bluuebunny/crossref_metadata_2025 huggingface dataset:
Trapping in acoustic standing waves: Effect of liquid drop compressibility
Authors: Marston Philip L.
Published: September 2023

The Reflections series takes a look back on historical articles from The Journal of the Acoustical Society of America that have had a significant impact on the science and practice of acoustics.
REVIEWS OF ACOUSTICAL PATENTS
Authors: Fulop Sean A.
Published: September 2023

The purpose of these acoustical patent reviews is to provide enough information for a Journal reader to decide whether to seek more information from the patent itself. Any opinions expressed here are those of the reviewers as individuals and are not legal opinions. Patents are available via the internet at the USPTO website.
Sound delivery to listening point using tangent line method
Authors: Kaizuka Tsutomu , Onodera Wataru
Published: September 2023

In personal audio systems, sounds should propagate toward the listening point and attenuate beyond the listening point. This study deals with controlling directivity and distance attenuation using loudspeaker arrays. The array signal processing is based on tangent line method (TLM), which can generate acoustic beams following arbitrary convex trajectories. A curvilinear acoustic beam is produced as an envelope of tangent lines, i.e., straight acoustic beams. Specifying the envelope length enables controlling distance attenuation while enhancing directivity. In this study, the TLM for arbitrary circular trajectories is formulated. Optimization algorithm is applied to identify the trajectory maximizing acoustic contrast.
Phonetic characteristics of German unstressed vowels: The case of opa vs Oper
Authors: Tomaschek Fabian , Berg Kristian
Published: September 2023

Kohler [Einführung in die Phonetik des Deutschen (Erich Schmidt Verlag, Berlin, Germany, 1995)] stated that German [ɐ] and [a] in unstressed syllables are merging. The present study tested this hypothesis. The contrast was found intact word-internally and word-finally. Neighborhood density enhanced its phonetic characteristics, but no effects of frequency and conditional probability were found.
Hearing diversity in 34 000 fish species: A personal perspective
Authors: Popper Arthur N.
Published: September 2023

I have been studying fish hearing since 1966. Over that time, my interests have evolved from basic mechanisms of hearing to “translational fish bioacoustics” where I help apply basic science to the protection of fishes from potential harm arising from anthropogenic sources. Yet, I am still most interested in basic science questions. Thus, this paper focuses on basic questions on fish hearing and shares my personal view of some of the interesting and important questions I think need to be asked about fish hearing by future investigators. Accordingly, I am not focusing on what has been learned, but, rather, I focus on the questions raised by what we have learned. Moreover, my focus is comparative—there are more than 34 000 extant fish species—and we know little about hearing in any one species. Indeed, most of our knowledge comes from about 100 species! Therefore, considering the immense importance of fishes, it is my contention that we need to know a great deal more about the sense that gives fishes rapid and highly directional information, often at a great distance, about the world around them.
Combination of inhibitors for two glycolytic enzymes portrays high synergistic efficacy against
Cryptosporidium parvum
Authors: Khan Shahbaz M. , Bajwa Muhammad Rashid , Lahar Rachael Y. , Witola William H.
Published: September 2023

Cryptosporidium
is an intracellular protozoan parasite that causes serious enteric disease in humans and in a wide range of animals worldwide. Despite its high prevalence, no effective therapeutic drugs are available against life-threatening cryptosporidiosis in at-risk populations including malnourished children, immunocompromised patients, and neonatal calves. Thus, new efficacious drugs are urgently needed to treat all susceptible populations with cryptosporidiosis. Unlike other apicomplexans,
Cryptosporidium parvum
lacks the tricarboxylic acid cycle and the oxidative phosphorylation steps, making it solely dependent on glycolysis for metabolic energy production. We have previously reported that individual inhibitors of two unique glycolytic enzymes, the plant-like pyruvate kinase (CpPyK) and the bacterial-type lactate dehydrogenase (CpLDH), are effective against
C. parvum
, both
in vitro
and
in vivo
. Herein, we have derived combinations of CpPyK and CpLDH inhibitors with strong synergistic effects against the growth and survival of
C. parvum
, both
in vitro
and in an infection mouse model. In infected immunocompromised mice, compound combinations of NSC303244 + NSC158011 and NSC252172 + NSC158011 depicted enhanced efficacy against
C. parvum
reproduction and ameliorated intestinal lesions of cryptosporidiosis at doses fourfold lower than the total effective doses of individual compounds. Importantly, unlike individual compounds, NSC303244 + NSC158011 combination was effective in clearing the infection completely without relapse in immunocompromised mice. Collectively, our study has unveiled compound combinations that simultaneously block two essential catalytic steps for metabolic energy production in
C. parvum
to achieve improved efficacy against the parasite. These combinations are, therefore, lead compounds for the development of a new generation of efficacious anti-cryptosporidial drugs.
Isolation of ACE2-dependent and -independent sarbecoviruses from Chinese horseshoe bats
Authors: Guo Hua , Li Ang , Dong Tian-Yi , Si Hao-Rui , Hu Ben , Li Bei , Zhu Yan , Shi Zheng-Li , Letko Michael
Published: September 2023

