAp73-deficient cells. These findings further establish the critical role of TAp73 on glucose metabolism regulation, demonstrating that TAp73 can activate 6PGD expression to support oncogenic cell growth.
Implications:
By transcriptional upregulation of 6PGD, TAp73 promotes the generation of Ru5P and NADPH, and enhances tumor cell proliferation.
Data from Truncation of GalNAc-type O-glycans suppresses CD44-mediated osteoclastogenesis and bone metastasis in breast cancer
Authors: Lin Neng-Yu , Lee Jian-Jr , Chen Syue-Ting , Lin Jung-An , Lin Chia-Hsuan , Lin Hsuan-Yu , Su Yong-Han , Chen Cheng-Chang , Lin Mei-Chun , Kuo Ching-Ying , Haung Min-Chuan
Published: May 2023

Abstract
The glycoprotein CD44 is a key regulator of malignant behaviors in breast cancer cells. To date, hyaluronic acid (HA)-CD44 signaling pathway has been widely documented in the context of metastatic bone diseases. Core 1 β1,3-galactosyltransferase (C1GALT1) is a critical enzyme responsible for the elongation of O-glycosylation. Aberrant O-glycans are recognized as a hallmark in cancers. However, the effects of C1GALT1 on CD44 signaling and bone metastasis remain unclear. In this study, immunohistochemical analysis indicated that C1GALT1 expression positively correlates with CD44 in breast cancer. Silencing C1GALT1 accumulates the Tn antigen on CD44, which decreases CD44 levels and osteoclastogenic signaling. Mutations in the O-glycosites on the stem region of CD44 impair its surface localization as well as suppress cell-HA adhesion and osteoclastogenic effects of breast cancer cells. Furthermore, in vivo experiments demonstrated the inhibitory effect of silencing C1GALT1 on breast cancer bone metastasis and bone loss. In conclusion, our study highlights the importance of O-glycans in promoting CD44-mediated tumorigenic signals and indicates a novel function of C1GALT1 in driving breast cancer bone metastasis.

Implications: Truncation of GalNAc-type O-glycans by silencing C1GALT1 suppresses CD44-mediated osteoclastogenesis and bone metastasis in breast cancer; targeting the O-glycans on CD44 may serve as a potential therapeutic target for blocking cancer bone metastasis.
Supplementary Figures from Netrin-1 Promotes the Immunosuppressive Activity of MDSCs in Colorectal Cancer
Authors: Xia Xueli , Mao Zhenwei , Wang Wenxin , Ma Jie , Tian Jie , Wang Shengjun , Yin Kai
Published: May 2023

Supplementary Figures S1-S9
Supplementary Data from Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer
Authors: Hinshaw Dominique C. , Benavides Gloria A. , Metge Brandon J. , Swain Courtney A. , Kammerud Sarah C. , Alsheikh Heba A. , Elhamamsy Amr , Chen Dongquan , Darley-Usmar Victor , Rathmell Jeffrey C. , Welner Robert S. , Samant Rajeev S. , Shevde Lalita A.
Published: May 2023

Supplementary Figures and Table
Supplementary Tables from Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma
Authors: Romano Gabriele , Paradiso Francesca , Li Peng , Shukla Pooja , Barger Lindsay N. , El Naggar Olivia , Miller John P. , Liang Roger J. , Helms Timothy L. , Lazar Alexander J. , Wargo Jennifer A. , Taraballi Francesca , Costello James C. , Kwong Lawrence N.
Published: May 2023

Supplementary Tables S1-S3
Supplementary Tables from SWI/SNF Complex Genomic Alterations as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Multiple Cancers
Authors: Wang Di , Wang Jianchao , Zhou Dongmei , Wu Zhixian , Liu Wei , Chen Yanping , Chen Gang , Zhang Jing
Published: May 2023

Supplementary Tables S1-S12
Supplementary Figures from SWI/SNF Complex Genomic Alterations as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Multiple Cancers
Authors: Wang Di , Wang Jianchao , Zhou Dongmei , Wu Zhixian , Liu Wei , Chen Yanping , Chen Gang , Zhang Jing
Published: May 2023

Supplementary Figures S1-S5
Supplementary Data from Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma
Authors: Yeo Alan T. , Shah Rushil , Aliazis Konstantinos , Pal Rinku , Xu Tuoye , Zhang Piyan , Rawal Shruti , Rose Christopher M. , Varn Frederick S. , Appleman Vicky A. , Yoon Joon , Varma Hemant , Gygi Steven P. , Verhaak Roel G.W. , Boussiotis Vassiliki A. , Charest Al
Published: May 2023

supplementary figures & legends
Supplementary Data Table 2 from Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma
Authors: Yeo Alan T. , Shah Rushil , Aliazis Konstantinos , Pal Rinku , Xu Tuoye , Zhang Piyan , Rawal Shruti , Rose Christopher M. , Varn Frederick S. , Appleman Vicky A. , Yoon Joon , Varma Hemant , Gygi Steven P. , Verhaak Roel G.W. , Boussiotis Vassiliki A. , Charest Al
Published: May 2023