While the spike proteins from severe acute respiratory syndrome coronaviruses-1 and 2 (SARS-CoV and SARS-CoV-2) bind to host angiotensin-converting enzyme 2 (ACE2) to infect cells, the majority of bat sarbecoviruses cannot use ACE2 from any species. Despite their discovery almost 20 years ago, ACE2-independent sarbecoviruses have never been isolated from field samples, leading to the assumption these viruses pose little risk to humans. We have previously shown how spike proteins from a small group of ACE2-independent bat sarbecoviruses may possess the ability to infect human cells in the presence of exogenous trypsin. Here, we adapted our earlier findings into a virus isolation protocol and recovered two new ACE2-dependent viruses, RsYN2012 and RsYN2016A, as well as an ACE2-independent virus, RsHuB2019A. Although our stocks of RsHuB2019A rapidly acquired a tissue-culture adaption that rendered the spike protein resistant to trypsin, trypsin was still required for viral entry, suggesting limitations on the exogenous entry factors that support bat sarbecoviruses. Electron microscopy revealed that ACE2-independent sarbecoviruses have a prominent spike corona and share similar morphology to other coronaviruses. Our findings demonstrate a broader zoonotic threat posed by sarbecoviruses and shed light on the intricacies of coronavirus isolation and propagation
in vitro
.

IMPORTANCE

Several coronaviruses have been transmitted from animals to people, and 20 years of virus discovery studies have uncovered thousands of new coronavirus sequences in nature. Most of the animal-derived sarbecoviruses have never been isolated in culture due to cell incompatibilities and a poor understanding of the in vitro requirements for their propagation. Here, we built on our growing body of work characterizing viral entry mechanisms of bat sarbecoviruses in human cells and have developed a virus isolation protocol that allows for the exploration of these understudied viruses. Our protocol is robust and practical, leading to successful isolation of more sarbecoviruses than previous approaches and from field samples that had been collected over a 10-year longitudinal study.
TBX20loss-of-function variants in families with left ventricular non-compaction cardiomyopathy
Authors: Chang Yuchen , Wacker Julie , Ingles Jodie , Macciocca Ivan , King Ingrid ,   The Australian Genomics Cardiovascular Disorders Flagship, Semsarian Christopher , McGaughran Julie , Weintraub Robert G , Bagnall Richard D
Published: September 2023

TBX20encodes a cardiac transcription factor that is associated with atrial septal defects. Recent studies implicate loss-of-functionTBX20variants with left ventricular non-compaction cardiomyopathy (LVNC), although clinical and genetic data in families are limited. We report four families withTBX20loss-of-function variants that segregate with LVNC. Genetic testing using genome or exome sequencing was performed in index cases, variants were validated with Sanger sequencing, and cascade genetic testing was performed in family members. A multi-exon deletion, small deletion, essential splice site variant and nonsense variant inTBX20were found in four families. The index cases in two families were symptomatic children with identical congenital heart diseases and LVNC who developed different cardiomyopathy phenotypes with one developing heart failure requiring transplantation. In another family, the child index case had LVNC and congestive heart failure requiring heart transplantation. In the fourth family, the index case was a symptomatic adult with LVNC. In all families, the variants segregated in relatives with isolated LVNC, or with congenital heart disease or cardiomyopathy. Family members displayed a clinical spectrum from asymptomatic to severe presentations including heart failure. Our data strengthenTBX20loss-of-function variants as a rare cause of LVNC and supportTBX20inclusion in genetic testing of LVNC.
COVID-19-associated pulmonary aspergillosis in mechanically ventilated patients: a prospective, multicentre UK study
Authors: Hurt William , Youngs Jonathan , Ball Jonathan , Edgeworth Jonathan , Hopkins Philip , Jenkins David R , Leaver Susannah , Mazzella Andrea , Molloy Síle F , Schelenz Silke , Wise Matt P , White P Lewis , Yusuff Hakeem , Wyncoll Duncan , Bicanic Tihana
Published: September 2023

Background

Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort.

Methods

From March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples.

Results

Twenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7–16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77).

Interpretation

In this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables.
Algorithmic Harms in Child Welfare: Uncertainties in Practice, Organization, and Street-level Decision-making
Authors: Saxena Devansh , Guha Shion
Published: September 2023

Algorithms in public services such as child welfare, criminal justice, and education are increasingly being used to make high-stakes decisions about human lives. Drawing upon findings from a two-year ethnography conducted at a child welfare agency, we highlight how algorithmic systems are embedded within a complex decision-making ecosystem at critical points of the child welfare process. Caseworkers interact with algorithms in their daily lives where they must collect information about families and feed it to algorithms to make critical decisions. We show how the interplay between systemic mechanics and algorithmic decision-making can adversely impact the fairness of the decision-making process itself. We show how functionality issues in algorithmic systems can lead to process-oriented harms where they adversely affect the nature of professional practice, and administration at the agency, and lead to inconsistent and unreliable decisions at the street level. In addition, caseworkers are compelled to undertake additional labor in the form of repair work to restore disrupted administrative processes and decision-making, all while facing organizational pressures and time and resource constraints. Finally, we share the case study of a simple algorithmic tool that centers caseworkers’ decision-making within a trauma-informed framework and leads to better outcomes, however, required a significant amount of investments on the agency’s part in creating the ecosystem for its proper use.
Relieving Popularity Bias in Interactive Recommendation: A Diversity-Novelty-Aware Reinforcement Learning Approach
Authors: Shi Xiaoyu , Liu Quanliang , Xie Hong , Wu Di , Peng Bo , Shang MingSheng , Lian Defu
Published: September 2023

Whilepersonalizationincreases the utility of item recommendation, it also suffers from the issue of popularity bias. However, previous methods emphasize adopting supervised learning models to relieve popularity bias in the static recommendation, ignoring the dynamic transfer of user preference and amplification effects of the feedback loop in the recommender system (RS). In this paper, we focus on studying this issue in the interactive recommendation. We argue that diversification and novelty are both equally crucial for improving user satisfaction of IRS in the aforementioned setting. To achieve this goal, we propose aDiversity-Novelty-awareInteractiveRecommendation framework (DNaIR) that augments offline reinforcement learning (RL) to increase the exposure rate of long-tail items with high quality. Its main idea is first to aggregate the item similarity, popularity, and quality into the reward model to help the planning of RL policy. It then designs a diversity-aware stochastic action generator to achieve an efficient and lightweight DNaIR algorithm. Extensive experiments are conducted on the three real-world datasets and an authentic RL environment (Virtual-Taobao). The experiments show that our model can better and full use of the long-tail items to improve recommendation satisfaction, especially those low popularity items with high-quality ones, thus achieving state-of-the-art performance.
Data from Pre-existing immunity drives the response to neoadjuvant chemotherapy in esophageal adenocarcinoma
Authors: Arbore Giuseppina , Albarello Luca , Bucci Gabriele , Punta Marco , Cossu Andrea , Fanti Lorella , Maurizio Aurora , Di Mauro Francesco , Bilello Vito , Arrigoni Gianluigi , Bonfiglio Silvia , Biancolini Donatella , Puccetti Francesco , Elmore Ugo , Vago Luca , Cascinu Stefano , Tonon Giovanni , Rosati Riccardo , Casorati Giulia , Dellabona Paolo
Published: September 2023

Abstract
Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathological complete response to nCT, which correlates with increased 5-year survival compared to non-responders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies. Here, we investigated the immune mechanisms involved in nCT response by multi-dimensional profiling of pre-treatment tumor biopsies and blood from 68 EAC patients (34 prospectively and 34 retrospectively collected), comparing complete responders versus non-responders to nCT. At the tumor level, complete response to nCT was associated with molecular signatures of immune response and proliferation, increased putative anti-tumor tissue-resident memory CD39+CD103+CD8+ T cells and reduced immunosuppressive T regulatory cells and M2-like macrophages. Systemically, complete responders showed higher frequencies of immunostimulatory CD14+CD11c+HLA-DRhigh cells and reduced PDL1+ monocytic myeloid-derived suppressor cells, along with high plasma GM-CSF (pro-inflammatory) and low IL-4, CXCL10, C3a, and C5a (suppressive). Plasma pro-inflammatory and suppressive cytokines correlated directly and inversely, respectively, with the frequency of tumor-infiltrating CD39+CD103+CD8+ T cells. These results suggest that pre-existing immunity in baseline tumors drives the clinical activity of nCT in locally advanced EAC. Furthermore, it may be possible to stratify patients based on predictive immune signatures, enabling tailored neoadjuvant and/or adjuvant regimens.
Data from Nanoparticle-based combination therapy enhances fulvestrant efficacy and overcomes tumor resistance in ER-positive breast cancer
Authors: Li Bozhao , Qi Feilong , Zhu Fei , Lu Zefang , Wang Meiqi , Chu Tianjiao , Wu Suying , Wei Jingyan , Song Zhenchuan , Sukumar Saraswati , Zhang Cheng , Xu Jiangfei , Li Suping , Nie Guangjun
Published: September 2023