Supplementary table 2
Supplementary Data from Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer
Authors: Felices Martin , Wesley Erin , Bendzick Laura E. , Kodal Behiye , Hopps Rachel , Grzywacz Bartosz , Hinderlie Peter , Miller Jeffrey S. , Geller Melissa A.
Published: May 2023

Supplemental Table 1 and Supplemental Figures 1-5
Data from HDAC3 Inhibition Promotes Antitumor Immunity by Enhancing CXCL10-Mediated Chemotaxis and Recruiting of Immune Cells
Authors: Li Lili , Hao Shumin , Gao Meiling , Liu Junxiao , Xu Xin , Huang Jianfei , Cheng Genhong , Yang Heng
Published: May 2023

Abstract
It is generally believed that histone deacetylase (HDAC) inhibitors, which represent a new class of anticancer agents, exert their antitumor activity by directly causing cell-cycle arrest and apoptosis of tumor cells. However, in this study, we demonstrated that class I HDAC inhibitors, such as Entinostat and Panobinostat, effectively suppressed tumor growth in immunocompetent but not immunodeficient mice. Further studies with Hdac1, 2, or 3 knockout tumor cells indicated that tumor-specific inactivation of HDAC3 suppressed tumor growth by activating antitumor immunity. Specifically, we found that HDAC3 could directly bind to promotor regions and inhibit the expression of CXCL9, 10, and 11 chemokines. Hdac3-deficient tumor cells expressed high levels of these chemokines, which suppressed tumor growth in immunocompetent mice by recruiting CXCR3+ T cells into the tumor microenvironment (TME). Furthermore, the inverse correlation between HDAC3 and CXCL10 expression in hepatocellular carcinoma tumor tissues also suggested HDAC3 might be involved in antitumor immune regulation and patient survival. Thus, our studies have illustrated that HDAC3 inhibition suppresses tumor growth by enhancing immune cell infiltration into the TME. This antitumor mechanism may be helpful in guiding HDAC3 inhibitor–based treatment.
Data from Microparticle-delivered Cxcl9 prolongs Braf inhibitor efficacy in melanoma
Authors: Romano Gabriele , Paradiso Francesca , Li Peng , Shukla Pooja , Barger Lindsay N. , El Naggar Olivia , Miller John P. , Liang Roger J. , Helms Timothy L. , Lazar Alexander J. , Wargo Jennifer A. , Taraballi Francesca , Costello James C. , Kwong Lawrence N.
Published: May 2023

Abstract
Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining chemokine signaling could impair MRD maintenance through increased recruitment of effector T cells. We found that intratumoral administration of recombinant Cxcl9 (rCxcl9), either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete pathologic responses after microparticle-delivered rCxcl9 combined with BRAF and MEK inhibition. Our experiments constitute proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of frontline treatment methods.
FIGURE 3 from Ultra High-plex Spatial Proteogenomic Investigation of Giant Cell Glioblastoma Multiforme Immune Infiltrates Reveals Distinct Protein and RNA Expression Profiles
Authors: Bonnett Shilah A. , Rosenbloom Alyssa B. , Ong Giang T. , Conner Mark , Rininger Aric B.E. , Newhouse Daniel , New Felicia , Phan Chi Q. , Ilcisin Saskia , Sato Hiromi , Lyssand John S. , Geiss Gary , Beechem Joseph M.
Published: May 2023

Assessment of SPG performance on human tissue. FFPE colorectal cancer sections were stained with the GeoMx NGS Human Protein modules (147-plex), WTA, and antibodies against PanCK (Tumor) and CD45 (Immune). A, Representative image of colorectal cancer sample used in the assessment of SPG data quality versus the respective RNA and Protein control data. Two ROIs showing strong enrichment of immune cells (CD45; magenta) and tumor cells (PanCK, green). Concordance between the proteogenomic assay and single analyte protein (B) and RNA controls (C). Concordance between the initial and stored proteogenomic slide for protein (D) and RNA analytes (E). F, Multiplexed protein and RNA characterization of colorectal cancer sample with representative images highlighting the segmentation of 300 μm circular ROIs into tumor- (PanCK+) and immune- (CD45+) enriched regions. Segments illuminated in white were collected, black regions were not. Protein targets with SNR ≥ 3 and WTA RNA targets with SNR ≥ 4 were used in the analysis. Unsupervised hierarchical clustering of top 250 differentially expressed RNA (G) and detect protein targets for colorectal cancer (H). I, Combined volcano plot of Protein and RNA expression in colorectal cancer. A subset of differentially expressed genes is labeled with colors matching their analyte.
Supplementary Table S3 from Chemokine analysis in patients with metastatic uveal melanoma suggests a role for CCL21 signaling in combined epigenetic therapy and checkpoint immunotherapy
Authors: Sah Vasu R , Jespersen Henrik , Karlsson Joakim , Nilsson Lisa M , Bergqvist Mattias , Johansson Iva , Carneiro Ana , Helgadottir Hildur , Levin Max , Ullenhag Gustav J. , Ståhlberg Anders , Olofsson Bagge Roger , Nilsson Jonas A. , Ny Lars
Published: May 2023