Abstract
Nanoparticles (NPs) spanning diverse materials and properties have the potential to encapsulate and protect a wide range of therapeutic cargos to increase bioavailability, prevent undesired degradation, and mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader (SERD), is commonly used for treating estrogen receptor (ER)-positive breast cancer patients, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. Additionally, the NP was co-loaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.
Table S9 from Using DEPendency of Association on the Number of Top Hits (DEPTH) as a Complementary Tool to Identify Novel Colorectal Cancer Susceptibility Loci
Authors: Lai John , Wong Chi Kuen , Schmidt Daniel F. , Kapuscinski Miroslaw K. , Alpen Karen , MacInnis Robert J. , Buchanan Daniel D. , Win Aung K. , Figueiredo Jane C. , Chan Andrew T. , Harrison Tabitha A. , Hoffmeister Michael , White Emily , Le Marchand Loic , Pai Rish K. , Peters Ulrike , Hopper John L. , Jenkins Mark A. , Makalic Enes
Published: September 2023

Supplementary Table S9 shows the number of risk regions that are common to both CCFR and GECCO in stage 3 DEPTH analysis, as well as whether they are detected by logistic regression analysis or were in previous CRC GWAS studies.
Table S6 from Using DEPendency of Association on the Number of Top Hits (DEPTH) as a Complementary Tool to Identify Novel Colorectal Cancer Susceptibility Loci
Authors: Lai John , Wong Chi Kuen , Schmidt Daniel F. , Kapuscinski Miroslaw K. , Alpen Karen , MacInnis Robert J. , Buchanan Daniel D. , Win Aung K. , Figueiredo Jane C. , Chan Andrew T. , Harrison Tabitha A. , Hoffmeister Michael , White Emily , Le Marchand Loic , Pai Rish K. , Peters Ulrike , Hopper John L. , Jenkins Mark A. , Makalic Enes
Published: September 2023

Supplementary Table S6 shows the number of risk regions identified by first stage DEPTH analysis.
Table S2 from Using DEPendency of Association on the Number of Top Hits (DEPTH) as a Complementary Tool to Identify Novel Colorectal Cancer Susceptibility Loci
Authors: Lai John , Wong Chi Kuen , Schmidt Daniel F. , Kapuscinski Miroslaw K. , Alpen Karen , MacInnis Robert J. , Buchanan Daniel D. , Win Aung K. , Figueiredo Jane C. , Chan Andrew T. , Harrison Tabitha A. , Hoffmeister Michael , White Emily , Le Marchand Loic , Pai Rish K. , Peters Ulrike , Hopper John L. , Jenkins Mark A. , Makalic Enes
Published: September 2023

Supplementary Table S2 shows the QC and harmonisation steps for both the GECCO and CCFR datasets
Figure S3 from Using DEPendency of Association on the Number of Top Hits (DEPTH) as a Complementary Tool to Identify Novel Colorectal Cancer Susceptibility Loci
Authors: Lai John , Wong Chi Kuen , Schmidt Daniel F. , Kapuscinski Miroslaw K. , Alpen Karen , MacInnis Robert J. , Buchanan Daniel D. , Win Aung K. , Figueiredo Jane C. , Chan Andrew T. , Harrison Tabitha A. , Hoffmeister Michael , White Emily , Le Marchand Loic , Pai Rish K. , Peters Ulrike , Hopper John L. , Jenkins Mark A. , Makalic Enes
Published: September 2023

Supplementary Figure S3 shows further filtering of SNPs that had greater than 20% difference in odds ratio or P values when comparing odds ratios and P values before and after adjusting for the first four principal components.
Supplementary Figure S1 from Development of a Breast Cancer Risk Prediction Model Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Korean Women
Authors: Choi Jihye , Ha Tae-Woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: September 2023

Distribution of PRS38_ASN+PRS190_EB among participants with (case) and without breast cancer (control).
Table S3 from Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility
Authors: Gregga Isabelle , Pharoah Paul D. P. , Gayther Simon A. , Manichaikul Ani , Im Hae Kyung , Kar Siddhartha P. , Schildkraut Joellen M. , Wheeler Heather E.
Published: September 2023

Table S3. PWAS meta-FDR<0.05 proteins with ovarian cancer associations.
Supplementary Figure S1 from Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility
Authors: Gregga Isabelle , Pharoah Paul D. P. , Gayther Simon A. , Manichaikul Ani , Im Hae Kyung , Kar Siddhartha P. , Schildkraut Joellen M. , Wheeler Heather E.
Published: September 2023

Supplementary Figure S1: Workflow illustrating the methods.
Table 1 from Characteristics of Cancer Epidemiology Studies That Employ Metabolomics: A Scoping Review
Authors: Yu Catherine T. , Farhat Zeinab , Livinski Alicia A. , Loftfield Erikka , Zanetti Krista A.
Published: September 2023

Study-, population-, and metabolomics-related characteristics of population-based cancer metabolomics studies.
Supplementary Table S1 from Characteristics of Cancer Epidemiology Studies That Employ Metabolomics: A Scoping Review
Authors: Yu Catherine T. , Farhat Zeinab , Livinski Alicia A. , Loftfield Erikka , Zanetti Krista A.
Published: September 2023

Supplementary Table S1 shows metabolite super-pathways examined in semi-targeted population-based cancer metabolomics studies.
Supplementary Figure S6 from Characteristics of Cancer Epidemiology Studies That Employ Metabolomics: A Scoping Review
Authors: Yu Catherine T. , Farhat Zeinab , Livinski Alicia A. , Loftfield Erikka , Zanetti Krista A.
Published: September 2023

Supplementary Figure S6 shows pie chart displaying breakdown of studies that used an LC-MS semi-targeted approach.
Figure 2 from Characteristics of Cancer Epidemiology Studies That Employ Metabolomics: A Scoping Review
Authors: Yu Catherine T. , Farhat Zeinab , Livinski Alicia A. , Loftfield Erikka , Zanetti Krista A.
Published: September 2023

Pie chart displays the breakdown of study design types used in metabolomic epidemiology studies of cancer. *Other includes meta-analysis of multiple nested case–control studies.
Supplementary Table 2 from Relationship between ABO Blood Group Alleles and Pancreatic Cancer Is Modulated by Secretor (FUT2) Genotype, but Not Lewis Antigen (FUT3) Genotype
Authors: Kim Jihye , Yuan Chen , Amundadottir Laufey T. , Wolpin Brian M. , Klein Alison P. , Risch Harvey A. , Kraft Peter
Published: September 2023

Table S2 lists eight SNPs that characterize ABO blood groups, secretor status, and Lewis antigen.
Supplementary Table 1 from Sex-specific Associations between Body Mass Index and Thyroid Cancer Incidence among Korean Adults
Authors: Kim Kyoung-Nam , Kim Kyungsik , Lee Sangjun , Park Sue K.
Published: September 2023

Supplementary Table 1 shows the characteristics of the cohort participants and incident thyroid cancer cases in the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) and the Korean Multi-center Cancer Cohort (KMCC)
Supplemental Table 3 from Validating Wave 1 (2014) Urinary Cotinine and TNE-2 Cut-points for Differentiating Wave 4 (2017) Cigarette Use from Non-use in the United States Using Data from the PATH Study
Authors: Edwards Kathryn C. , Khan Asia , Sharma Eva , Wang Lanqing , Feng June , Blount Benjamin C. , Sosnoff Connie S. , Smith Danielle M. , Goniewicz Maciej L. , Pearson Jennifer , Villanti Andrea C. , Delnevo Cristine D. , Bover-Manderski Michelle T. , Hatsukami Dorothy K. , Niaura Raymond , Everard Colm , Kimmel Heather L. , Duffy Kara , Rostron Brian L. , Del Valle-Pinero Arseima Y. , van Bemmel Dana M. , Stanton Cassandra A. , Hyland Andrew
Published: September 2023

Supplemental Table 3 provides prevalence rates of any tobacco use using cotinine cut-points.
Data from Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC) Unveils New Actionable Genomic Aberrations in PACC
Authors: Florou Vaia , Elliott Andrew , Bailey Matthew H. , Stone David , Affolter Kajsa , Soares Heloisa P. , Nevala-Plagemann Chris , Scaife Courtney , Walker Phillip , Korn W. Michael , Lou Emil , Shroff Rachna T. , Hosein Peter J. , Garrido-Laguna Ignacio
Published: September 2023