Patient sample information
Figure S2 from Chemokine analysis in patients with metastatic uveal melanoma suggests a role for CCL21 signaling in combined epigenetic therapy and checkpoint immunotherapy
Authors: Sah Vasu R , Jespersen Henrik , Karlsson Joakim , Nilsson Lisa M , Bergqvist Mattias , Johansson Iva , Carneiro Ana , Helgadottir Hildur , Levin Max , Ullenhag Gustav J. , Ståhlberg Anders , Olofsson Bagge Roger , Nilsson Jonas A. , Ny Lars
Published: May 2023

Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out
using DESeq2 and FDR-adjusted P-values were denoted with *, P < 0.05; **, P < 0.01; ***, P
< 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints
divided among response groups, PD, SD, PR. c) TK1 values in different response groups
Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy
Authors: Sah Vasu R. , Jespersen Henrik , Karlsson Joakim , Nilsson Lisa M. , Bergqvist Mattias , Johansson Iva , Carneiro Ana , Helgadottir Hildur , Levin Max , Ullenhag Gustav , Ståhlberg Anders , Olofsson Bagge Roger , Nilsson Jonas A. , Ny Lars
Published: May 2023

Purpose:

Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed.

Patients and Methods:

We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival.

Results:

Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival.

Conclusions:

This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients.

Significance:

The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.
Politicisation of Islam and a Culture of Atrocities against Religious Minorities in Modern-Day Pakistan
Authors: Rashid Khadija
Published: May 2023

Since independence, the politicisation of Islam in Pakistan has fostered a culture of atrocities against religious minorities. This explains why Pakistan tops the list of countries at the risk of mass killings. The Islamic revivalist movement that emerged under the military dictatorship of General Zia-ul-Haq during the 1970s-80s is often equated with Pakistan’s descent into religious intolerance. The controversial blasphemy laws modified under his regime continue to abet atrocity crimes across Pakistan. This article reflects on the constitutional and legal frameworks to understand the prevalence of hate speech and incitement in the country. Through case studies of recent episodes of violence, it sheds light on the state’s complex governance structures, its struggle to counter episodes that incite violence, and the barriers to implementing rule of law. Furthermore, the article highlights the need for key reforms on both national and international level to push for the implementation of atrocity prevention frameworks.
Imperforate tracheary element classification for studies of xylem structure-function relations
Authors: Olson Mark E.
Published: May 2023

Discovering how xylem function emerges from xylem structure requires approaches that are distinct from those invented for wood identification. I exemplify this need for different approaches by discussing the classification of imperforate tracheary elements, the cells that go by names such as “fibers,” tracheids, fiber-tracheids, and libriform fibers. Currently, there are two classification systems, one for wood identification and one championed by Sherwin Carlquist for research on xylem function. I emphasize that neither is globally “correct” for all applications, but instead each is appropriate for the aims of its field. Wood identification uses an easily-applied classification of imperforate tracheary elements, designed to remain stable over the long term. This stability allows anatomists to build large databases of wood data that are maximally useful for wood identification. In contrast, functional xylem biologists need flexible definitions that serve as hypotheses of imperforate tracheary element function to be tested, modified, and tested again, in an open-ended process of refining knowledge of xylem structure-function relations. I highlight some of the many open questions that the functional classification points to, such as the morphological correlates of the conductive/nonconductive imperforate tracheary element distinction, how imperforate tracheary element features are associated with vessel grouping, whether the libriform fiber-fiber tracheid distinction is arbitrary or not, and other topics. Recognizing that the purpose of a functional classification is to drive research shifts focus away from debates about whether a given cell type classification is “correct” and onto the empirical priorities that need study. While there is a solid tradition within comparative wood anatomy of training in wood identification, there is a need to train functional comparative wood anatomists, who can guide and interact with xylem physiologists to build more robust explanations of xylem structure and function.