AbstractPurpose:
Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets.
Experimental Design:
PACC specimens (n = 51) underwent next-generation sequencing of DNA (n = 29) or whole exome (n = 22) and RNA (whole transcriptome, n = 29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC; n = 4,205). In parallel, we conducted a retrospective review of patients with PACC treated at Huntsman Cancer Institute (HCI).
Results:
The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared with PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the 7 patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than 3 years.
Conclusions:
There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.
Data from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
Authors: Heinze Karolin , Cairns Evan S. , Thornton Shelby , Harris Bronwyn , Milne Katy , Grube Marcel , Meyer Charlotte , Karnezis Anthony N. , Fereday Sian , Garsed Dale W. , Leung Samuel C.Y. , Chiu Derek S. , Moubarak Malak , Harter Philipp , Heitz Florian , McAlpine Jessica N. , DeFazio Anna , Bowtell David D.L. , Goode Ellen L. , Pike Malcolm , Ramus Susan J. , Pearce C. Leigh , Staebler Annette , Köbel Martin , Kommoss Stefan , Talhouk Aline , Nelson Brad H. , Anglesio Michael S.
Published: September 2023

AbstractPurpose:
Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited.
Experimental Design:
We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC.
Results:
Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P > 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1–14.7; P < 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes.
Conclusions:
Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
Data from Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma
Authors: Akshintala Srivandana , Sundby R. Taylor , Bernstein Donna , Glod John W. , Kaplan Rosandra N. , Yohe Marielle E. , Gross Andrea M. , Derdak Joanne , Lei Haiyan , Pan Alexander , Dombi Eva , Palacio-Yance Isabel , Herrera Kailey R. , Miettinen Markku M. , Chen Helen X. , Steinberg Seth M. , Helman Lee J. , Mascarenhas Leo , Widemann Brigitte C. , Navid Fariba , Shern Jack F. , Heske Christine M.
Published: September 2023

AbstractPurpose:
Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti–IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701).
Patients and Methods:
Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT).
Results:
Thirteen eligible patients, median age 18 years (range 8–29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response.
Conclusions:
The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
Data from CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression
Authors: Kohlmeyer Jordan L. , Lingo Joshua J. , Kaemmer Courtney A. , Scherer Amanda , Warrier Akshaya , Voigt Ellen , Raygoza Garay Juan A. , McGivney Gavin R. , Brockman Qierra R. , Tang Amy , Calizo Ana , Pollard Kai , Zhang Xiaochun , Hirbe Angela C. , Pratilas Christine A. , Leidinger Mariah , Breheny Patrick , Chimenti Michael S. , Sieren Jessica C. , Monga Varun , Tanas Munir R. , Meyerholz David K. , Darbro Benjamin W. , Dodd Rebecca D. , Quelle Dawn E.
Published: September 2023

AbstractPurpose:
Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models.
Experimental Design:
Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti–PD-L1 response.
Results:
Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti–PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression.
Conclusions:
CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti–PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
Empower the Potential of Trastuzumab Deruxtecan with Novel Combinations
Authors: Rolfo Christian , Del Re Marzia , Russo Alessandro
Published: September 2023

Trastuzumab deruxtecan (T-DXd) is reshaping the therapeutic landscape of HER2-positive tumors. A recent article reports on the preclinical activity of the combination of T-DXd plus adavosertib, WEE1 kinase inhibitor, which promises to expand the use of this antibody–drug conjugate in HER2-positive tumors with CCNE1 coamplification.

See related article by DiPeri et al., p. 4385
Supplementary Figure 5 from Targeting the ATF6-Mediated ER Stress Response and Autophagy Blocks Integrin-Driven Prostate Cancer Progression
Authors: Macke Amanda J. , Pachikov Artem N. , Divita Taylor E. , Morris Mary E. , LaGrange Chad A. , Holzapfel Melissa S. , Kubyshkin Anatoly V. , Zyablitskaya Evgeniya Y. , Makalish Tatiana P. , Eremenko Sergey N. , Qiu Haowen , Riethoven Jean-Jack M. , Hemstreet George P. , Petrosyan Armen
Published: September 2023

Figure S5. (A, B) Representative EM images of PC-3 (A) and DU145 (B) cells. Note phagophore nucleation from Golgi (arrowheads) and autophagosomes localizing close to the Golgi (arrow). Orange boxes indicate the areas magnified at the right. (C) WIPI2 W-B of the Golgi fractions isolated from LNCaP, PC-3, and DU145 cells. Samples were normalized by GM130.
Supplementary Fig S4 from Chromatin-Associated SIN3B Protects Cancer Cells from Genotoxic Stress-Induced Apoptosis and Dictates DNA Damage Repair Pathway Choice
Authors: Morales-Valencia Jorge , Petit Coralie , Calderon Alexander , Saini Siddharth , David Gregory
Published: September 2023

SIN3B deletion results in unchanged H4K16 Acetylation levels upon DSB induction.
Supplementary Table S2 from Single-Cell Evolutionary Analysis Reveals Drivers of Plasticity and Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Afeworki Tecleab Yohannes , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2023

Description of samples in the xenograft study
Supplementary Figure S7 from Single-Cell Evolutionary Analysis Reveals Drivers of Plasticity and Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Afeworki Tecleab Yohannes , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2023

Determination of LBC counts by PCR error correction.
Supplementary Table S6 from Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma
Authors: Wang Xin , Kutschat Ana P. , Aggrey-Fynn Joana , Hamdan Feda H. , Graham Rondell P. , Wixom Alexander Q. , Souto Yara , Ladigan-Badura Swetlana , Yonkus Jennifer A. , Abdelrahman Amro M. , Alva-Ruiz Roberto , Gaedcke Jochen , Ströbel Philipp , Kosinsky Robyn Laura , Wegwitz Florian , Hermann Patrick , Truty Mark J. , Siveke Jens T. , Hahn Stephan A. , Hessmann Elisabeth , Johnsen Steven A. , Najafova Zeynab
Published: September 2023

Supplementary Table S6 contains list of qPCR primers used in the study.
Supplementary Table 1 from Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis
Authors: Mohammed Sabira , Thadathil Nidheesh , Ohene-Marfo Phoebe , Tran Albert L. , Van Der Veldt Michael , Georgescu Constantin , Oh Sangphil , Nicklas Evan H. , Wang Dawei , Haritha Nair Hariprasad , Luo Wenyi , Janknecht Ralf , Miller Benjamin F. , Wren Jonathan D. , Freeman Willard M. , Deepa Sathyaseelan S.
Published: September 2023

List of Differentially Expressed Genes from RNA Seq analysis
Supplementary Figure 6 from Oncostatin-M and OSM-Receptor Feed-Forward Activation of MAPK Induces Separable Stem-like and Mesenchymal Programs
Authors: Polak Kelsey L. , Tamagno Ilaria , Parameswaran Neetha , Smigiel Jacob , Chan E. Ricky , Yuan Xueer , Rios Brenda , Jackson Mark W.
Published: September 2023

S6. Generation and analysis of SMAD3 knock-out cells.
Supplementary Figure 1 from Oncostatin-M and OSM-Receptor Feed-Forward Activation of MAPK Induces Separable Stem-like and Mesenchymal Programs
Authors: Polak Kelsey L. , Tamagno Ilaria , Parameswaran Neetha , Smigiel Jacob , Chan E. Ricky , Yuan Xueer , Rios Brenda , Jackson Mark W.
Published: September 2023

S1. OSM induces tumor initiation.
Data from Fibronectin Contributes to a BRAF Inhibitor–driven Invasive Phenotype in Thyroid Cancer through EGR1, Which Can Be Blocked by Inhibition of ERK1/2
Authors: Hicks Hannah M. , Pozdeyev Nikita , Sams Sharon B. , Pugazhenthi Umarani , Bales Elise S. , Hofmann Marie-Claude , McKenna Logan R. , Schweppe Rebecca E.
Published: September 2023

Abstract
Mutations in BRAF are common in advanced papillary and anaplastic thyroid cancer (PTC and ATC). However, patients with BRAF-mutant PTC currently lack therapies targeting this pathway. Despite the approved combination of BRAF and MEK1/2 inhibition for patients with BRAF-mutant ATC, these patients often progress. Thus, we screened a panel of BRAF-mutant thyroid cancer cell lines to identify new therapeutic strategies. We showed that thyroid cancer cells resistant to BRAF inhibition (BRAFi) exhibit an increase in invasion and a proinvasive secretome in response to BRAFi. Using reverse-phase protein array (RPPA), we identified a nearly 2-fold increase in expression of the extracellular matrix protein, fibronectin, in response to BRAFi treatment, and a corresponding 1.8- to 3.0-fold increase in fibronectin secretion. Accordingly, the addition of exogenous fibronectin phenocopied the BRAFi-induced increase in invasion while depletion of fibronectin in resistant cells resulted in loss of increased invasion. We further showed that BRAFi-induced invasion can be blocked by inhibition of ERK1/2. In a BRAFi-resistant patient-derived xenograft model, we found that dual inhibition of BRAF and ERK1/2 slowed tumor growth and decreased circulating fibronectin. Using RNA sequencing, we identified EGR1 as a top downregulated gene in response to combined BRAF/ERK1/2 inhibition, and we further showed that EGR1 is necessary for a BRAFi-induced increase in invasion and for induction of fibronectin in response to BRAFi.
Implications:
Together, these data show that increased invasion represents a new mechanism of resistance to BRAF inhibition in thyroid cancer that can be targeted with an ERK1/2 inhibitor.
Supplementary Table 2 from Rates of Intervention and Cancer Detection on Initial versus Subsequent Whole-body MRI Screening in Li-Fraumeni Syndrome
Authors: Kagami Laura A.T. , Du Yun K. , Fernandes Conrad J. , Le Anh N. , Good Madeline , Duvall Melani M. , Baldino Sarah E. , Powers Jacquelyn , Zelley Kristin , States Lisa J. , Mathew Manoj C. , Katona Bryson W. , MacFarland Suzanne P. , Maxwell Kara N.
Published: September 2023

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.
Data from Risk Factors for Early-onset Sporadic Colorectal Cancer in Male Veterans
Authors: Imperiale Thomas F. , Myers Laura J. , Barker Barry C. , Larson Jason , Stump Timothy E. , Daggy Joanne K.
Published: September 2023

Abstract
Identifying risk factors for early-onset colorectal cancer (EOCRC) could help reverse its rising incidence through risk factor reduction and/or early screening. We sought to identify EOCRC risk factors that could be used for decisions about early screening. Using electronic databases and medical record review, we compared male veterans ages 35 to 49 years diagnosed with sporadic EOCRC (2008–2015) matched 1:4 to clinic and colonoscopy controls without colorectal cancer, excluding those with established inflammatory bowel disease, high-risk polyposis, and nonpolyposis syndromes, prior bowel resection, and high-risk family history. We ascertained sociodemographic and lifestyle factors, family and personal medical history, physical measures, vital signs, medications, and laboratory values 6 to 18 months prior to case diagnosis. In the derivation cohort (75% of the total sample), univariate and multivariate logistic regression models were used to derive a full model and a more parsimonious model. Both models were tested using a validation cohort. Among 600 cases of sporadic EOCRC [mean (SD) age 45.2 (3.5) years; 66% White], 1,200 primary care clinic controls [43.4 (4.2) years; 68% White], and 1,200 colonoscopy controls [44.7 (3.8) years; 63% White], independent risk factors included age, cohabitation and employment status, body mass index (BMI), comorbidity, colorectal cancer, or other visceral cancer in a first- or second-degree relative (FDR or SDR), alcohol use, exercise, hyperlipidemia, use of statins, NSAIDs, and multivitamins. Validation c-statistics were 0.75–0.76 for the full model and 0.74–0.75 for the parsimonious model, respectively. These independent risk factors for EOCRC may identify veterans for whom colorectal cancer screening prior to age 45 or 50 years should be considered.
Prevention Relevance:
Screening 45- to 49-year-olds for colorectal cancer is relatively new with uncertain uptake thus far. Furthermore, half of EOCRC occurs in persons < 45 years old. Using risk factors may help 45- to 49-year-olds accept screening and may identify younger persons for whom earlier screening should be considered.

See related Spotlight, p. 479
Data from Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk
Authors: Chen Simin , Tamimi Rulla M. , Colditz Graham A. , Jiang Shu
Published: September 2023

Abstract
Mammographic percentage of volumetric density is an important risk factor for breast cancer. Epidemiology studies historically used film images often limited to craniocaudal (CC) views to estimate area-based breast density. More recent studies using digital mammography images typically use the averaged density between craniocaudal (CC) and mediolateral oblique (MLO) view mammography for 5- and 10-year risk prediction. The performance in using either and both mammogram views has not been well-investigated. We use 3,804 full-field digital mammograms from the Joanne Knight Breast Health Cohort (294 incident cases and 657 controls), to quantity the association between volumetric percentage of density extracted from either and both mammography views and to assess the 5 and 10-year breast cancer risk prediction performance. Our results show that the association between percent volumetric density from CC, MLO, and the average between the two, retain essentially the same association with breast cancer risk. The 5- and 10-year risk prediction also shows similar prediction accuracy. Thus, one view is sufficient to assess association and predict future risk of breast cancer over a 5 or 10-year interval.
Prevention Relevance:
Expanding use of digital mammography and repeated screening provides opportunities for risk assessment. To use these images for risk estimates and guide risk management in real time requires efficient processing. Evaluating the contribution of different views to prediction performance can guide future applications for risk management in routine care.